Physiology of Behavior [13 ed.] 2020021981, 2020021982, 9780135709832, 9780135455708, 9780135455623, 9780135455562, 0135709830

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13th EDITION

Physiology of Behavior

Neil R. Carlson Melissa A. Birkett

Physiology of Behavior Thirteenth edition

NEIL R. CARLSON University of Massachusetts, Amherst

MELISSA A. BIRKETT Southern Oregon UniversihJ

@ Pearson

Please contact https:/ /support.pearson.com/ getsupport/s/ with any queries on this content. Cover: Cover illustration created by Integra based on a photo by Alena Kaz/Shutterstock Copyright © 2021, 2017, 2013 by Pearson Education, Inc. or its affiliates, 221 River Street, Hoboken, NJ 07030. All Rights Reserved. Manufactured in the United States of America. This publication is protected by copyright, and permission should be obtained from the publisher prior to any prohibited reproduction, storage in a retrieval system, or transmission in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise. For information regarding permissions, request forms, and the appropriate contacts within the Pearson Education Global Rights and Permissions department, please visit www.pearsoned.com/permissions/. Acknowledgments of third-party content appear on the appropriate page within the text. PEARSON, ALWAYS LEARNING, and REVEL are exclusive trademarks owned by Pearson Education, Inc. or its affiliates in the U.S. and/or other countries. Unless otherwise indicated herein, any third-party trademarks, logos, or icons that may appear in this work are the property of their respective owners, and any references to third-party trademarks, logos, icons, or other trade dress are for demonstrative or descriptive purposes only. Such references are not intended to imply any sponsorship, endorsement, authorization, or promotion of Pearson's products by the owners of such marks, or any relationship between the owner and Pearson Education, Inc., or its affiliates, authors, licensees, or distributors. Library of Congress Cataloging-in-Publication Data Names: Carlson, Neil R., 1942- author. I Birkett, Melissa A., 1979- author. Title: Physiology of behavior I Neil R. Carlson, University of Massachusetts, Amherst, Melissa A. Birkett, Southern Oregon University. Description: Thirteenth edition. I Hoboken : Pearson, 2020. I Includes bibliographical references and index. I Summary: "The first part of the book is concerned with foundations of behavioral neuroscience: the history of the field, the structure and functions of neurons, neuroanatomy, psychopharmacology, and research methods. The second part is concerned with inputs and outputs that guide behavior: the sensory systems and the motor system. The third part deals with classes of species-typical behavior: sleep, reproduction, emotional behavior, and ingestion. The chapter on reproductive behavior includes parental behavior as well as courting and mating. The chapter on emotion includes a discussion of fear, anger and aggression, communication of emotions, and feeling emotions. The chapter on ingestive behavior includes the neural and metabolic bases of drinking and eating. The fourth part of the book explores learning, including research on synaptic plasticity, the neural mechanisms that are responsible for perceptual learning and stimulus-response learning (including classical and operant conditioning), human amnesia, and the role of the hippocampal formation in relational learning. The final part of the book examines the neural basis of human communication as well as neurological, mental, and behavioral disorders. Behavioral disorders are addressed in four chapters; the first is a new chapter combining information about development of the nervous system with information about disorders of development, autism spectrum disorders, and attention deficit/hyperactivity d isorder; the second discusses schizophrenia and the affective disorders; the third discusses stress and anxiety; and the fourth discusses substance abuse. Each chapter begins with a Case Study, which describes the experience of people whose lives are impacted by an important issue in neuroscience. Other case studies are included within the text of the chapters. Learning Objectives to guide your reading are found at the beginning of each major section of the text. The learning objectives can help you identify and understand the key points from each section and are also summarized at the end of each module. Thought Questions are also located at the end of each module and are designed to stimulate your thinking about what you have learned. Chapter Review Questions conclude each chapter. They provide useful reviews of each chapter and a more comprehensive opportunity to test your understanding."- Provided by publisher. Identifiers: LCCN 2020021981 (print) I LCCN 2020021982 (ebook) I ISBN 9780135709832 (paperback) I ISBN 9780135455708 (epub) I ISBN 9780135455623 (pdf) I ISBN 9780135455562 (pdf) Subjects: LCSH: Psychophysiology. Classification: LCC QP360 .C35 2020 (print) I LCC QP360 (ebook) I DOC 612.8--C

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Contents Preface

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1 Introduction

3 3 4

Natural Selection and Evolution Functionalism and the Inheritance of Traits Evolution of Human Brains

9 9 11

Ethical Issues in Research with Humans and Other Animals Research with Animals Research with Humans

14 14 15

The Future of Neuroscience: Careers and Strategies for Learning Careers in Neuroscience Strategies for Leaming

17 17 17

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47 48 49 50 51

1

Foundations of Behavioral Neuroscience The Goals of Research Roots of Behavioral Neuroscience

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Activa1tion of Receptors Postsynaptic Potentials Effects of Postsynaptic Potentials: Neural Integration Termination of Postsynaptic Potentials Autoreceptors Other Types of Synapses Nonsyinaptic Chemical Communication

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Structure and Functions of Cells of the Nervous System

Cells of the Nervous System The Nervous System: An Overview Neurons Supporting Cells The Blood-Brain Barrier Communication Within a Neuron Neural Communication: An Overview Electrical Potentials of Axons The Membrane Potential The Action Potential Conduction of the Action Potential Communication Between Neurons Structure of Synapses Release of Neurotransmitters

22

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Basic Features of the Nervous System Anatomical Directions The Meninges and Ventricular System

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Structure .and Function of the Peripheral Nervous System (PNS) Cranial Nerves Spinal Nerves The Autonomic Nervous System

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Structure .and Function of the Central Nervous System (CNS) The Forebrain: Telencephalon The Forebrain: Diencephalon The Mi db rain: Mesencephalon The Hindbrain: Metencephalon and M yelencephalon The Spinal Cord

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34 35 35

Structure of the Nervous System

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Ps.ychopharmacology and Nceurotransmitters

Principles of Psychopharmacology An Ov•erview of Psychopharmacology Pharm.acokinetics Drug Effectiveness

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77 79 79

80 82

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vi Contents Effects of Repeated Administration Placebo Effects Sites of Drug Action Effects on Production of Neurotransmitters Effects on Storage and Release of Neurotransmitters Effects on Receptors Effects on Reuptake or Deactivation of Neurotransmitters Neurotransmitters and Neuromodulators Amino Acids Acetylcholine (ACh) The Monoamines Peptides Lipids

5

83

84 85 86

87 87 88 89 89 92 94 101 102

Methods and Strategies of Research 105

Experimental Ablation Evaluating the Behavioral Effects of Brain Damage Producing Brain Lesions Stereotaxic Surgery Histological Methods Tracing Neural Connections Studying the Structure of the Living Human Brain

107 107 108

109 111 113 117

Recording and Stimulating Neural Activity Recording Neural Activity Recording the Brain's Metabolic and Synaptic Activity Stimulating Neural Activity

122

Neurochemical Methods Finding Neurons That Produce Particular Neurochemicals Localizing Particular Receptors Measuring Chemicals Secreted in the Brain

130

Genetic Methods Twin Studies Adoption Studies Genomic Studies Targeted Mutations Antisense Oligonucleotides CRISPR-Cas Methods

122

6

Vision

The Eye Introduction to Sensation and Perception The Stimulus: Light Anatomy of the Eye Photorecept ors Transduction Central and Peripheral Vision Overview of the Visual Pathway Other Rehn.al Pathways

139 141 141 142 142 144 145 146

147 147

Brain Regions Jlnvolved in Visual Processing Lateral Geniculate Nucleus Striate Cortex Extrastriate Cortex

149

Perceiving Color Role of the Retinal Ganglion Cells Role of the Retina Role of the Striate and Extrastriate Cortex

154 155 157

Perceiving Fonm Role of the Striate Cortex Role of the Extrastriate Cortex

161 161 162

Perceiving Spatial Location Role of the Retina Role of the Striate and Extrastriate Cortex Perceiving Orientation and Movement Role of the Striate Cortex Role of the Extrastriate Cortex

168 168 168 171 171

149

149 152 154

171

124 126

130 131

132 134 134 134 135 135 136 136

7

Audition, the Body Senses, and the Chemical Senses

Audition The Stimulus: Sound Anatomy of the Ear Auditory Hair Cells Transduce Auditory Information

177 179 179 180 182

Contents

The Auditory Pathway Perceiving Pitch Perceiving Loudness Perceiving Timbre Perceiving Spatial Location Perceiving Complex Sounds Perceiving Music

183 186 187 188 188 191 193

Vestibular System Anatomy of the Vestibular Apparatus The Vestibular Pathway

196 196

Somatosenses The Stimuli Anatomy of the Skin and Its Receptive Organs Perceiving Cutaneous Stimulation The Somatosensory Pathways Perceiving Pain

200 200 200 200 204 206

Gustation The Stimuli Anatomy of the Taste Buds and Gustatory Cells Perceiving Gustatory Information The Gustatory Pathway Olfaction The Stimulus and Anatomy of the Olfactory Apparatus Transducing Olfactory Information Perceiving Specific Odors

212 212 213 213 214 216

8

Control of Movement

Deficits of Skilled Movements: Apraxias and Dyspraxia Limb Apraxia Constructional Apraxia Dyspraxia

247 248 248 249 249

198

216 218 218

221

Skeletal Muscle Anatomy The Physical Basis of Muscular Contraction Sensory Feedback from Muscles

223 223 223 225

Control of Movement by the Spinal Cord The Monosynaptic Stretch Reflex The Gamma Motor System Polysynaptic Reflexes

227 227 229 229

Control of Movement by the Brain Cortical Structures

231 231

Planning and Initiating Movements: 232 Role of the Motor Association Cortex Subcortical Structures 236 Cortical Control of Movement: Descending Pathways 241 Complex Motor Behavior Imitating and Comprehending Movements: Role of the Mirror Neuron System

Control of Reaching and Grasping: Role of the Parietal Cortex

vii

244 244

9

Sleep and Biological Rhythms

252

What ls Sleep? Stages of Sleep Brain Activity During Sleep

254 254 257

Why Do We Sleep? Functions of Sleep Functions of Slow-Wave Sleep Functions of REM Sleep Sleep and Learning

259 259 260 261 262

Physiological Mechanisms of Sleep and Waking Neural Control of Sleep Neural Control of Arousal Neural Control of Sleep /Waking Transitions Neural Control of Transition to REM

264 264

265 269 272

Disorders of Sleep Insomnia Narcolepsy REM Sleep Behavior Disorder Problems Associated with Slow-Wave Sleep

275 275 276 277 278

Biological Clocks 279 Circadian Rhythms and Zeitgebers 279 The Suprachiasmatic Nucleus 280 Control of Seasonal Rhythms: The Pineal Gland and Melatonin 284 Changes in Circadian Rhythms: Shift Work and Jet Lag 284

10

Reproductive and Parental Behavior 287

Sexual Development Production of Gametes and Fertilization Development of the Sex Organs Sexual Maturation

289 289 289 293

viii Contents Control of Sexual Behavior by Hormones and Pheromones Hormonal Control of Female Reproductive Cycles Hormonal Control of Sexual Behavior of Laboratory Animals Organizational Effects of Androgens on Behavior: Masculinization and Defeminization Human Sexual Behavior Effects of Pheromones

298 298 301

Neural Control of Sexual Behavior Male Sexual Behavior Female Sexual Behavior Formation of Pair Bonds

305 305 307 309

Sexual Orientation Activational and Organizational Effects of Hormones Role of Steroid Hormones Sexual Orientation and the Brain Role of Prenatal Environment in Sexual Orientation Heredity and Sexual Orientation

310 311 311 312

Parental Behavior Maternal Behavior of Rodents Hormonal Control of Maternal Behavior Neural Control of Maternal Behavior Neural Control of Paternal Behavior

316 316 317 318 320

295 295 296

314 314

12

Ingestive Behavior

Drinking Physiological Regulatory Mechanisms Two Types of Thirst Neural Mechanisms of Thirst

363 363 364 367

What Is Metab1olism? The Short-llerm Reservoir The Long-Term Reservoir Fasting Phase Absorptive Phase

368 369 370 370 371

What Starts a Meal? Environmental Factors

372 372

Gastric Factors Metabolic Signals

11

Emotion

323

Fear Components of Emotional Response Research with Laboratory Animals Research with Humans

325 325 325 329

Aggression Research with Laboratory Animals

331 331

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Hormonal Control of Aggressive Behavior Impulse Control Role of the vmPFC Brain Development and Impulse Control Serotonin and Impulse Control Moral Decision Making

333 339 339 341 341 342

Communication of Emotions Facial Expression of Emotions: Innate Responses Neural Basis of the Communication of Emotions: Recognition Neural Basis of the Communication of Emotions: Expression

344 344

Feeling Emotions The James-Lange Theory Feedback from Emotional Expressions

345 351 355 356 358

361

372 373

What Stops a Meal? Short-Term Satiety Environmental Factors Sensory Factors Gastric Factors Intestinal Factors Liver Factors Insulin Adipose Tissue Factors

375 376 377 377 377 377 378 379 379

Brain Mechanisms Brain Stem Hypothalamus

381 381 382

Obesity Possible Causes Treatment

388 389 391

Eating Disorders Possible Causes Treatment

395 396 398

Contents ix

13

Learning and Memory

Overview of Learning and Memory Types of Learning Types of Memory Stimulus-Response Learning Classical Conditioning Operant Conditioning Motor Learning Role of the Cortex Role of the Basal Ganglia Perceptual Learning Role of the Cortex Retaining Perceptual Information in Short-Term Memory Relational Learning Role of the Hippocampus Role of the Cortex Amnesia Role of the Hippocampus Stimulus-Response Learning Motor Learning Perceptual Learning Relational Leaming Long-Term Potentiation Induction of Long-Term Potentiation Role of NMDA Receptors Role of AMPA Receptors Role of Synaptic Changes

14

H uman Communication

Language Production and Comprehension: Brain Mechanisms Lateralization Language Production and Comprehension in the Brain Bilingualism Prosody Voice Recognition Disorders of Language Production and Comprehension

400 403 403 406 409 409 411 416 416 416 417 417 418 420 420 425 425 426 428 428 429 429 433 433 434 436 437

Disorders of Language Production: Broca's Aphasia Disorders of Language Comprehension: Wernicke's Aphasia Conduction Aphasia Aphasia in People Who Are Deaf Stuttering Disordlers of Reading and Writing Pure Alexia Toward an Understanding of Reading Toward an Understanding of Writing

15

The Developing Nervous System

451 453 459 461 462 465 465 467 473

477

Development of the Nervous System An Overview of Brain Development Prenatal Brain Development Postnatal Brain Development Disordlers of Development Toxic Chemicals Inherited Metabolic Disorders Down Syndrome

478 479 479 483 485 485 485 487

Autism Spectrum Disorder Symptoms Genetic and Environmental Factors Brain Changes Attention-Deficit/Hyperactivity Disorder Syn1ptoms Genetic and Environmental Factors Brain Changes

489 489 490 490 494 494 495 496

442 444

444 446 447 448 449

451

16

Neurological Disorders

Tumors and Seizures Tumors Seizures Cerebrovascular Accidents Causes

498 500 500 502 506 506

x Contents frcatments Traumatic Brain Injury Caus1.s • ~cit· 11..

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Degenerative Disorders fo m Encephalopathies Tr.u sr ss, -,( C,1 l Parkin. . on's Disease Huntington's Dbeasc Amyotrophic I.ateral Sclerosis Multiple Sderosis Dementia Korsakoff's Syndrome Disorders Caused by Infectious Diseases Encephaht1s Meningitis

17

Schizophrenia and the Affective Disorders

Schizophrenia Description Genetic Factors Environmental Factors Anomalies in Schizophrenia The Mesolimbic Dopamine Pathway: Positi\'e Symptoms The Mesocortical Dopamine PQ)

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and discovered the use of fire. Our own species, Homo sapiens, evolved in East Africa around 100,000 years ago. Some of our ancestors migrated to other parts of Africa and out of Africa to Asia, Polynesia, Australia, Europe, and the Americas. (See Figure 1.9.) Humans possessed several characteristics that allowed them to compete with other species. Their agile hands enabled them to make and use tools. Their excellent color vision helped them to spot ripe fruit, prey, and dangerous predators. Their mastery of fire enabled them to cook food, provide warmth, and frighten nocturnal predators. Their upright posture and bipedalism (ability to walk using two rear limbs) made it possible for them to walk long distances efficiently, with their eyes far enough from the ground to see long distances across the plains. Bipedalism also permitted them to carry tools and food with them, which meant that they could bring fruit, roots, and pieces of meat back to their tribe. Their linguistic abilities enabled them to combine the collective knowledge of all the members of the tribe, to make plans, to pass information on to subsequent generations, and to form complex civilizations that established their status as the dominant species. All of these characteristics required a primate brain capable of these complex abilities. Sophisticated primate brains developed within the constraints of the size of a mother's birth canal, and an

upright postuire limits the size of a woman's birth canal. A newborn primate's head is about as large as it can safely be. Because a baby's brain is not large or complex enough to pedorm the physical and intellectual abilities of an adult, t:he brain must continue to grow after the baby is born. In fact, all mammals (and all birds, for that matter) requi:re parental care for a period of time while the nervous system develops. The fact that young mammals (particularly young humans) are guaranteed to be exposed to the adults who care for them means that a period of apprenticeship is possible. Consequently, the evolutionary process did not have to produce a brain that consisted solely of specialized circuits of neurons that performed specialized tasks. Instead, it produced a primate brain1with an abundance of neural circuits that could be modlified by experience. Adults would nourish and protect their offspring and provide them with the skills they would need as adults. Some specialized circuits were necessary (for example, those involved in analyzing the complex sounds we use for speech), but, by and large, the· primate brain is more similar to a generalpurpose, programmable computer. What counts, as far as intellectual ability goes, is having a brain with plenty of neurons that are available for behavior, learning, remembering, reasoning, and making plans. Herculano-Houzel and colleagues (2007)

Introduction

Figure 1.9

13

Migration of Homo sapiens

The figure shows proposed migration routes of Homo sapiens after evolution of the species in East Africa. Source: Redrawn with permission from Cavalli-Sforza, L. L. (1991.) Genes, peopJ,es and languages. Scientific American, 265(5), p. 75.

Equator 50-60,000(?) years ago

compared the brains of several species of rodents and primates and found that primate brains contain more neurons per gram than rodent brains. (See Figure 1.10.) Reflecting on their results, the researchers concluded that "our standing among primates as the proud owners of the largest living brain assures that, at least among primates, we enjoy the largest number of neurons from which to derive cognition and behavior as a whole" (Herculano-Houzel, 2009, p. 10). Can you predict what types of functions these additional neurons might be devoted to in humans? What types of genetic changes were responsible for the evolution of the human brain? This question will be addressed in more detail in Chapter 15, but evidence suggests that the most important principle is slowing the process of brain development, allowing more time for growth. As we will see, the prenatal period of cell division in the brain is prolonged in humans, which results in a brain that weighs an average of 350 g and contains approximately 86 billion neurons (Azevedo et al., 2009). After birth the brain continues to grow. Production of new neurons almost ceases, but those that are already present grow and establish connections with each other, and other brain cells, which protect and support neurons, begin to proliferate. Not until late adolescence does the human brain reach its adult size of approximately 1,400 g-about four times the weight of a newborn's brain. This prolongation of maturation is known as neoteny (roughly translated as "extended youth"). The mature human head and brain retain some

infantiile characteristics, including their disproportionate size refative to the rest of the body.

Figure 1.10

Comparison of Mammalian Brains

Specie:> with more complex behaviors have brains with more neuron:> that are available for behavior, learning, remembering , reasoning, and making plans. Primate brains contain more neurons per gram than rodent brains and more neurons in the cortex. Source: Herculano-Houzel, S., and Marino, L. (1998.) A Comparison of Encephalization between Odontocete Cetaceans and Anthropoid Primates. Brain, B1~havior and Evolution, 51(4), 230-238.

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14 Chapter 1

Module Review: Natural Selection and Evolution Functionalism and the Inheritance of Traits LO 1.3 Describe the role of natural selection in the evolution of behavioral traits.

Natural selection is the process responsible for evolution of structures with specific functions. Members of a species possess a variety of structures. If the structures permit an individual to reproduce more successfully, its offspring will also have these structures, and they will become more prevalent in the population. An example of inherited structures responsible for behavior is the set of brain structures responsible for male song behavior in some species of songbirds.

Evolution of Human Brains LO 1.4 Identify factors involved in the evolution of human brains.

The evolution of specialized structures responsible for functions such as color vision, fine motor control,

Ethical Issues in Research with Humans and Other Animals This book contains many facts about what is currently known about the structure and function of the nervous system. Where do these facts come from? They are the result of carefully designed experiments that can include computer simulations, individual cells, and often humans and other animals. Neuroscience research involving humans and other animals is subject to important ethical considerations and oversight. This section addresses these issues in more detail.

Research with Animals LO 1.5

Outline reasons for the use of animals in behavioral neuroscience research.

Much of the research described in this book involves experimentation on living animals. Any time we use another species of animals for our own purposes, we should be sure that what we are doing is both humane and worthwhile. It is important that a good case can be made that research in behavioral neuroscience qualifies on both counts. Humane treatment is a matter of procedure. We know how to maintain laboratory animals in good health in comfortable, sanitary conditions. We know how to administer anesthetics and analgesics so that animals do not suffer during or after

complex vision, and language required a more complex primate brain. Primate brains contain many more neurons per gram than other species. These additional cells are responsible for behavior, learning, remembering, reasonimg, and making plans. Additional brain developmenlt occurs after birth and throughout an extended period of development and parental care in humans.

Thought Question Kavoi and Jameela (2011) reported that a part of the brain responsible for olfaction, the olfactory bulb, is larger in dogs than in humans, even after accounting for differences in overall brain size. Using the principles of natural or artificial selection, hypothesize how dogs came to have this larger structure in their brain and predict how it might impact their behavior.

surgery, and we know how to prevent infections with proper surgical procedures and the use of antibiotics. Most industrially developed societies have strict regulations about the care of animals and require approval of the experimental procedures that are used on them. There is no excuse for mistreating animals in our care. In fact, the vast majority of laboratory animals are treated humanely and many animal researchers are also strong animal welfare advocates. Whether an experiment is worthwhile can be difficult to say. We use animals for many purposes. We eat their meat and eggs, and we drink their milk; we turn their hides into leather; we extract insulin and other hormones from their organs to treat people's diseases; we train them to do useful work on farms or to entertain us. Even having a pet is a form of exploitation; it is we-not they-who decide that they will live iin our homes. The fact is we have been using other animals throughout the history of our species. Pet ownership has the potential to cause much more suffering among animals than scientific research does. Pet owners are not required to receive permission from a board of expe1rts that includes a veterinarian to house their

pets, nor are tlhey subject to periodic inspections to be sure that their home is clean and sanitary, that their pets have enough space to exercise properly, or that their pets' diets are approprialte. Scientific researchers are required to have all those things. The disproportionate amount of concern that animal riights activists show toward the use of animals in resea:rch and education is puzzling, particularly because this is the one indispensable use of animals. We

Introduction

can survive without eating animals, we can live without hunting, we can do without furs; but without using animals for research and for training future researchers, we cannot make progress in understanding and treating diseases. In not too many years scientists will probably have developed a vaccine that will prevent the further spread of diseases such as Ebola virus disease, malaria, or AIDS. Even diseases that we have already conquered would impact new lives if drug companies could no longer use animals to develop and test new treatments. If they were deprived of animals, these companies could no longer extract hormones used to treat human diseases, and they could not prepare many of the vaccines we now use to prevent disease. Our species is beset by medical, psychological, and behavioral problems, many of which can be solved only through biological research. Consider some of the major neurological disorders. Strokes, like the one experienced by Jeremiah at the beginning of this chapter, are caused by bleeding or obstruction of a blood vessel within the brain, and often leave people partly paralyzed, unable to read, write, or converse with their friends and family. Basic animal research on the means by which nerve cells communicate with each other has led to important discoveries about the causes of the death of brain cells. This research was not directed toward a specific practical goal; the potential benefits actually came as a surprise to the investigators. Experiments based on these results have shown that if a blood vessel leading to the brain is blocked for a few minutes, the part of the brain that is nourished by that vessel will die. However, the brain damage can be prevented by first administering a drug that interferes with a particular kind of neural communication. This research is important, because it may lead to medical treatments that can help to reduce the brain damage caused by strokes. But it involves operating on a laboratory animal, such as a rat, and pinching off a blood vessel. (The animals are anesthetized.) Some of the animals will sustain brain damage, and all will be euthanized so that their brains can be examined. However, you will probably agree that research like this is just as legitimate as using animals for food. As you will learn later in this book, research with laboratory animals has produced important discoveries about the possible causes or potential treatments of neurological and mental disorders, including Parkinson's disease, schizophrenia, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, anorexia nervosa, obesity, and substance abuse. Although much progress has been made, these problems persist, and they cause much human suffering. Unless we continue our research with laboratory animals, they will not be solved. Some people have suggested that instead of using laboratory animals in our research, we could use tissue

15

cultures or computers. While these techniques can be used to pursue some research questions, unfortunately, tissue cultures or computers are not substitutes for complex, living organisms. We have no way to study behavioral problems such as substance abuse in tissue cultures, nor can we program a computer to sim ulate the workings of an animal's nervous system. (If we could, that would mean we already had all the answers.) OVERSIGHT OF ANIMAL RESEARCH LO 1.E>

Identify mechanisms for oversight of animal research.

In the United States, any institution that receives federal research funding to use animals in research is required to have an Institutional Animal Care and Use Committee (IACUC). The IACUC is typically composed of a veterinarian, scientists who work with animals, non-scientist members, and community members not affiliated with the institution. This group reviews all proposals for research involving animals, with the intent of ensuring humane and ethical[ treatment of all animals involved. Even noninvasive research with animals (such as fieldwork or observational studies) must pass review and be approved by the IACUC. This approval process ensures not only the welfare of the animals, but also that the research is compliant with local, state, and federal regulations.

Research w ith Humans LO 1."l

Discuss ethical considerations in research with human participants.

Not all neuroscience research is conducted with animal modells. Much of what we currently understand about the brain and behavior is the result of research with humain participants. In addition to humane research conditions, research with human participants must also includle informed consent and precautions to protect the identity of the participants. Informed consent describes the process in which researchers must inform any potentiall participant about the nature of the study, how any data will be collected and stored, and what the anticipated benefits and costs of participating will be. Only after obtaining this information can the participant make an informed decision about whether to participate in a study. Violating the informed consent process can have ethica l, legal, and financial consequences. In 2010, the case of Havasupai Tribe v. Arizona Board of Regents was settled, including the return of biological samples and a payment of $700,000 to the Havasupai tribe after six years of dispute. The settlement was issued in response to a vague and incomplete informed consent process that resulted in the use of blood samples originally intended for research on diabetes being used in contested research

16

Chapter 1

involving factors related to schizophrenia (Van Assche et al., 2013). Protecting the identity of participants is crucial for all research with human participants, and particularly important in behavioral neuroscience research investigating potentially sensitive topics (for example, the use of illicit drugs in studies of brain changes in substance abuse). An emerging interdisciplinary field, n euroethics, is devoted to better understanding implications of and developing best practices in ethics for neuroscience research with human participants. A 2014 report from a panel of national experts explored the ethical challenges of neuroscience research by investigating (1) neuroimaging and brain privacy; (2) dementia, personality, and changed preferences; (3) cognitive enhancement and justice; and (4) deep brain stimulation research and the ethically difficult history of psychosurgery (Presidential Commission for the Study of Bioethical Issues, 2014). The panel recommendations included integrating ethics and science through education at all levels.

Figure 1.11. Behavioral Neuroscience Research w ith Human Particiipants Researchers wo1rk with volunteers to learn more about the brain mechanisms responsible for functions such as emotion, learning, memory, and behavior.

OVERSIGHT OF HUMAN RESEARCH

LO 1.8

Identify m ech anisms for oversight of human research.

Much like animal research, research with human volunteers is essential to advancing our knowledge of the brain in health and disease. Also similar to animal research, work with human participants is subject to strict regulation and must be reviewed and approved by a board of experts and

laypeople. Thie Institutional Review Board (IRB) functions similarly to the IACUC to ensure ethical treatment of volunteers in resiearch. (See Figure 1.11.) The IRB is typically composed of scientific experts, laypeople, and members of the community. This group is tasked with protecting human research participants.

Module Review: Ethical Issues in Research with Humans and Other Animals Research with Animals

Research with Humans

LO 1.5 Outline reasons for the use of animals in b ehavioral n euroscience research.

LO 1. 7 Discuss ethical considerations in research w ith human participants.

Animals are used in behavioral neuroscience research to improve understanding of the nervous system and develop treatments for disease and injury. Animal models are used when it is not possible or it is inappropriate to conduct research with human participants and when cell models or computer programs cannot simulate the complexity of the nervous system.

Ethical considerations for research involving human participants include protections such as informed consent and confiden1tiality. The field of neuroethics is devoted to better understanding implications of and developing best practices in ethics for neuroscience research with human participants.

LO 1.6 Identify m ech anism s for oversight of animal research.

The humane treatment of research animals is governed by local, state, and federal regulations. The IACUC is tasked with reviewing animal research proposals and protecting the welfare of animals in research.

LO 1.8 Identify m echanisms for oversight of human resea:rch.

The IRB is rei;ponsible for the protection of human research participants. It is composed of scientific experts, laypeople, and community members. The IRB reviews proposals for 1research involving people.

Introduction

Thought Question Behavioral neuroscience research presents unique ethical considerations. For example, developing drugs to enhance attention and learning, refining imaging techniques to reveal a person's mood or beliefs, or designing

The Future of Neuroscience: Careers and Strategies for Learning What is behavioral neuroscience, and what do behavioral neuroscientists do? What are the best ways to learn more about this diverse and exciting field? By the time you finish this book, you will have a much richer answer to these questions. The next section will describe the field-and careers open to those who specialize in it. Likewise, we want to provide you with some strategies to help you learn as you study this fascinating discipline.

Careers in Neuroscience LO 1.9

Identify careers in behavioral neuroscience.

Behavioral neuroscience belongs to a larger field that is simply called neuroscience. Neuroscientists concern themselves with all aspects of the nervous system: its anatomy, chemistry, physiology, development, and functioning. The research of neuroscientists ranges from the study of molecular genetics to the study of social behavior. Behavioral neuroscientists study all behavioral phenomena that can be observed in humans and animals. They attempt to understand the role of the nervous system, interacting with the rest of the body (especially the endocrine system, which secretes hormones), in controlling behavior. They study such topics as sensory processes, sleep, emotional behavior, ingestive behavior, aggressive behavior, sexual behavior, parental behavior, and learning and memory. They also study animal models of symptoms that humans experience, such as anxiety, depression, phobia, and obsessions and compulsions. Although the original name for the field described in this book was physiological psychology, several other terms are now in general use, such as biological psychologt;, biopsychology, psychobiology, and-the most common onebehavioral neuroscience. Two other fields often overlap with that of behavioral neuroscience: neurologt; and cognitive neuroscience. Neurologists are physicians who diagnose and treat diseases of the nervous system. Most neurologists are solely involved in the practice of medicine, but some engage in research. They study the behavior of people whose brains have been damaged by natural causes,

17

tests bo predict aggressive behavior all present challenging ethical dilemmas. For one of these examples, identify the ethical challenge and suggest whether this research should be conducted and why. If it is conducted, what precautions should be in place to protect the rights of particiipants?

using advanced brain-imaging techniques to study the activity of various regions of the brain as a person participates in various behaviors. This research is also carried out by cognitive neuroscientists-researchers with a Ph.D. (usually in psychology) and specialized training in the principles and procedures of neurology. Most professional behavioral neuroscientists have received! a Ph.D. from a graduate program in psychology or from an interdisciplinary program. Programs can include faculty members from departments such as psychology, biology, chemistry, biochemistry, or computer science. Most professional behavioral neuroscientists are employed by colleg1es and universities, where they are engaged in teaching and research. Others are employed by institutions devoted to research-for example, in laboratories owned and operated by national governments or by private philanthropic organizations. A few work in industry, usually for pharmaceutical companies that are interested in assessing the effects of drugs on behavior. To become a professor or independent researcher, one must receive a doctorate-usually a Ph.D., although some people turn to research after receiving an M.D. Most behavioral neuroscientists spend two years or more in a postdoctoral position after completing their graduate degree, working in the laboratory of a senior scientist to gaiin more research experience. During this time they write articles describing their research findings and submit them for publication in scientific journals. These publications are an important factor in obtaining an independent position. Not all people who are engaged in neuroscience research have doctoral degrees. Research technicians with bachellor's or master's level degrees perform essentialand intellectually rewarding-services working with senior scientists. Technicians can continue to gain experience and education on the job, enabling them to assume responsibility for managing and completing projects independently. (See Figure 1.12).

Strategies for Learning LO 1.110 Describe effective learning strategies for

studying behavioral neuroscience. The brain is a complicated organ. After all, it is responsible for all our abilities and all our complexities. Scientists have been studying this organ for many years and (especially in

18

Chapter 1

Figure 1.12

Pursuing a Research Career in Neuroscience

What kinds of training are required for a career in neuroscience? Where do neuroscientists work? Explore this timeline to learn more.

Students interested in neuroscience may take courses in biology, chemistry, psychology, or other sciences in high school.

College

Students interested in neuroscience may study biology, chemistry, psychology, neuroscience, or other related areas. Some students work as research assistants in laboratories and develop mentored relationships w ith researchers. College graduates interested in neurosci ence can work as research technicians or assistants.

Graduate Training

Students can pursue advanced graduate training for one or more years after college. Graduate training typically involves advanced coursework and more independent research. Graduate students are expected to conduct research (with the guidance of a research mentor) and disseminate the results of their work. After completing a graduate program, individuals may teach in a secondary or postsecondary institution, conduct research, or work in industry.

Postgraduate Training

Postgraduate positions are more independent and often involve additional training in specialized research areas or with specialized research techniques. After completing postgraduate training, individuals may teach in a secondary or postsecondary institution, conduct research, or work in industry.

Introduction

recent years) have been learning a lot about how it works. It is impossible to summarize this progress in a few simple sentences; therefore, this book contains a lot of information. We have tried to organize this information logically, telling you what you need to know in the order in which you need to know it. (To understand some things, you sometimes need to understand other things first.) We have also tried to write as clearly as possible, making examples as simple and as vivid as we can. Still, you cannot expect to fully understand the information in this book by simply giving it a passive read; you will have to do some work. Learning about behavioral neuroscience involves much more than memorizing facts. Of course, there are facts to be memorized: names of parts of the nervous system, names of chemicals and drugs, scientific terms for particular phenomena and procedures used to investigate them, and so on. But the quest for information is nowhere near completed; we know only a small fraction of what we have to learn. And almost certainly, many of the "facts" that we now accept will someday be shown to be incorrect. If all you do is learn facts, where will you be when these facts are revised? Our goal is to offer some practical advice about studying. You have been studying throughout your academic career, and you have undoubtedly learned some usefuJ strategies along the way. Even if you have developed efficient and effective study skills, at least consider the possibility that there might be some ways to improve them. This section is intended to provide you with suggestions to maximize your learning about behavioral neuroscience. These suggestions are supported by empirical research on learning. • Write notes that organize information into meaningful g roups; don't just highlight. Connecting new information to prior knowledge is an important means for learning. To do this will require actively thinking about the new information at hand and finding ways to link it to your current understanding. This is an active and involved process that will take some time and effort. Highlighting or underlining without combining the information into your own notes is passive and does not facilitate learning and retention the way that writing or typing your own notes does. Previous research has demonstrated that highlighting and underlining alone do not improve test scores, and in some cases may even be detrimental to learning (Dunlosky et al., 2013). • Teach yourself by teaching someone else. After reading a section or chapter, consider how you would teach the information to someone else-a classmate, a friend, or maybe a curious family member. This activity will help you to think about the most important aspects of the section. Nestojko and colleagues (2014) found that students who prepared to teach others about the content of a complex reading assignment performed better on a later test than students who had prepared themselves for a test on the reading.

19

• Study in the environment you will be tested in or vary your study environments. State-dependent learning theory says that information learned in one environment is most readily recalled in the same environment. The rationale behind this performance-boosting effect of environment is that the context (e.g., the color of the walls, the cbtair, the people around you) provides important cues that help you recall what was previously learned in that environment. If you're not able to study in the same environment as you will be tested, you can try to incorporate as many of the same elements as possible (e.g., use the same computer, pens, procedure for note taking, etc.) or you can study in many different environments (e.g., at home, in the student union, in your residence hall) so that you will not become dependent on an y one single cue or set of cues when you are tested. In an interesting te:st of state dependent learning, Godden and Baddeley (1975) tested college student scuba divers on information th.ey read while underwater or on land. Students recalled information learned underwater the best in an underwater test. The students performed most poorly on the tests of information in a different context (for example, information learned underwater but tested on land). • Study with the absolute minimum of distractions. Your brain works best when it focuses on one challenging task (like learning about neuroscience!) at a time (Hattie and Yates, 2014). Turn off televisions, social media, and phones whenever possible, and try to study in a quiet environmen t. Lee and colleagues (2012) assigned college studen ts learning about science, history, and politics to three groups: reading in sillence, reading with a TV show playing in the background that students could ignore, and reading with a TV show playing in the background that students would later be tested on so that they would be sure to pay attention to both the TV show and their assigned study material. Students were instructed to read and answer multiple choice questions. As you might have guessed, students who tried to read and pay attention to the TV show performed the worst on the test. • Don' t cram! Spread out your study sessions. Studying new information in two shorter but separated sessions leads to more effective recall than studying in one long session. Don't cram. Instead, plan to study something new once, then study it again a differen t day before being asked to recall or apply it on a final test or assignment. Though you should plan your own study sessions around your schedule and based on assignment or test due dates in your cl.ass, some cognitive spacing has already been built into this book for you. While there is no "one size fits all" time period for spacing out reading and study sessions, one to several days is a good rule of thumb (Carpenter et al., 2012).

20 Chapter 1 • Study the most challenging topic first or last. Classic studies in psychology revealed that when people were asked to learn long lists of words, the first words learned (the primacy effect) and the last words learned (the recency effect) were the most likely to be recalled. The same principles can hold true for learning about behavioral neuroscience. For example, if you are reading about the cortex, the thalamus, and the meninges in Chapter 3, and you already know most of the parts of the meninges, but are not feeling confident about your understanding of the cortex and thalamus, plan to study the cortex first, then the meninges and finally the thalamus information. • Use mnemonics. Mnemonics are shortcuts for helping retain new information. For example, you could try ston; chaining by inventing a short story to link together discrepant items; method of loci to use images of physical locations enabling you to position items along an imaginary walk; and acrostics to use a word to represent a list (such as FPOT for the lobes of the cortex: frontal, parietal, occipital, temporal) (Hattie and Yates, 2014). • Draw a picture. Trying to learn a new term or concept? Try drawing a picture of it. Drawing improved memory for new information compared to copying definitions, improved memory in younger and older learners, and was effective when people spent only four seconds drawing. Researchers attribute the improved learning to the involvement of motor activity and active elaboration involved in drawing (Fernandes et al., 2018; Meade et al., 2018). How this book is organized: • The text, animations, interactives, and illustrations are integrated as closely as possible. In our experience,

one of the most frustrating aspects of reading some books is not knowing when to look at an illustration. Here, eve1rything is presented to you as you need it. • Each chapter begins with a case study that profiles a person's real-life experience and a list of learning objectives. The case studies are meant to personalize and make more relatable the concepts we will discuss in the chapter. The learning objectives are included to help you focus on the key ideas included in the chapter. • You will rnotice that some words in the text are italicized, and others are printed in boldface. Italics mean that either the word is being stressed for emphasis or it is a new term. Terms in bold (listed in the glossary of this book) are key terms that are part of the vocabulary of the behaviioral neuroscientist. You will see many of these terms used again in later chapters. • At the end of each section, you will find two different types of review activities: module reviews and thought questions. The module reviews will remind you of key points from the chapter, and the though t questions will challenge you to apply what you have learned to a new context or to expand your thinking on a relevant topic. Finally, there are chapter review questions at the end of each chapter to help you assess your understanding of the concepts. Now that you have a sense of what the field of behavioral neuroscience entails, welcome to the rest of this book! The next chapter starts with the structure and functions of neurons and supporting cells, the most important elements of the nervous system.

Module Review: The Future of Neuroscience: Careers and Strategies for Learning Careers in Neuroscience LO 1.9 Identify careers in behavioral neuroscience.

Researchers in this area work in the fields of general neuroscience, behavioral neuroscience, and cognitive neuroscience. Neurologists are physicians who specialize in the nervous system. Individuals pursuing careers in neuroscience typically work in academia or industry and often pursue graduate education.

Strategies for Learning LO 1.10 Describe effective learning strategies for studying behavioral neuroscience.

Active strategies for learning are most effective. Taking notes, practicing teaching or sharing information with another person, making sure your study and test-taking

environment share some common features, studying with as few distractions as possible, spacing out your study sessions, carefully planning when to study challenging material, and using mnemonics whenever possible can enhance your learning.

Thought Question What is it lik1e to work as a behavioral neuroscientist? Conduct an online search and locate a job advertisement for a position in behavioral neuroscience. Read the job description and qualifications carefully. What qualifications are reqULired for the job? Why do you think these experiences or this training is required? What kinds of responsibilities and activities will the person in this position engage in.?

Introduction

21

Chapter Review Questions 1. Explain the goals of behavioral neuroscience research. 2. Describe the historical roots of behavioral neuroscience. 3. Describe the role of natural selection in the evolution of behavioral traits. 4. Explain the evolution of the human species and brain. 5. Evaluate the value of behavioral neuroscience research with animals.

6. Identify important ethical considerations of behavioral neuroscience research involving human participants.

7. Summarize the education one must complete to become a neuroscientist. 8. Describe career opportunities in neuroscience. 9. Describe how you could apply two effective study strategies to learning about behavioral neuroscience.

Chapter 2

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Neurons a re the cells of the nervous system that are specialized for communication.

Chapter Outline Cells of the Nervous System

The Nervous System: An Overview Neurons Supporting Cells The Blood-Brain Barrier Communication Within a Neuron

Neural Communication: An Overview Electrical Potentials of Axons The Membrane Potential The Action Potential Conduction of the Action Potential

22

Communication Between Neurons

Structure of Synapses Release 0 1f Neurotransmitters Activation of Receptors Postsynaptic Potentials Effects of Postsynaptic Potentials: Neural Integration Termination of Postsynaptic Potentials Autoreceptors Other Types of Synapses Nonsynaptic Chemical Communication

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Structure and Functions of Cells of the Nervous System

23

Learning Objectives

LO 2.1

Contrast features of the central and peripheral nervous systems.

LO 2:10

Identify the presynaptic structures involved in synaptic communication.

LO 2.2

Distinguish among the structures of a neuron.

LO 2:11

Describe the process of neurotransmitter release.

LO 2.3

Compare supporting cells in the central and peripheral nervous systems.

LO 2:12

Contrast ionotropic and metabotropic receptors.

LO 2.4

Assess the function of the blood- brain barrier.

LO 2:13

Compare EPSPs and IPSPs in postsynaptic cells.

LO 2.5

Explain the process of neural communication in a reflex.

LO 2:14

Summarize neural integration of EPSPs and IPSPs.

LO 2.6

Describe membrane potential, resting potential, hyperpolarization, depolarization, and the action potential.

LO 2:15

Explain how postsynaptic potentials are terminated.

LO 2:16

Distinguish autoreceptors from postsynaptic receptors.

LO 2. ·17

Identify synapses other than those involved in neural integration.

LO 2:18

Describe examples of nonsynaptic communication.

LO 2.7

Summarize how diffusion, electrostatic pressure, and the sodium- potassium pump help establish membrane potential.

LO 2.8

Summarize the series of ion movements during the action potential.

LO 2.9

Describe conduction of the action potential.

Kathryn was getting desperate. She was healthy, ate well, and stayed active with sports and regular exercise. She went to the

see, - her eyelids were drooping, and her head felt incredibly hea1vy. Just then, one of her supervisors came over and asked

gym almost every day for card io classes and swimming. But lately she had been having trouble keeping up with her usual

As she spoke, she found herself getting weaker and weaker. It

schedule. At first , she started getting tired toward the end of her exercise classes. Her arms, particularly, seemed to get heavy.

even felt as if breathing took a lot of effort. She managed to finish the conversation, but immediately afterward she went home.

her to report on the progress she had made on a new project.

Then when she started swimming, it was hard to lift her arms

She called her physician, who arranged for her to go to the

over her head. She did not have any other symptoms, so she

hospital to be seen by a neurologist. The neurologist listened to a

told herself that she needed more sleep.

description of Kathryn's symptoms and examined her briefly. The

Over the next few weeks, things only got worse. Her exercise classes were more and more difficult to complete. Her instructor

neu1rologist thought she might know what was wrong. She prepared an injection and gave it to Kathryn. She started questioning

became concerned and suggested that Kathryn see her doctor. She made an appointment, but her doctor found nothing wrong

Ka~hryn about her job. Kathryn answered slowly, her voice almost a whisper. As the questions continued, she realized that it was get-

with her. She was not sick, showed no signs of an infection, and seemed to be generally healthy. Her doctor asked how things were

ting easier and easier to talk. She straightened her back and took a d(:iep breath. She stood up and raised her arms above her head.

going at work Kathryn explained that she had been experiencing

"Look," she said, her excitement growing. "I can do this again. I've

a particularly stressful month at her job. Kathryn and her physician agreed that increased stress could be the cause of her problem.

got my strength back! What did you give me? Am I cured?"

The doctor did not prescribe any medication, but asked Kathryn to make another appointment if she did not feel better soon.

she' said. "No, I'm afraid you aren't cured, but now we know w hat is causing your weakness. There is a treatment. The in-

She did feel better for a while, but then all of a sudden her symptoms got worse. She quit going to the gym and even had

jecti on I gave you lasts only for a few minutes. but I can give youi some pills that have effects that last much longer." Indeed,

trouble finishing a day at work. One afternoon she tried to look

as she was talking, Kathryn felt herself weakening, and she sat down again.

up at the clock on the wall and realized that she could hardly

The neurologist smiled ruefully. "I wish it were that simple,"

24

Chapter 2

All we are capable of doing-perceiving, thinking, learning, remembering, acting-is made possible by the integrated activity of the cells of the nervous system. To understand how the nervous system controls behavior, we need to understand its parts-the cells that compose it. In Kathryn's case, the cells of her nervous system were not functioning appropriately, causing her symptoms of fatigue. Kathryn was diagnosed with myasthenia gravis. The term literally means "grave muscle weakness." It is an uncommon disorder, but many experts believe that mild cases go undiagnosed. Although there are drug treatments for myasthenia gravis, unfortunately there is currently no cure. Developing new treatment options could benefit more people like Kathryn and improve the quality of their lives (Binks et al., 2016; Breiner et al., 2016). Myasthenia gravis is an autoimmune disease. For unknown reasons the immune system breaks down proteins in the nervous system that allow cells to receive messages. Understanding the structure and function of the cells of the nervous system allowed the neurologist to diagnose and treat Kathryn. Kathryn's case highlights many of the key topics you will learn about in this chapter, including communication within and between cells of the nervous system. To learn more abou t the specific cells involved in myasthenia gravis, look ahead to the section "Termination of the Postsynaptic Poten tials" on acetykholine.

Figure 2.1

The Central and Peripheral Nervous

Systems The central nervous system (in pink) includes the brain and spinal cord. The peripheral nervous system (in blue) includes all of the nerves that relay information between the central nervous system and the rest of tt1e body.

Cells of the Nervous System Just how many nerve cells, or neurons, are there in the human brain? The best estimate is around 86 billion neurons. Our brains contain approximately the same number of non-neuronal cells too (Azevedo et al., 2009; von Bartheld et al., 2016). The rest of the human nervous system contains even more cells. The cells comprise the two basic divisions of the nervous system: the central nervous system and the peripheral nervous system.

The Nervous System: An Overview LO 2.1

Contrast features of the central and peripheral nervous systems.

The central nervous system (CNS) consists of the brain and the spinal cord. The peripheral nervous system (PNS) consists of the nerves and most of the sensory organs. (See Figure 2.1.) The CNS communicates with the rest of the body through nerves attached to the brain and to the spinal cord. Nerves are bundles of thousands of individual neurons, all wrapped in a tough, protective membrane. Under a microscope, nerves look something like electrical cables,

containing many bundles of wires. (See Figure 2.2.) Like the individual! wires in a cable, nerve fibers transmit messages through the nerve, from a sense organ to the brain or from the brain to a muscle or gland. Information, in the form of light, sound, odors, tastes, or contact with objects, is gathered from the environment by specialized cells of the PNS called sensory neurons. Motor behavior requires contracting muscles, which are controlled by motor neurons in the PNS. Between sensory neurons and motor neurons are the interneurons-neurons that lie entirely within the CNS. Local interneurons form circuits with nearby neurons and analyze small pieces of information. Relay interneurons connect circuits of local interneurons in one region of the brain with those in other

regions. Through these connections, circuits of neurons throughout the brain perform functions essential to tasks such as perceiiving, learning, remembering, deciding, and controlling complex behaviors. (See Figure 2.3.) The rest of this module describes the most important cells of the nervous system-neurons and their supporting cells-and the blood- brain barrier, which chemically isolates cells in the CNS from the rest of the body.

Structure and Functions of Cells of the Nervous System

Figure 2.2

Nerves

A nerve consists of a membrane sheath encasing bundles of axons.

25

Neuroins come in many shapes and varieties, according to the specialized jobs they perform. Most neurons have, in one form or another, the following four structures or regions: (1) cell body, or soma; (2) dendrites; (3) axon; and (4) terminal buttons.

SOMA The soma (cell body) contains the nucleus and much of the machinery involved in the life processes of the cell!. (See Figure 2.4.) Soma shape can vary in different kinds of neurons.

Figure 2.3

Sensory, Motor, and lnterneurons

These three types of neurons relay information between the central and peripheral nervous systems. In this example, the person sees the glass of water, and sensory nerves relay the sensory information toward the central nervous system. The motor output from the central nervous system allows the person to lift the glass to take a drink.

Sensory neuron

Motor neuron

DENDRITES Dendron is the Greek word for tree, and the branched dendrites of the neuron look a lot like trees. (See Figure 2.4.) Neurons communicate with one another, and dendrites receive these messages. Dendrites function much like antennas to receive messages from other neurons. Just like am antenna can receive a message over a distance (think of an antenna that detects radio or Wi-Fi signals), dendrites receive neural messages that are transmitted across the synapse (also referred to as the synaptic cleft), a small space betweie n the terminal buttons (described later) of the sending celll and a portion of the somatic or dendritic membrane of the receiving cell. Communication at a synapse typically proceeds in one direction: from the terminal button (on the presynaptic cell, or sending cell) to the membrane of the other •cell (the postsynaptic cell, or receiving cell). There are exceptions to this pattern, and as we will see in Chapter 4, some synapses pass information in both directions. AXON The axon is a long, thin tube. The outer surface of the axon carries information from the cell body to the terminal buttons. The axon functions much like an electrical cord carrying an electrical message from an outlet to an appliance. (See Figure 2.4.) However, the basic message the axon carries is called an action potential, and it involves both an electrical and a chemical component. This is an important concept and will be described in more detail later in the chapter. An action potential is a brief electrical and chemical event that starts at the end of the axon near the cell body at a point called the axon hillock, and travels to the ends of the terminal buttons. In any given axon an action potential is always exactly the same size and duration. If an action potential reaches a point where the axon branches, it splits lbut does not diminish in size. Each branch receives a full-st1rength action potential. Like dendrites, axons and their branches come in different shapes. Axons can be extremely long relative to their

diameter and the size of the soma. For example, the longest

Neurons LO 2.2

Distinguish among the structures of a neuron.

The neuron is the basic information-processing and information-transmitting unit of the nervous system.

axon in a human stretches from the foot to the base of the brain. Because some distant parts of the neuron may need items that can be produced only in the soma, there must be a system that can transport these items rapidly and efficiently inside the axon (like a subway system). This process is axoplasmic transport. Action potentials occur along the surface of the axon, but axoplasmic transport moves substances

26

Chapter 2

Figure 2.4

Parts of a Neuron Dendrites

Ternninal

b"ttOM ~ /

Myelin sheath

I

I

Axon (inside myelin sheath)

along "tracks" that run inside the length of the axon. (See Figure 2.5.) This form of transport is accomplished by molecules of a protein called kinesin. In the cell body, kinesin molecules, which resemble a pair of legs and feet, attach to

Figure 2.5

Direction of messages

-~

the item being transported down the axon. The kinesin molecule then walks down a microtubule, carrying the cargo to its destination (Yildiz et al., 2004). Energy for this process is supplied by adenosine triphosphate (ATP) molecules

Axoplasmic Transport

This figure shows how kinesin molecules transport cargo along the cytoskeleton from the soma to the terminal button. Another protein, dynein, carries cargo from the terminal buttons to the soma.

Terminal

buttons ~ Axon (inside myelin sheath)

/

lo Vesicle

Microtubules

I

-~

I

Structure and Functions of Cells of the Nervous System

produced by the mitochondria. Another protein, dynein, carries substances from the terminal buttons to the soma, a process known as retrograde axoplasmic transport. Anterograde axoplasmic transport is remarkably fast, moving contents at up to 500 millimeters (mm) per day. Retrograde axoplasmic transport is about half as fast as anterograde transport.

Most axons divide and branch many times. At the ends of the branches are little knobs called terminal buttons. Terminal buttons have a very important function: When an action potential traveling down the axion reaches them, they secrete a chemical called a neurotransmitter. This neurotransmitter (there are many different ones) either excites or inhibits the receiving cell and helps determine whether an action potential occurs in the receiving cell's axon. The release of neurotransmitters from the terminal buttons is similar to being asked to open an oven while :something delicious is cooking. The axon sends a message to the terminal buttons (check the oven) and a chemical message is released to diffuse into the synapse, relaying a message from the presynaptic cell to the postsynaptic cell (the smell of the food from the open oven diffuses across a kitchein, alerting another person of the meal to come). Details of this process will be described later in this chapter. An individual neuron receives information from the terminal buttons of axons of other neurons-and the terminal buttons of its axons form synapses with other neurons. A neuron may receive information from dozens or even hundreds of other neurons, each of which can form a large number of synap1tic connections with it. Figure 2.7 illustrates the nature of these connections. As you can see, terminal buttons can form synapses on the membrane of the dendrites or the soma (or even another axon, as you'll see at the end of this chapter). TERM INAL BUTTONS

MYELIN SHEATH The axon is often covered by a myelin

sheath. Myelin is a fatty substance that provides insulation for the electrical message carried along the axon membrane, much like insulation on a wire isolates an electrical current. (See Figures 2.4 and 2.5). Bundles of myelinated axons appear as white matter in the brain and in nerves. In the brain, these bundles of myelinated axons are sometimes referred to as tracts. When looking at brain tissue that has been removed from the skull and sectioned, the bundles appear white because of the fat content in the myelin. Specialized neuroimaging techniques can be used to visualize the myelin-dense white matter tracts in the brains of living organisms. These techniques often add color overlays to the tracts to help researchers better identify them in magnetic resonance imaging (MRI) images (See Figure 2.6.)

Figure 2.6

27

Image of Tracts in the Brain

White matter fibers overlaid on an MRI scan and a female head. The fibers transmit action potentials between brain regions and between the brain and the spinal cord.

OTHER CELL STRUCTURES Figure 2.8 illustrates the inter-

nal structure of a typical neuron. Let's start from the outside of the neuron and work our way in. Much like your skin, the cell m embrane defines the boundary of the neuron. It consists olf a double layer of lipid (fatlike) molecules. Embedded in the membrane are a variety of protein molecules that have speciall functions. Some proteins detect substances outside the cell (such as hormones) and pass information about the presence of these substances to the interior of the cell. Other proteins control access to the interior of the cell, allowing some substances to enter but preventing others from entering. Still other proteins act as transporters, using energy to transport certain molecules into or out of the cell. Because the proteins that are found in the membrane of the neuron are especially important for transmitting information, their characteristics will be~ discussed in more detail later in this chapter. The interior of the neuron contains a framework of protein strands. Much like the bones of your skeletal system, ~ this framework, called the cytoskeleton, gives the neuron ~ its shape. The cytoskeleton is made of three kinds of protein i~ strands, linked to each other to form a cohesive mass. The ~ thickest of these strands, microtubules, are bundles of 13 pro~ tein filaments arranged around a hollow core. In addition to providling structural support to the neuron, the microtubules form tlhe "tracks" for axoplasmic transport. (See Figure 2.5.) ~ m Cytop lasm is a semiliquid, jellylike substance that g fills the space surrounded by the membrane, including the §o..:i:

28 Chapter 2

Figure 2.7

Overview of Struct ure and Synaptic Connections Between Neuirons

The arrows represent the direction information is traveling.

Synapse on soma Soma Myelin sheath

~\ Synapse on dendrite

/

Axon

soma. It contains small, specialized structures, just as the human body contains specialized organs. The generic term for these structures is organelle, or "little organ." Some important organelles are described next. Deep inside the cell is the nucleus. The nucleus is enclosed by the nuclear membrane. The nucleus contains the chromosomes. Chromosomes consist of long strands of deoxyribonucleic acid (DNA). The chromosomes have an important function: They function like cookbooks and contain the recipes for making proteins. Portions of the chromosomes, called genes, contain the individual recipes for individual proteins.

Figure 2.8

Genes are responsible for initiating the process of protein syn thesis in the cell. An overview of protein synthesis is described next, followed by additional details in thE! subsequent paragraphs. When they are active, the genes help produce another complex molecule, messe111ger ribonucleic acid (mRN A). The mRNA copies the information stored by the gene. The mRNA then leaves the nucleus with the copied information and attaches to ribosomes in the soma. The ribosomes use the copied information from the mRNA to synthesize proteins for the call. (See Figure 2.9.)

Internal Structures of a Neuron

Structure and Functions of Cells of the Nervous System

Figure 2.9

29

Protein Synt hesis

When a gene is active, a copy of the information is made onto a molecule of messenger RNA (transcription). The mRNA leaves the nucleus and attaches to a ribosome, where the protein is produced (translation). Detail of Nucleus

Ribosome

Protein synthesis a two-step process. In the first step of the process, transcription, information from DNA (which cannot leave the nucleus) is transcribed into a portable form: mRNA. mRNA takes this information to the ribosomes for the second step of the process: translation. During translation, the ribosomes use the information from the mRNA to create proteins from sequences of amino acids. To help you remember the process of protein production, compare it to making a cake from a top-secret recipe. Imagine that the recipe for the cake is found in a rare cookbook in a library, and you cannot remove the cookbook from the library. You can go into the library and take a picture of the recipe with the camera on your cell phone. Now you have the information in a new, more portable form. Next, you bring the picture of the recipe home with you to your kitchen. There, you use the recipe information to combine raw ingredients like flour, eggs, and milk into the cake batter that you will bake. In this example, the cookbook locked in the library is like the DNA stored in the nucleus. The process of photographing the cookbook and removing the recipe information from the library represents transcription of information from DNA in the nucleus to a new, more portable form of information, mRNA. Taking the photo home and using the information it contains to assemble raw materials into a fina l product represents translation as the mRNA leaves the nucleus and

takes information to the ribosomes, which the ribosomes then uise to create proteins. Proteins are important to cell functions. In addition to providing structure, proteins serve as enzymes, which direct the chemical processes of a cell by controlling chemical reactions. Enzymes are the cell's construction and demolition crews: They join particular molecules together or split them apart. In this way, enzymes determine what gets made from the raw materials in the cell and determine which molecules remain intact. Found in the cytoplasm, mitochondria use nutrients such as glucose to provide the cell with energy to perform its functions. Mitochondria produce a chemical called adenosine triphosphate (ATP), which can be used throughout the cell as an energy source. Mitochondria perform a vital role in the economy of the cell. Many of the biochemical steps involved in extracting energy by breaking down nutrients take place within mitochondria, and are controlled by enzymes located there. Most cell biologists believe that many eons ago, mitochondria were free-Ii ving organisms that came to "infect" larger cells. Because the mitochondria could extract energy more efficiently than the cells they infected, the mitochondria became useful to the cells and eventually became a permanent part of them. Because of their role in generating usable energy, mitochondria can be considered the "power plants" of neurons.

30 Chapter 2

Supporting Cells LO 2.3

Compare supporting cells in the central and peripheral nervous systems.

Neurons constitute only about half the volume of the CNS. The rest of the CNS contains of a variety of supporting cells. Neurons have a very high rate of metabolism but have no means of storing nutrients, and they must constantly be supp)jed with nutrients and oxygen or they will quickly die. Because of this, the cells that support and protect neurons are critical to our existence. S UPPORTIN G CELLS OF THE CENTRAL NERVOUS SYSTEM The most important supporting cells of the CNS

are the neuroglia, or "nerve glue." Glia (also called glial cells) do much more than just hold the nervous system together. Glial cells have a wide variety of important functions in the nervous system. Neurons lead a very sheltered existence. They are buffered physically and chemically from the rest of the body by the glial cells. Glial cells surround neurons and hold them in place, regulating their supply of nutrients and some of the chemicals they need to exchange messages with other neurons. Glial cells also insulate neurons from one another so that neural messages do not get scrambled; destroy and remove pathogens or dead neurons; are involved in growth, repair, and development of the nervous system; and can be involved in synaptic communication. Here we will focus on introducing three important types of glial cells: astrocytes, oligodendrocytes, and

microglia. Additional types of glia have been recently d iscovered but the full extent of their function in the nervous system is not yet known (Dimou and Gatz, 2014). Astrocytes Astrocyte means "star cell," a name that refers to the shape of these cells. Astrocytes provide physical support to neurons and clean up debris within the brain. (See Figures 2.10 and 2.13.) They produce some of the chemicals that neurons need to fulfill their functions. They help to control the chemical composition of the fluid surrounding neurons by actively taking up or releasing substances whose concentrations must be kept within critical levels. The somatic and dEmdritic membranes of neurons are largely surrounded by asltrocytes, and astrocytes are involved in providing nourishment to neurons. In addition, astrocytes function as "neuron glute" and help hold neurons in place. These cells also surround .and isolate synapses, limiting the dispersion of neurotransmitters that are released by the terminal buttons. When cells in the central nervous system die, certain kinds of astrocytes clear away the debris. These cells are able to travel around the CNS. When these astrocytes contact a piece of debris from a dead neuron, they engulf and digest it. This process is called phagocytosis. If there is a lot of injured tissue to be cleaned up, astrocytes will divide and produce e:nough new cells to do the job. Once the dead tissue has been broken down, a framework of astrocytes will be left to fill in the vacant area, and a specialized kind of astrocyte will form scar tissue, walling off the area.

Figure 2.10 Structure and Location of Astrocytes The processes of astrocytes surround capillaries and neurons of the central nervous system. Astrocytes regulate chemicals in the synapses (upper panel) and the chemical composition of the fluid surrounding neurons (lower panel).

Structure and Functions of Cells of the Nervous System 31 Oligodendrocytes The principal functions of oligod endrocytes are to provide support to axons and to produce the myelin sheath, which insulates most axons from one another. Myelin, 80 percent lipid and 20 percent protein, is produced by the oligodendrocytes in the form of a tube surrounding the axon. This tube does not form a continuous sheath. Instead, it consists of a series of segments, each approximately 1 mm long, with a small (1-2 µm) portion of uncoated axon between the segments. (A micrometer, abbreviated µrn, is one-miJJjonth of a meter, or one-thousandth of a millimeter.) The bare portion of axon is called a node of Ranvier, after the person who discovered it. The myelinated axon, then, resembles a string of elongated beads. A given oligodendrocyte produces up to 50 segments of myelin. During the development of the CNS, oligodendrocytes form arms shaped like oars or canoe paddles. Each of these paddle-shaped arms then wraps itself many times around a segment of an axon and, while doing so, produces layers of myelin. Each paddle becomes a segment of an axon's myelin sheath. (See Figure 2.11.) Microglia As their name indicates, microglia are the smallest of the glial cells. Like some types of astrocytes, they act as phagocytes, engulfing and breaking down dead and dying neurons. But, in addition, they serve as part of the immune system in the brain, protecting the brain from invading microorganisms. Microglia are primarily responsible for the inflammatory reaction in response to brain damage, such as in a traumatic brain injury (Corps et al., 2014; Loane and Kumar, 2016). SUPPORTING CELLS O F THE PERIPHERAL NERVOUS SYSTEM In the central nervous system, the oligodendro-

cytes support axons and produce myelin. In the peripheral

Figure 2.11 Oligodendrocyte An oligodendrocyte forms the myelin that surrounds many axons in the central nervous system. Each cell forms segments of myelin for several adjacent axons. Myelinated axons

~

/

Node of Ranvier

Figure 2.12 Formation of Myelin In the p1eripheral nervous system, an entire Schwann cell tightly wraps itself many times around an individual axon and forms one segment of the myelin sheath.

nervoius system, the Schwann cells perform the same functions. Most axons in the PNS are myelinated in segments, just as. neurons are in the CNS. Each myelin segment consists of a single Schwann cell wrapped many times around the axon. In the CNS the oligodendrocytes grow paddleshaped arms that wrap around multiple axons. In the PNS a Schwann cell provides myelin for only one axon, and the entire Schwann cell-not just a part of it-surrounds the axon. {See Figure 2.12.) Schwann cells also differ from their CNS counterparts, the oliigodendrocytes, in an important way. A nerve consists o:f a bundle of many myelinated axons, all covered in a sheath of tough, elastic connective tissue. If damage occurs to such a nerve, Schwann cells help digest the dead and dying axons. Then the Schwann cells arrange themselves in a series of cylinders that act as guides for regrowth of the axons. The distal portions of the severed axons die, but the stump of each severed axon grows sprouts, which then spread in all directions. If one of these sprouts encounters a cylinder provided by a Schwann cell, the sprout will grow through the tube quickly (at a rate of up to 3-4 mm a day), while the other, nonproductive sprouts wither away. If the cut ends of the nerve are still located close enough to each other, the axons will reestablish connections with the muscles and sense organs they previously served. Unfortunately, the gjjal cells of the CNS are not as cooperative as the supporting cells of the PNS. If axons in the brain or spinal cord are damaged, new sprouts will form, as in the PNS. However, the budding axons encounter scar tissue produced by the astrocytes, and they cannot cross this barrier. Even if the sprouts could get through, the axons would not reestablish their original connections without guidance similar to that provided by the Schwann cells of the PNS. During development, axons have two modes of growth. The fiirst mode causes them to elongate so that they reach their target, which could be as far away as the other end of the brain or spinal cord. Schwann cells provide this signal to injured axons. The second mode causes axons to stop elongating and begin sprouting terminal buttons because they have reached their target. Liuzzi and Lasek (1987) found that even when astrocytes do not produce scar tissue, they appear to produce a chemical signal that instructs regenerating axons to begin the second mode of growth: to stop elongating and

32

Chapter 2

start sprouting terminal buttons. This means that the difference in the regenerative properties of axons in the CNS and the PNS results from differences in the characteristics of the supporting cells, not from differences in the axons. Not all myelin is the same. The chemical composition of myelin differs between the CNS and PNS. This has an important implication in multiple sclerosis. The autoimmune attack in multiple sclerosis is specific to myelin produced by oligodendrocytes in the CNS. The following case of Dr. C. illustrates the brain changes and symptoms that result from this disorder.

One evening, after dinner with her spouse at her favorite restaurant, Dr. C. stumbled and almost fell. This was the final straw: A retired neurologist, she realized that she had been ignoring some symptoms that she should have recognized earlier. Her symptoms fit those of multiple sclerosis. She had occasionally experienced double vision, sometimes felt unsteady on her feet, and noticed tingling sensations in her right hand. None of these symptoms was serious, and they lasted for only a short while, so she ignored them-or perhaps denied to herself that they were important. After her formal diagnosis, Dr. C. lived with multiple sclerosis for more than two decades. She ultimately died of a heart attack. A few weeks after Dr. C.'s death, a group of medical students and neurological residents gathered in an autopsy room at the medical school. Dr. D., the school's neuropathologist, displayed a stainless-steel tray on which were lying a brain and a spinal cord. "These belonged to Dr. C.," he said. "Several years ago, she donated her organs to the medical school." Everyone

don't all occur at once, and they can be caused only by damage to several diffment parts of the nervous system, which means that they can't be the result of a stroke."

The Blood-Brain Barrier LO 2.4

Assess the function of the blood-brai n barrier.

Over 100 yeairs ago, Paul Ehrlich (1854-1915) discovered that if a blue dye is injected into an animal's bloodstream, all tissues except the brain and spinal cord will be tinted blue. However, if the same dye is injected into the fluid-filled ventricles of the brain, the blue color will spread throughout the CNS (Bradbwy, 1979). This experiment demonstrates that a barrier exists between the blood and the fluid that surrounds the cells of the brain: the blood-brain barrier. Some substances can cross the blood-brain barrier and enter the CNS, but others cannot. The blood-brain barrier is selectively p.ermeable. In most of the body the cells that line the smallest blood vessels, the capillaries, do not fit together absollutely tightly. Small gaps between the capillary cells permit the free exchange of most substances between the blood and the fluid outside the capillaries that surrounds the cells of the body. In the CNS the capillaries don't have gaps, and many substances cannot leave the blood to enter the brain. The walls of the capillaries in the brain make UJP the blood-brain barrier. (See Figure 2.13.) Some substan•ces must be actively transported through the

looked at the brain more intently, knowing that it had belonged to a skilled physician and teacher whom they all knew by reputa-

Figure 2 .13:

tion, if not personally. Dr. D. showed the students MRI scans. He pointed out

The blood-brain barrier is selectively permeable. Some substances, such as water molecules, can pass through the cells of the capillaries passively. Other molecules require expending energy to move between tile tightly packed cells of the capillaries. Astrocytes further strengthen the barrier by closely regulating any substances entering the brai1n from the capillaries. In the rest of the body, larger gaps between thie cells in the capillaries allow greater movement of substances in and out of tissues.

some white spots that appeared on one scan. "This scan clearly shows some white-matter lesions, but they are gone on the next one, taken six months later. And here is another one, but it's gone on the next scan. The immune system attacked the myelin sheaths in a particular region, and then glial cells cleaned up the debris. Once the myelin is gone, the axons can no longer conduct their messages."

T he B lood- Brain Barrier

He put on a pair of gloves, picked up Dr. C.'s brain, and cut it in several slices. He picked one up. "Here, see this?" He pointed out a spot of discoloration in a band of white matter. "This is a sclerotic plaque-a patch that feels harder than the surrounding tissue. There are many of them, located throughout the brain and spinal cord, which is why the disease is called multiple sclerosis." Dr. D. put the spinal cord down and said, "Who can tell me the basis of this disorder?" One of the students spoke up. "It's an autoimmune disease.

Tight juction prevents free flow of substances from blood to brain

The immune system gets sensitized to the body's own myelin protein and periodically attacks it, causing a variety of different neurological symptoms. Some say that a childhood viral illness somehow causes the immune system to start seeing the protein as foreign." "That's right," said Dr. D. "The primary criterion for the diagnosis of multiple sclerosis is the presence of neurological symptoms that repeatedly come and go over time. The symptoms

Brain

Structure and Functions of Cells of the Nervous System

capillary walls by special proteins. For example, glucose transporters bring the brain its fuel, and other transporters rid the brain of toxic waste products (Rubin and Staddon, 1999; Zlokovic, 2008). What is the function of the blood-brain barrier? Transmitting messages from place to place in the brain depends on a delicate balance between substances within neurons and those in the extracellular fluid that surrounds them. If the composition of the extracellular fluid is changed even slightly, the transmission of these messages will be disrupted, which means that brain functions will be disrupted. The presence of the blood-brain barrier makes it easier to regulate the composition of this fluid. In addition, many of the foods that we eat contain chemicals that would interfere with the transmission of information

33

betweie n neurons. The blood-brain barrier prevents these chemi cals from reaching the brain. The blood-brain barrier is not uniform everywhere in the ne:rvous system. In several places the barrier is more permeable, allowing substances that are excluded elsewhere to cross freely. For example, the area postrema is a part of the brain that controls vomiting. The blood-brain barrier is much weaker there, permitting neurons in this region to detect the presence of toxic substances in the blood. (A barrier around the area postrema prevents substances from diffusing from this region into the rest of the brain.) A poison that enters the circulatory system from the stomach can stimulate the area postrema to initiate vomiting. With luck, the poison can be expelled from the stomach before causing too much damage. 1

Module Review: Cells of the Nervous System The Nervous System: An Overview LO 2.1 Contrast features of the central and peripheral

nervous systems. The central nervous system (CNS) contains the brain and spinal cord. The peripheral nervous system (PNS) includes the nerves and most sensory organs outside the brain and spinal cord. The PNS communicates with the CNS via nerves that relay sensory and motor information between the brain and spinal cord, and the rest of the body.

Neurons LO 2.2 Distinguish among the structures of a neuron.

Neurons include four basic structures: the soma, dendrites, axon, and terminal buttons. The soma contains the nucleus and many of the organelles. The dendrites are branched structures attached to the soma that receive messages from other neurons. The axon is a long, thin extension of the soma that conveys a message to the terminal buttons. The myelin sheath insulates the electrical message carried along the axon membrane. The terminal buttons are extensions of the axon that convert the message to a chemical form by releasing neurotransmitters into the synapse. Other important structures include the cell membrane, cytoskeleton, cytoplasm, nucleus, and mitochondria.

Supporting Cells LO 2.3 Compare supporting cells in the central and

peripheral nervous systems. In the CNS, astrocytes, oligodendrocytes, and microglia support neurons by creating an environment conducive

to neuronal function, providing a myelin sheath, and activating immune responses. In the PNS, Schwann cells provide myelin and faci litate recovery from injury to neuro1ns.

The Blood- Brain Barrier LO 2.4 Assess the function of the blood-brain

barrier. The b.lood-brain barrier protects the CNS, selectively permitting only some substances to enter. The barrier is made of capillary walls and helps regulate the composition of fluids in the brain, protecting neuronal transmission. Capillaries in the brain are surrounded by astrocytes, which also help regulate contents of the fluid surrounding the capillaries. The blood-brain barrier is more permeable in the area postrema, permitting neuro1ns in this region to detect the presence of toxic substances in the blood.

Thought Question While the blood-brain barrier helps prevent pathogens from entering the brain, it can also prevent therapeutic molecules from entering. Developing drugs that target sites in the brain can be complicated by the difficulty of get1ting the molecules past the blood-brain barrier to treat symptoms such as those of Alzheimer's and Parkinson's diseases. Imagine that you have been selected to research techniques to enhance drug delivery across the bkiod-brain barrier. What strategies might you test and why?

34 Chapter 2

Communication Within a Neuron Building on an understanding of the structure and function of neurons, we will next explore how neurons commu-

nicate. This module describes the nature of communication within a neuron-the ways in which neurons establish a membrane potential and generate an action potential beginning at the axon hillock and traveling along the axon to the terminal buttons, informing them to release some neurotransmitter. As we will see in this module, an action potential consists of a series of alterations in the membrane of the axon that permit small charged particles called ions to move between the inside and outside of the axon. These ion exchanges produce electrical currents. The next module will describe synaptic transmission-how the message is then conveyed to other neurons.

Neural Communication: An Overview LO 2.5

Explain the process of neural communication in a reflex.

Before discussing the action potential, let's step back

and see how neurons can interact to produce a useful behavior, such as a reflex. In Figures 2.14 and 2.15 (and in subsequent figures that illustrate simple neural circuits), neurons are depicted as several-sided stars. The points of these stars represent dendrites, and only one or two terminal buttons are shown at the end of the axon. The sensory neuron in this example detects painful stimuli. When its dendrites are stimulated (such as by contact

with a hot object), it sends messages down the axon to the terminal buttons, which are located in the spinal cord. (See Figure 2.14.) The terminal buttons of the sensory neuron 1release a neurotransmitter that excites the interneuron, causing it to send messages down its axon. The terminal buttons of the interneuron release a neurotransmitter that excites the motor neuron, which sends messages down its axon. The axon of the motor neuron joins a nerve :and travels to a muscle. When the terminal buttons of thE: motor neuron release their neurotransmitter, the muscle cells contract, causing the hand to move away from the hot object. So far, all of the synapses have had excitatory effects. Now let's see the effect of inhibitory synapses. Imagine that you pick up a cup of a steaming hot liquid. As you pick up the cup, the heat from the liquid causes pain in your hand. The pain caused by the heat triggers a withdrawal reflex that tends to make you drop the cup. Yet you manage to hold it long enough to get to a table and put it down. What prevented your withdrawal reflex from making you drop the cup on the: floor? The pain :from the hot cup increases the activity of excitatory synapses on the motor neurons, which tends to cause your hand to pulJ away from the cup. However, this excitation is counteracted by inhibition, supplied by another source: tthe brain. Your brain contains neural circuits that recognize: what a disaster it would be if you dropped the cup on the floor. These neural circuits send information to the spinal cord that prevents the withdrawal reflex from making you drop the cup. Figure 2.Jl5 shows how this information reaches the spinal cord. An axon from a neuron in the brain reaches the spinal cord, where its terminal buttons form synapses with an inhibitory interneuron. When the neuron in the

Figure 2.14 A Withdrawal Reflex The figure shows a simple example of a useful function of the nervous system. The painful stimulus causes the hand to pull away from the hot iron.

Brain

This interneuron excites a motor neuron, causing muscLilar contraction ..--

-~·-- ~ Spinal cord

Motor neuron

~ / /

This muscle causes withdrawal from source of pain Dendrites of

\ /

Y\ Axon of sensory neuron (pain)

Structure and Functions of Cells of the Nervous System

Figure 2.15

35

The Role of Inhibition

Inhibitory signals arising from the brain can prevent the withdrawal reflex from causing the person to drop the cup. This interneuron excites a motor neuron, causing ,....,. muscular contraction

This muscle causes withdrawal from source of pain

This interneuron inhibits the motor neuron, preventin1i muscular contraction

brain becomes active, its terminal buttons excite this inhibitory interneuron. The interneuron releases an inhibitory neurotransmitter, which decreases the activity of the motor neuron, blocking the withdrawal reflex. This circuit provides an example of a contest between two competing tendencies: to drop the cup and to hold onto it. Reflexes are generally more complicated than this description, and the mechanisms that inhibit them are even more so. Thousands of neurons are involved in this process. The few neurons shown in Figure 2.15 represent many others: Dozens of sensory neurons detect the hot object, hundreds of interneurons are stimulated by their activity, hundreds of motor neurons produce the contractionand thousands of neurons in the brain must become active to be able to inhibit the reflex. This simplified model provides an overview of the process of neural communication, which is described in more detail throughout the rest of this chapter.

Electrical Potentials of Axons LO 2.6

Describe membrane potential, resting potential, hyperpolarization, depolarization, and the action potential.

Next, we will examine the nature of the message that is conducted along the axon. This message consists of changes in electrical charge. An axon at rest is negatively charged inside the membrane. Researchers have developed electrical recording techruques using very small sensors called microelectrodes that can be inserted into a neuron to record changes in electrical activity across the axon membrane (see Chapter 5). When inserted into an axon at rest, the rnicroelectrode will detect a negative charge inside the membrane. Most neurons are approximately 70 units, or - 70 m V, more negatively charged inside the axon compared to outside. Any difference in charge (positive or negative) across

the membrane is called the membrane potential. The term potential refers to a stored-up source of energy- in this case, electrical energy. When the neuron is at rest and not involved in communicating with any other neurons, the membrane potential remains at approximately - 70 mV, which is called the neuron's resting potential. W'hen the inside of an axon becomes more negative (from resting potential) relative to the outside, it is called hyperpo!larization. When the inside of the axon becomes more positive (from resting potential) relative to the outside, the neuron is depolarized. A hyperpolarized axon is less likely to send an electrical message. A depolarized axon is more likely to send an electrical message. Each neuron has a threshold of exciitation, or a set point, for depolarization to trigger the main E~lectrical event in an axon-the action potential. The action potential is a burst of rapid depolarization followed by hyperpolarization. This spread of depolarization followed by hyperpolarization begins at the point where the soma meets the axon (the axon hillock) and travels all the way to the end of the terminal buttons, triggering the terminal buttons to release neurotransmitters into the synap:se. The following sections will describe the events contributing to the action potential.

The Membrane Potential LO 2.ir

Summarize how diffusion, electrostatic p ressure, and the sodium-potassium pump help establish membrane potential.

To understand what causes the action potential to occur, we must first understand the reasons for the existence of the membrane potential. The membrane potential is affected by two opposing forces: diffusion and electrostatic pressuire.

36 Chapter 2

When a spoonful of sugar is carefully poured into a container of water, it settles to the bottom. After a time the sugar dissolves, but it remains close to the bottom of the container. After a much longer time (probably several days) the molecules of sugar distribute themselves evenly throughout the water, even if no one stirs the liquid. The process whereby molecules distribute themselves evenly throughout the medium in which they are dissolved is called diffusion. When there are no forces or barriers to prevent them from doing so, molecules will diffuse from regions of high concentration to regions of low concentration. Molecules are constantly in motion, and their rate of movement is proportional to the temperature. Only at absolute zero [OK (kelvin) = - 273.15° C = -459.7° F] do molecules cease their random movement. At all other temperatures they move around, colliding and veering off in different directions and pushing one another away. The result of these collisions in the example of sugar and water is to force sugar molecules upward (and to force water molecules downward), away from the regions where they were most concentrated. THE FORCE OF DIFFUSION

THE FORCE OF ELECTROSTATIC PRESSURE When some substances are dissolved in water, they split into two particles, each with an opposing electrical charge. Substa nces with this property are called electrolytes. The charged particles are called ions. Ions are of two basic types: Cations have a positive charge, and anions have a negative charge. For example, when sodium chloride (NaCl, table salt) is dissolved in water, many of the molecules split into sodium cations (Na+) a nd chloride anions (Ci-). Particles with the same kind of charge repel each other (+ repels +, and - repels - ), but particles with different charges are attracted to each other (+ and - attract). This means that anions repel anions, cations repel cations, but anions and cations attract each other. The force exerted by this attraction or repulsion is called electrostatic p ressure. Just as the force of diffusion moves molecules from regions of high concentration to regions of low concentration, electrostatic pressure moves ions from place to place: Cations are pushed away from regions with an excess of cations, and anions are pushed away from regions with an excess of anions. (See Figure 2.16.) IONS IN THE EXTRACELLULAR AND INTRACELLULAR

FLUID The fluid inside cells is called intracellular fluid, while the fluid surrounding cells is called extracellular fluid. Intracellular and extracellular fluids contain different ions. The forces of diffusion and electrostatic pressure contributed by these ions help create the membrane potential. It is important to know the relative concentrations of ions in the intracellular and extracellular fluids in order to understand the membrane potential.

Figure 2.16

Force of Electrostatic Pressure

Ions evenly distriibute themselves throughout a medium.

l

• 0

t

t0 0

l

t

•• l

Electrostatic pressure pushes ions of opposite charges together and pushes ions with the same charges apart.

There are several important ions in these fluids. These include: organic anions (symbolized by A-), chloride ions (Ci-), sodium ions (Na+), and potassium ions (K+). Organic anions are fouind only in the intracellular fluid and cannot leave the cell. Although the other three ions are found in both the intraicellular and extracellular fluids, K+ is found predominantly in the intracellular fluid, whereas Na+ and c1- are found predominantly in the extracellular fluid. The sizes of the boxes in Figure 2.17 represent the relative concentrations of these four ions. One way to remember which ion is found where is to recall that the fluid that surrounds our cells is similar to seawater, which is predominantly a solution of salt, NaCL The primitive ancestors of our cells lived in the ocean, and the seawater was their extracellular fluid. Our extracellular fluid still resembles seawater. Let's consider the ions in Figure 2.17, examining the forces of diffusion and electrostatic pressure exerted on each type of ion and reasoning why each ion is located where it is. A-, the organic anion, is unable to pass through the membrane of the axon. It is located where it is because the membrane is impermeable to it. The potassium ion K+ is concentrated within the axon, and the force of diffusion tends to push it out of the cell. However, the outside of the cell is charged positively with respect to the inside, so electrostatic pressure tends to force this cation inside. The two opposing forces balance, and potassium ions te~nd to remain where they are. (See Figure 2.17.) The chloride ion CC is in greatest concentration outside the axon. The force of diffusion pushes this ion inward. However, because the inside of the axon is nega-

tively charged, electrostatic pressure pushes this anion outward. Again, two opposing forces balance each other. (See Figure 2.Jl7.) The sodium ion Na+ is also in greatest concentration outside the axon, so it, like o -, is pushed into the cell by the force of diffusion. But unlike chloride, the sodium ion is positively charged and the negative charge inside the axon attracts Na+. (See Figure 2.17.)

Structure and Functions of Cells of the Nervous System

Figure 2.17

37

Establishing the Membrane Potential

This figure shows the relative concentration of some important ions inside an1d outside the neuron and the forces acting on them.

High concentration

Low concentration

~

Positive Outside of Cell

er

+

+

Force of diffusion

K+

J_

T

t

1~ Electrostatic pressure

+

Na+

TI . •.JElectrostatic pressure

Force of . diffusion

+

+

Ion channel

Negative Inside of Cell

t

F~rce

of diffusion

tT

J_ Ele~trostatic pressure

er

Cannot leave cell

THE SODIUM-POTASSIUM PUMP How can Na+ remain highly concentrated in the extracellular fluid, even

though both forces (diffusion and electrostatic pressure) tend to push it inside the cell? The answer is this: Another force, provided by the sodium- potassium pump, continuously pushes Na+ out of the axon. The sodium- potassium pump consists of a large number of protein molecules embedded in the membrane, driven by energy provided by ATP produced by the mitochondria. These molecules, known as sodium-potassium transporters, exchange Na+ for K+, pumping three sodium ions out for every two potassium ions they pump in. (See Figure 2.18.) Because the membrane is not very permeable to Na+, sodium- potassium transporters very effectively keep the intracellular concentration of Na+ low. By transporting K+ into the cell, they also increase the intracellular concentration of K+ a small amount. The transporters that make up the sodium- potassium pump use considerable energy: up to 40 percent of a neuron's metabolic resources. Neurons, muscle cells, glia- in fact, most cells of the body- have sodium-potassium transporters in their membrane.

the membrane is not very permeable to this ion, and sodium--potassium transporters continuously pump out Na+, keeping the intracellular level of Na+ low. But imagine what would happen if the membrane suddenly became permeable to Na+. The forces of diffusion and electrostatic

Figure 2.18

The Sodium-Potassium Pump

These t ransporters are found in the cell membrane.

3 sodium ions pumped out

~~~

Sodium-potassium transporter

/~M~I

The Action Potential LO 2.8

Summarize the series of ion movements during the action potential.

As we have seen, the forces of both diffusion and electrostatic pressure tend to push Na+ into the cell. However,

Inside of Cell K+ K+ 2 potassium ions pumped in

38

Chapter 2

Figure 2.19

Ion Channels

When ion channels are open, ions can pass through them, entering or leaving the cell. Protein subunits of ion channel

Ions

Pore of ion c ~annel

Outside of Cell

Lipid molecules in membrane

Figure 2.20

Ion Movements During the Action Potential

The image at the top shows the opening of sodium channels at the threshold of excitation, their refractory condition at the peak of the action potential, and their resetting when the membrane potential returns to resting potential. The bottom figure outlines the phases of the action potential. Steps to Generate an Action Potential 1.

When the threshold of excitation is met, the sodium channels in the membrane open, and Na+ rushes in, propelled by

R•~fractory

Open

Reset

the forces of diffusion and electrostatic pressure. The opening of these channels is triggered by depolarization. The influx of sodium ions produces a rapid change in the membrane potential, from -70 mV to +40 mV.

2.

3.

4.

Opening voltage-dependent potassium channels requires a greater level of depolarization, and they begin to open later than the sodium channels. At about the time the action potential reaches its peak (in approximately 1 msec), the sodium channels become refractory and cannot open again until the resting membrane potential is reached. Voltage-dependent potassium channels in the membrane are open, letting K+ ions move freely through the membrane. At this time, the inside of the axon is positively charged, so K+ is driven out of the cell by diffusion and by electrostatic pressure. This outflow of cations causes the membrane potential to return toward its normal value. As it does so, the potassium channels begin to close again.

ions enter

ions leave

+ 40

.s> ~

:g

0 a.

c

~

Na+ channels --become refractory, no more Na• enters cell

3

0 K+ channels open, K+ 2 begins to leave cell

K+ continues to leave cell, causes membrane potential to return to resting level

.D

E

~

Na• channels open, Na• begins to enter cell

Threshold of excitation

K+ channels close, Na• channels reset

6 Extra K+ outside diffuses away

5.

Once the membrane potential returns to rest, the sodium channels reset so that another depolarization can cause them to open again.

6.

The membrane potential becomes more negative and gradually returns to resting membrane potential as the potassium channels finally close. Sodiu~potassiurn transporters remove the Na+ ions that leaked in and retrieve the K+ ions that leaked out. Extra K+ outside diffuses away.

Structure and Functions of Cells of the Nervous System

pressure would cause Na+ to rush into the cell. This sudden influx (inflow) of positively charged ions would drastically change the membrane potential by depolarization. This is precisely what causes the action potential: A brief increase in the permeability of the membrane to Na+ (allowing these ions to rush into the cell) is immediately followed by a brief increase in the permeability of the membrane to K+ (allowing these ions to rush out of the cell). What is responsible for these brief increases in permeability? Specialized protein molecules embedded in the membrane create ion channels, which contain passages for ions (also called pores) that can open or close. When an ion channel is open, specific ions can flow through the pore to enter or leave the cell. (See Figures 2.17 and 2.19.) Neural membranes contain thousands of ion channels. For example, each sodium channel can admit up to 100 million ions per second when it is open. The permeability of a membrane to a particular ion at a given moment is determined by the number of ion channels that are open. The action potential consists of a series of changes in opening and closing of ion channels and the resulting redistribution of ions. (See Figure 2.20.) First, the membrane potential must reach the th reshold of excitation. Then, sodium channels in the membrane open, and Na+ rushes in, propelled by the forces of diffusion and electrostatic pressure. These sodium channels are called voltage-dependent ion channels (or voltage-sensitive ion channels, or voltage-gated ion channels) because they are only opened by changes in the membrane potential. At this point, the interior of the cell starts to become more positive. Next, voltage-dependent potassium channels begin to open, allowing potassium to leave the cell. These potassium channels require a greater level of depolarization before they begin to open, and they begin to open later than the sodium channels. Remember that the interior of the cell is positively charged, so K+ is driven out of the cell by diffusion and by electrostatic pressure. At about this time (1 millisecond [msec] after they open), the sodium channels become refractory, which means the channels cannot open again until the membrane once more reaches the resting potential. The outflow of cations causes the membrane potential to return toward its normal resting value. As it does so, the potassium channels begin to close again. At this time, the sodium channels reset (are no longer refractory). The membrane briefly becomes more negative than its resting value (-70 m V) and only gradually returns to resting potential as the potassium channels finally close. Eventually, sodium-potassium transporters remove the Na+ ions that leaked in and retrieve the K+ ions that leaked out. (See Figure 2.20.)

39

Conduction of the Action Potential LO 2.H

Describe conduction of the action potential.

Now that you've read about the resting membrane potential and the action potential, let's next consider the movement of the message down the axon, or conduction of the action potential. As the action potential travels along the axon, it remains constant in size. (See Figure 2.21.) A basic law of axonal conduction is the all-or-none law. This law states that an action potential either occurs or does not occur, and, once triggered, it is transmitted down the axon to its end. An action potential always remains the exact same size, without growing or diminishing. And when an action potential reaches a point where the axon branches, it splits but does not diminish in size. An axon will transmit an action potential in either direction, or even in both directions, if it is started in the middle of the axon's length. However, because action potentials in living animals start at the end attached to the soma, action potentials normally travel one way. A·ction potentials in axons convey the varying strength of mw;cular contractions and the degree of light detected by the neiurons in the eye. But if action potentials are all-or-none events and every action potential is exactly the same size, how can they represent in a continuous fashion information that varies, such as strong to weak muscle contraction, or bright to dim light? The answer is surprising: Variable information is represented by an axon's rate of firing action potentials. A high rate of firing causes a strong muscular

Figure 2.21

Conduction of t he Action Potential

When c:1n action potential is triggered, its size remains the same as it travels down the axon. The graphs at the top of the figure represent the sizei (amplitude) of the action potential as it moves along the axon fmm left to right. Figure 2.20 provides more detail about the graph of an action potential. Conduction of the action potential can be meaisured using microelectrodes inserted along the axon, as shown in this figure.

l

Depolarizing stimu1lus

·~

0-

Direction of travel of action potential Axon

40

Chapter 2

Figure 2.22

The Rate Law

The strength of a stimulus is represented by the rate of firing of an axon. The magnitude (si:ze) of each action potential is always constant. Each blue line represents one action potential.

i Action potentials

I

Strong stimulus

Weak stimulus

II

I 111

III

Action potentials

-I

111111111111111111111111 On

On . . . . - - - - - - - - . Off

Off

Stimulus

Stimulus

i~

Time

contraction, and a strong stimulus (such as a bright light) causes a high rate of firing in axons that serve the eyes. For example, an axon might respond to a dim light such as a candle by firing 10 identical action potentials in a unit of time (a low rate of firing). The same axon might respond to a bright spotlight by firing 100 identical action potentials in the same unit of time (a high rate of firing). The rate law refers to the principle that variations in the intensity of a stimulus or other information being transmitted in an axon are represented by variations in the rate at which the axon fires. (See Figure 2.22.) As an example, imagine that every time you clap your hands, the sound occurs at the exact same volume. To show your enthusiasm for a great performance, you might clap your hands very quickly for 30 seconds (a high rate of firing). To show your response to a performance you didn't enjoy as much, you might only clap your hands a few times, slowly, for 30 seconds (a low rate of firing). You are using the same method of communication (clapping, or in the case of a neuron, sending action potentials), but you are varying the rate to convey different messages. Figure 2.22 shows an example of differences in firing rates corresponding to a weak visual stimulus (a dim candle) and a strong visual stimulus (a bright floodlight). Most axons in mammalian nervous systems are myelinated. Segments of the axons are covered by a myelin sheath produced by the oligodendrocytes of the CNS or the Schwann cells of the PNS. These segments are separated by gaps in the myelina tion, called the nodes of Ranvier. Conduction of an action potential in a myelinated axon is somewhat different from conduction in an unmyelinated axon. Schwann cells and the oligodendrocytes of the CNS wrap tightly around the axon, leaving no measurable extracellular fluid between them and the axon. The only place where a myelinated axon comes into contact with the extracellular fluid is at a node of Ranvier. In the myelinated areas, there can be no inward flow of Na+ when the sodium channels open because there is no contact with extracellular sodium. The axon conducts the electrical message from the action potential to the next node of Ranvier. The electrical message is conducted passively, the way an electrical signal is conducted through an insulated cable. The electrical message gets smaller as it passes down the axon, but it is still large enough to trigger

a new action potential at the next node. This decrease in the size of the electrical message is called decremental conduction. The action potential gets retriggered, or repeated, at each node of Ranvier, and the electrical message that results is conducted decrementally along the myelinated area to the next node. Transmission of this message, appearing to jump from node to node, is called saltatory conduction, from the Latin saltare, "to dance." (See Figure 2.23.) Saltatory conduction has two advantages. The first advantage is economic. Sodium ions enter axons during action potentials, and these ions must eventually be removed. Sodiutm-potassium transporters must be located along the entire length of unmyelinated axons because Na+ enters everywhere. However, because Na+ only enters myelinated axons at the nodes of Ranvier, much less gets in, and consequently much less has to be pumped out again. This way, myelinated axons need much less energy to maintain their sodium balance. The second advantage of saltatory conduction is speed. Conducting an action potential is faster in a myelinated axon because the transmission between the nodes is very fast. The other option to increase speed of action potential propagation is to increase the diameter of the neuron. However, even very large unmyelinated neurons cannot propagate an action potential as quiickly as a small myelinated neuron. Myelin is a valuable addition to a neuron. Increased speed allows an animal to react faster and (undoubtedly) to think faster.

Figure 2.23

Saltatory Conduction

The figure shows conduction of the action potential along a myelinated axon..

Myelin sheath

~~----.-

Decremental co1nduction under myelin sheath

'

\ Action potential is regenerated at nodes of Ranvier

Structure and Functions of Cells of the Nervous System

41

Module Review: Communication Within a Neuron Neural Communication: An Overview

The Action Potential

LO 2.5 Explain the process of neural comm unication

LO 2J3 Summarize the series of ion movements

in a reflex. A simple withdrawal reflex is made up of a sensory neuron that detects the s timulus, a spinal interneuron that excites a motor neuron, and a motor neuron that causes the withdrawal behavior. This reflex can be modified by input from the brain that can prevent the withdrawal behavior by inhibiting the motor neuron.

Electrical Potentials of Axons LO 2.6 Describe membrane potential, res ting

potential, hyperpolarization, depolarization, and the action potential. Resting potential in most neurons is approximately -70 mV, or 70 units (mV) more negative compared to outside. In general, hyperpolarization occurs when the inside of the neuron becomes more negative (for example, - 100 m V), and depolarization occurs when the inside of the cell becomes more positive (for example, +20 mV). An action potential occurs when a neuron is depolarized beyon d its threshold of excitation. An action potential is a burst of depolarization followed by hyperpolarization that conducts like a wave along the axon, starting at the point where the axon meets the soma and continuing to the terminal buttons.

The Membrane Potential LO 2.7 Summarize how diffusion, electrostatic

pressure, and the sodium- potassium pump help establish membrane potential. The difference in charge between the inside and the outside of the axonal membrane is generated by the force of diffusion, electrostatic pressure, and the activity of sodium-potassium pumps. The force of diffusion describes the process by which molecules distribute themselves evenly throughout the medium in which they are dissolved. Electrostatic pressure describes the phenomenon in which like charges repel and opposite charges are a t tracted to each other. The sodium-potassium pump helps maintain the resting membrane potential by pumping sodium ions out and potassium ions in to the cell.

during the action potential. After reaching the threshold of excitation, the voltagedependent sodium channels open, allowing sodium to ent,e r the cell. Sodium ion movement into the cell is driven by the forces of diffusion and electrostatic pressure. This depolarizes the axonal membrane. After approximately 1 msec, the sodium channels become refractory. The positive charge inside the cell next opens voltag;e-dependent potassium channels. Potassium exits the cell due to the forces of diffusion and electrostatic pressure due to the now positive charge on the inside of the cell. As potassium exits and diffuses away from the celll, the cell becomes hyperpolarized and eventually becomes even more negative than the resting potential. The potassium channels close, stopping potassium ions from exiting the cell, and the sodium-potassium pumps become active, helping to reestablish resting potential.

Conduction of the Action Potential LO 2.!~ Describe conduction of the action potential.

After being initiated at the axon hillock, the action potential travels toward the terminal buttons. The all-or-none law states that an action potential either occurs or does not occur, and, once triggered, is conducted along the axon to the terminals. In an unmyelinated axon, the action potential proceeds along the axon but is subject to decremental conduction. In a myelinated axon, the action potential is conducted via saltatory conduction, which speeds the message, reduces decremental conduction, and renews the action potential at the nodes of Ranvier. To vary the strength of the message conveyed by the action potential, the rate law explains that although each action potential event is identical, a stronger message can be co111veyed by firing action potentials at a higher rate.

Thought Question Have you ever received a local anesthetic to relieve pain from an injury or during a painful procedure? Local anesthetics such as Novocaine or Lidocaine produce their numbing effects by blocking sodium channels along the axons of sensory neurons. Explain how blocking these channels could reduce sensory function in these neurons.

42 Chapter 2

Communication Between Neurons With an understanding of the basic structure of neurons and the nature of communication within the neuron, it is time to examine the ways neurons can communicate with each other. These communications make it possible for circuits of neurons to gather sensory information, make plans, and initiate behaviors. The primary means of communication between neurons is synaptic transmission-the transmission of messages from one neuron to another across a synapse. As we have seen, these messages are carried by neurotransmitters that are released by terminal buttons of the sending, or presynaptic, cell. These neurotransmitters diffuse across the fluid-filled gap between the terminal buttons and the membranes of the neurons with which they form synapses, called the postsynaptic cells. Neurotransmitters then produce postsynaptic potentials-brief depolarizations or hyperpolarizations that increase or decrease the rate of firing of the axon of the postsynaptic neuron. Neurotransmitters exert their effects on cells by attaching to a particular region of a receptor molecule called the binding site. A molecule of the chemical fits into the binding site the way a key fits into a lock: The shape of the binding site and the shape of the molecule of the neurotransmitter are complementary. (See Figure 2.24.) A chemical that attaches to a binding site is called a ligand. Neurotransmitters are naturally occurring ligands, produced and released by neurons. But other chemicals found in nature (primarily in plants or in the poisonous venoms of animals) can serve as ligands too. In addition, artificial ligands can be produced in the laboratory. These chemicals are discussed in Chapter 4, which deals with drugs and their effects. One important characteristic of ligands is that they only bind to receptors. They cannot enter into a neuron through a binding site, although they may open ion channels that ions can use to enter or exit the cell. This concept will be discussed in more detail later in this section.

Structure of Synapses LO 2.10 Identify the p resynaptic structures involved in synaptic communication. Synapses are junctions between the terminal buttons at the ends of the axonal branches of one neuron and the membrane of another. Many synapses occur on the smooth surface of a dendrite or on dendritic

Figure 2.2~~ Neurotransmitters and Binding Sites Neurotransmitter molecules fit the binding sites of receptors like keys fits into locks. Neurotransmitter binding conveys the neural message to the postsynaptic cell.

1

Presynaptic cell

I' I'

\-r

~ Neurotransmitter molecules

Postsynaptlc cell Receptors

spines- small protrusions that stud the dendrites of several types of large neurons in the brain. Some synapses can occur on the soma and on other axons. (See Figure 2.25.) Let's exannine a basic synapse in more detail. The presynaptic membrane, located at the end of the terminal button, faces lthe postsynaptic membrane, located on the neuron that receives the message, across the synapse. The synapse contains extracellular fluid through which the neurotransmitter diffuses. As you may notice in Figure 2.26, two prominent structures are located in the cytoplasm of the terminal button: mitochondria and synaptic vesicles. We also see microtubu1es, which are responsible for transporting material between the soma and terminal button. The presence of mitochondria implies that the terminal button needs energy to perform its functions. Synaptic vesicles are small, rounded structures made of membrane and filled with molecules. A terminal button can contain from a few hundred to nearly a million synaptic vesicles. Synaptic vesicles are found in greatest numbers around the part of the presynaptic membrane that faces the synaptic cleft, the region from which neurotransmitter is released. Many terminal buttons contain two types of synaptic

vesicles: large and small. Small synaptic vesicles (found in all terminal buttons) contain molecules of the neurotransmitter. They range in number from a few dozen to several hundred. The membrane of small synaptic vesicles consists of approximately 10,000 lipid molecules

Structure and Functions of Cells of the Nervous System

Figure 2.25

43

Types of Synapses

Axodendritic synapses can occur on the smooth surface of a dendrite (a) or on deindritic spines (b). Axoaxonic synapses consist of synapses between two terminal buttons (c). Dendritic

Postsynaptic Presynaptic terminal button terminal button

Smooth dendrite

(a)

(b)

into which are inserted about 200 protein molecules. Transport proteins fill vesicles with the neurotransmitter, and trafficking proteins are involved in the release of neurotransmitters and the recycling of the vesicles. Synaptic vesicles are found in greatest numbers around the part of the presynaptic membrane that faces the synaptic cleft-near the release zone, the region from which the neurotransmitter is released. In many terminal buttons we see a scattering of large, dense-core synaptic vesicles.

Figure 2.26

(c)

These vesicles contain one of a number of different peptides, the functions of which are described later in this chapter. Small synaptic vesicles are produced in the soma and are carried by fast axoplasmic transport to the terminal button. As we will see, some are also produced from recycled materiial in the terminal button. Large synaptic vesicles are produced only in the soma and are transported through the axoplasm to the terminal buttons.

Details of a Synapse

The structures of the synapse involved in synaptic communication. Detail of Synapse

Mitochondrion Microtubule

~ being Synaptictransported vesicle from soma

Synaptic cleft

zone Neuron

Postsynaptic density

Presynaptic membrane

Postsynaptic membrane

44

Chapter 2

Release of Neurotransmitters LO 2.11 Describe the process of neurotransmitter

release. When the cell secretes molecules of neurotransmitter, it uses a process called exocytosis. In exocytosis, the membrane-wrapped product migrates to the inside of the outer membrane of the cell, fuses with the membrane, and bursts, spilling its contents into the flujd surrounding the cell. As we will see, neurons communicate with one another by secreting chemicals by this means. When action potentials are conducted down an axon (and down all of its branches), something happens inside all of the terminal buttons: A number of small synaptic vesicles located just inside the presynaptic membrane fuse with the membrane and then break open, spilling their contents into the synaptic cleft through exocytosis. In Figure 2.27, the axon has just been stimulated, and synaptic vesicles in the termmal button are in the process of releasing the neurotransmitters. Note that some vesicles are fused with the presynaptic membrane, formmg the shape of an omega (Q).

Figure 2.27

How does an action potential cause synaptic vesicles to release nemotransmitters? The process begins when a population of synaptic vesicles becomes "docked" against the presynapltic membrane, ready to release their neurotransmitter into the synaptic cleft. Docking is accomplished when clusters of protein molecules attach to other protein molecules located in the presynaptic membrane. (See Figure 2.27.) The relea:se zone of the presynaptic membrane contains voltage-dependent calcium channels. When the membrane of the termmal button is depolarized by an arriving action potential, the calcium channels open. Like sodium ions, calcium ions (Ca2+) are located in highest concentration in the ext1racellular fluid. When the voltage-dependent calcium channels open, Ca2+ flows into the cell, propelled by electrostatiic pressure and the force of diffusion. The entry of Ca2+ iis an essential step in neural communication. If neurons are placed in a solution that contains no calcium ions, an action potential no longer causes the release of a neurotransmitter. (Calcium transporters, similar in operation to sodiwn-potassium transporters, later remove the intracellular Ca2+.)

Release of a Neurotransmitter

An action potential opens calcium channels, which allow calcium ions to enter and bind wi1th the protein embedded in the membrane of synaptic vesicles docked at the release zone. The fusion pores open, and the neurotransmiitter is released into the synaptic cleft.

~--

Cluster of protein molecules in membrane of synaptic vesicle

Cluster of protein in presynaptic membrane

Calcium channel

Entry of calcium opens fusion pore

Fusion pore widens, membrane of synaptic vesicle fuses with presynaptic membrane

v·

Molecules of neurotransmitter begin to leave terminal button

Presynaptic • membrane

Structure and Functions of Cells of the Nervous System

As we will see later in this chapter and in subsequent chapters of this book, calcium ions play many important roles in biological processes within cells. Calcium ions can bind with various types of proteins, changing their characteristics. Some of the calcium ions that enter the terminal button bind with the clusters of protein molecules that join the membrane of the synaptic vesicles with the presynaptic membrane. This event makes the segments of the clusters of protein molecules move apart, producing a fusion pore-a hole through both membranes that enables them to fuse together. The process of fusion takes approximately 0.1 msec. (Look again at Figure 2.27.) Research indicates that there are three distinct pools of synaptic vesicles (Rizzoli and Betz, 2005). Release-ready vesicles are docked against the inside of the presynaptic membrane, ready to release their contents when an action potential arrives. These vesicles constitute less than 1 percent of the total number found in the terminal. Vesicles in the recycling pool constitute 10-15 percent of the total pool of vesicles, and those in the reserve pool make up the remaining 85-90 percent. If the axon fires at a low rate, only vesicles from the release-ready pool will be called on. If the rate of firing increases, vesicles from the recycling pool and finally from the reserve pool will release their contents. What happens to the leftover membrane of the synaptic vesicles after they have broken open and released the neurotransmitter they contain? It appears that many vesicles in the ready-release pool use a process known as kiss and run. These synaptic vesicles release most or all of their neurotransmitter, the fusion pore closes, and the vesicles break away from the presynaptic membrane and get filled with neurotransmitter again. Other vesicles (primarily those in the recycling pool) merge and recycle and consequently lose their identity. The membranes of these vesicles merge with the presynaptic membrane. Little buds of membrane then pinch off into the cytoplasm and become synaptic vesicles. The appropriate proteins are inserted into the membrane of these vesicles, and the vesicles are filled with molecules of the neurotransmitter. The membranes of vesicles in the reserve pool are recycled through a process of bulk endocytosis. (Endocytosis means "the process of entering a cell.") Large pieces of the membrane of the terminal button fold inward, break off, and enter the cytoplasm. New vesicles are formed from small buds that break off of these pieces of membrane. The recycling process takes less than a second for the ready-release pool, a few seconds for the recycling pool, and a few minutes for

the reserve pool. (See Figure 2.28.)

Activation of Receptors LO 2.12 Contrast ionotropic and metabotropic receptors.

How do molecules of a neurotransmitter depolarize or hyperpolarize the postsynaptic membrane? Neurotransmitter

Figure 2.28

45

Recycling Synaptic Vesicle Membrane

After the synaptic vesicles have released a neurotransmitter into the synaptic cleft, the following takes place: In kiss and run, a vesicle fuses with the presynaptic membrane, releases the neurotransmitter, reseals., leaves the docking site, becomes refilled with the neurotransmitter, and mixes with other vesicles in the terminal button. In merge and recycle, the vesicle completely fuses with the postsynaptic membrane, losing its identity. Extra membrane from fused vesicles pinches off into the cytoplasm and forms vesicles, which are filled with the neurotransmitter. The membranes of vesicles in the reserve pool are recycled through a process of bulk endocytosis. Large pieces of the membrane of the terminal button fold inward, break off, and enter the cytoplasm. New vesicles are formed from small buds that break off of these pieces of membrane.

Kiss and run

Merge and recycle

molecules diffuse across the synaptic cleft and attach to the binding sites of special protein molecules located in the postsynaptic membrane, called postsynaptic receptors. Once binding occurs, the postsynaptic receptors open neurotransmitterdependent ion channels (sometimes called ligand-gated ion channels), which permit the passage of specific ions into or out of the cell. The presence of the neurotransmitter in the synaptic cleft aJllows particular ions to pass through the postsynaptic membrane, changing the local membrane potential. Notice that neurotransmitter molecules bind to specific binding sites on the receptors and cannot enter into the postsynaptic cellonly ions can enter the cell through ion channels. Neurotransmitters open ion channels by at least two different methods: direct and indirect. The direct method is simpler, so we will describe it first. Figure 2.29 illustrates a neurolt ransmitter-dependent ion channel that is equipped with its own binding site. When a molecule of the appropriate neurotransmitter attaches to it, the ion channel opens. The formal name for this combination receptor/ion channel is an ionotropic receptor.

46

Chapter 2

Figure 2.29

lonot ropic Receptors

The ion channel opens w hen a molecule of a neurotransmitter attaches to the binding site. For purposes of clarity the drawing is schematic; molecules of neurotransmitters are actually much larger than individual ions.

Molecule of Binding site of receptor

\. ~-

CI o se d ion channel

to the membrane-a G protein. When a molecule of the neurotransmitter binds with a metabotropic receptor, the receptor activates a G protein situated inside the membrane next to the receptor. When activated, the G protein activates an enzyme that stimulates the production of a chemical call1?d a second messenger. (The neurotransmitter is the first messenger.) Molecules of the second messenger travel through the cytoplasm, attach themselves to nearby ion channels, and cause them to open. Compared with the effects produced by ionotropic receptors, those: produced by metabotropic receptors (also called G-proteiin-coupled receptors) take longer to begin and last longer. (S1?e Figure 2.30.) The original second messenger to be discovered was CIJclic AMP, a chemical that is synthesized from ATP. Since then, several other second messengers have been discovered. As you will see in later chapters, second messengers play an important role: in both synaptic and nonsynaptic communication. And they can do more than open ion channels. For example, they can travel to the nucleus or other regions of the neuron and initiate biochemical changes that affect the functions of the cell. They can even turn specific genes on or off, controlling; the production of particular proteins.

Postsyna ptic Potentials The indirect method of opening ion channels is more complicated. Ligand binding to some receptors does not open ion channels directly but instead starts a chain of chemical events. These receptors are called metabotropic receptors because they involve steps that require that the cell expend metabolic energy. Metabotropic receptors are located in close proximity to another protein attached

Figure 2.30

LO 2.13 Com.pare EPSPs and IPSPs in postsynaptic cells . As we mentioned earlier, postsynaptic potentials can be either depolarizing (excitatory) or hyperpolarizing (inhibitory). What determines the nature of the postsynaptic potential at a particular synapse is not the neurotransmitter itself. Instead, it is determined by the characteristics of the

Metabotropic Receptors

When a molecule of neurotransmitter binds with a receptor, a chain of chemical events is initiated. The end result of the chain of events is to indirectly open an ion channel or produce another intracellular change in the c ell. Molecule of neurotransmitter

~

Metabotropic Receptor

8 / Ions

Structure and Functions of Cells of the Nervous System

Figure 2.31

47

Ionic Movements During Postsynaptic Potentials

Outside of Cell

+

+

+

Cl a

Influx of Na+ causes depolarization (EPSP)

b Efflux of K+ causes hyperpolarization (IPSP)

postsynaptic receptors-more specifically, by the particular type of ion channel they open. There are four major types of neurotransmitterdependent ion channels found in the postsynaptic membrane: sodium (Na+), potassium (K+), chloride (Ci-), and calcium (Ca 2+). (See Figure 2.31.) The neurotransmitter-dependent sodium channel is the most importan t source of excitatory postsynaptic potentials. As we have seen, sodium-potassium transporters concentrate sodium outside the cell, waiting for the forces of diffusion and electrostatic pressure to push it in. When sodium channels are opened, the result is a depolarization- an excitatory postsynaptic potential (EPSP). (See Figure 2.3la.) We also saw that sodium- potassium transporters maintain a small surplus of potassium ions inside the cell. If potassium channels open, some of these cations will follow this gradient and leave the cell. Because K+ is positively charged, its outflow will hyperpolarize the membrane, producing an inhibitory postsynaptic potential (IPSP). (See Figure 2.3lb.) At many synapses, inhibitory neurotransmitters open the chloride channels, instead of (or in addition to) potassium channels. The effect of opening chloride channels depends on the membrane potential of the neuron. If the membrane is at the resting potential, nothing happens, because (as we saw earlier) the forces of diffusion and electrostatic pressure balance perfectly for the chloride ion. However, if the membrane potential has already been depolarized by the activity of excitatory synapses located nearby, then opening chloride channels will permit er to enter the cell. The influx of anions (negatively charged ions) will bring the membrane potential

c

Influx of c1- causes hyperpolarization (IPSP) d Influx of Ca 2 + acti vates enzyme

back to its normal resting condition. In this way, opening chloride channels helps neutralize EPSPs. (See Figure 2.31c.) The fourth type of neurotransmitter-dependent ion channiel is the calcium channel. Calcium ions (Ca2+), being positively charged and being located in highest concentration oiutside the cell, move like sodium ions. Opening calcium channels depolarizes the membrane, producing EPSPs. But cailcium does even more. For example, when calcium enters the terminal button, it triggers the migration of synaptic vesicles and the release of the neurotransmitter. In the dendriites of the postsynaptic cell, calcium binds with and activates: special enzymes. These enzymes have a variety of effects, including the production of biochemical and structural chang1~s in the postsynaptic neuron. (See Figure 2.3ld.)

Effects of Postsynaptic Potentials: Neural Integration LO 2.114 Summarize neural integration of EPSPs and IPSPs. The interaction of the effects of excitatory and inhibitory synapses on a particular neuron is called neural integration. The rate at which a neuron fires actional potentials is controlled by the relative activity of the excitatory and inhibito1ry synapses on its dendrites and soma. If the activity of exciitatory synapses goes up, the rate of action potential firing will increase. If the activity of inhibitory synapses goes up, the rate of action potential firing will decrease. Figure 2.32 illustrates the effects of excitatory and inhibitory synapses on a postsynaptic neuron. The left panel shows what happens when several excitatory synapses become

48 Chapter 2

Figure 2.32 Neural Integration (a) If several excitatory synapses are active at the same time, the EPSPs they produce (shown in red) summate as they travel toward the axon, and the axon fires. (b} If several inhibitory synapses are active at the same time, the IPSPs they produce (shown in blue) diminish the size of the EPSPs and prevent the axon from firing. Activity of inhibitory synapses produces IPSPs (blue) in postsynaptic neuron

Activity of excitatory synapses produces EPSPs (red) in postsynaptic neuron

Axon hillock reaches threshold of excitation; action potential is triggered in axon (a)

active. The release of a neurotransmitter produces depolarizing EPSPs in the dendrites of the neuron. These EPSPs (represented in red) are then transmitted down the dendrites, across the soma, to the axon hillock located at the base of the axon. If the depolarization is still strong enough to rise above the threshold of excitation when it reaches this point, the axon will fire an action potential. (See Figure 2.32a.) Let's consider what would happen if, at the same time, inhibitory synapses also become active. IPSPs are hyperpolarizing-they bring the membrane potential away from the threshold of excitation and tend to cancel the effects of EPSPs. (See Figure 2.32b.) Note that neural inhibition (that is, an inhibitory postsynaptic potential) does not always produce behavioral inhibition. For example, suppose a group of neurons inhibits a particular movement. If these neurons are inhibited, they will no longer suppress the behavior. Inhibiting the inhibiton; neurons makes the behavior more likely to occur. Of course, the same is true for neural excitation. Excitation of neurons that inhibit a behavior suppresses that behavior. For example, when we are dreaming, a particular set of inhibitory neurons in the brain becomes active and prevents us from getting up and acting out our dreams. (As we will see in Chapter 9, if these neurons are damaged, people will act out their dreams.) Neurons are elements in complex circuits. Without knowing the details of these circuits, you cannot predict the effects of exciting or inhibiting one set of neurons on behavior.

IPSPs counteract EPSPs; action potential is not triggered in axon (b}

Termination of Postsynaptic Potentials LO 2.15 Explain how postsynaptic potentials are terminated. Postsynaptic potentials are depolarizations or hyperpolarizations caused by the activation of postsynaptic receptors with molecules of a neurotransmitter. Postsynaptic potentials are terminated by two mechanisms: reuptake and enzymatic deactivation of neurotransmitter molecules. REUPTAKE The postsynaptic potentials produced by most neurotransmitters are terminated by reuptake. This process is an 'e xtremely rapid removal of neurotransmitter from the synaptic cleft by the terminal but ton. The neurotransmitter does not return in the vesicles that get pinched off t he membrane of the terminal button. Instead, the membrane contains special transporter molecules that draw on the cell's energy reserves to force molecu les of t:he neurotransmitter from the synaptic cleft directly into lthe cytoplasm-just as sodium-potassium transporters move Na+ and K+ across the membran e. When an action potential arrives, th e terminal button releases a smalll amount of neurotransmit ter into the synaptic cleft and then takes it back, giving the postsynaptic receptors only a brief exposure to the neurotransmitter. (See Figure 2.33.)

Structure and Functions of Cells of the Nervous System

Figure 2.33

49

Reuptake

Molecules of a neurotransmitter released into the synaptic cleft are transported back into the presynaptic terminal button.

Molecules of neurotransmitter returned to terminal button

/

• •

•

ENZYMATIC DEACTIVATION Enzymatic deactivation is accomplished by an enzyme that destroys molecules of the neurotransmitter. For example, postsynaptic potentials are terminated in this way for acetykholine (ACh) and for neurotransmitters that consist of peptide molecules. Transmission at synapses on muscle fibers and at some synapses between neurons in the CNS is mediated by ACh. Postsynaptic potentials produced by ACh are short lived because the postsynaptic membrane at these synapses contains an enzyme called acetykholinesterase (AChE). AChE destroys ACh by breaking it into its constituents: choline and acetate. Because neither of these substances is capable of activating postsynaptic receptors, the postsynaptic potential is terminated once the molecules of ACh are broken apart. Kathryn, the woman featured in the case study that opened this chapter, had progressive muscular weakness. As her neurologist discovered, Kathryn had myasthenia gravis, a disease in which the immune system destroys ACh receptors, reducing the amount of information conveyed from the ACh system to the muscles, and resulting in muscle weakness. Her physician administered Kathryn a drug that blocks AChE. The result of administering this drug was to increase the amount of ACh available in the synapse (because it was not broken down by AChE).

•

•

•

"Omega figure"remnants of synaptic vesicle that has released its neurotransmitter

• • •

• • • • Postsynaptic • receptor • • ,, • • • • • · f: • •

Although she still lacked a large number of ACh receptors, the increased ACh in the synapse sufficiently flooded her remaining ACh receptors and amplified the message to her miuscles. As a result, Kathryn's ACh system could once again convey messages to her muscles, and her muscle weakness was reversed.

Autoreceptors LO 2.116 Distinguish autoreceptors from postsynaptic receptors.

Postsynaptic receptors detect the presence of a neurotransmitter in the synaptic cleft and initiateexcita tory or inhibitory postsynaptic potentials. But the postsynaptic membrane is not the only place where receptors respond to neurotransmitters. Many neurons also possess receptors that

respond to the neurotransmitter that they themselves release, called autoreceptors, from the Greek auto, meaning "s,elf" or "same." Autoreceptors are part of a negative feedback mechanism that allows presynaptic cells to monitor the amount of neurotransmitter they release into the synapse and adjust the amounts to fine-tune their chemical message. This system prevents the presynaptic cell from releasing too much or too little neurotransmitter.

50 Chapter 2

Autoreceptors can be located on the membrane of any part of the cell, but we will focus on those located on the terminal button. In most cases, these autoreceptors do not control ion channels. When stimulated by a molecule of the neurotransmitter, autoreceptors do not produce changes in the membrane potential of the terminal button. Instead, they regulate internal processes, including the synthesis and release of the neurotransmitter. In most cases the effects of autoreceptor activation are inhibitory. When a neurotransmitter binds to an autoreceptor, it typically decreases the rate of synthesis or release of the neurotransmitter from the presynaptic cell. Most researchers believe that autoreceptors are part of a regulatory system that controls the amount of neurotransmitter that is released. If too much neurotransmitter is released, the autoreceptors inhibit both production and release. If too little neurotransmitter is released, the rates of production and release go up.

Other Types of Synapses LO 2.17 Identify synapses other than those involved in

neural integration. So far, the discussion of synaptic activity has referred only to the effects of postsynaptic excitation or inhibition. These effects occur when terminal synapses occur on postsynaptic dendrites or somas. Synapses can also occur on axons. These synapses work differently. Axoaxonic synapses do not contribute directly to neural integration. Instead, they alter the amount of neurotransmitter released by the terminal buttons of the postsynaptic axon. They can produce presynaptic modulation: presynaptic inhibition or presynaptic facilitation. The release of a neurotransmitter by a terminal button is initiated by an action potential. Normally, a particular terminal button releases a fixed amount of neurotransmitter each time an action potential arrives. However, the release of a neurotransmitter can be modulated by the activity of axoaxonic synapses. If the activity of the axoaxonic synapse decreases the release of the neurotransmitter, the effect is called presynaptic inhibition. If it increases the release, it is called presynaptic facilitation. (See Figure 2.34.) By the way, as we will see in Chapter 4, a psychoactive chemical in marijuana exerts its effects on the brain by binding with presynaptic receptors. Many very small neurons have extremely short processes and apparently lack axons. These neurons form dendrodendritic synapses, or synapses between dendrites. Because these neurons lack long axonal processes, they do not transmit information from place to place within the

brain. Most investigators believe that they perform regulatory functions, perhaps helping to organize the activity of groups of neuirons. Some larger neurons also form dendrodendritic synapses. Some of these synapses are chemical, indicated by the presence of synaptic vesicles in one of the juxtaposed dendrites and a postsynaptic thickening in the membrane of the other. Other synapses are electrical. The membranes of the cells meet and almost touch, forming a gap junction. The membranes on both sides of a gap junction contain chanl1lels that permit ions to diffuse from one cell to another. Thus, changes in the membrane potential of one neuron induce changes in the membrane of the other. Although most gap junctions in vertebrate synapses are dendrodendritic, gap junctions at postsynaptic dendrites and somas can also occur. Gap junctions are common in invertebrates. Their functions in the vertebra te nervous system are currently under investigation. Electrical synapses appear to play important roles in the vertebrate retina, olfactory bulb, cerebral cortex, hippocampus, suprachiasmatic nucleus, hypothalamus, medulla, spinal cord, and parts of the thalamus and enteric nervous system (part of the nervous system in the gastrointestinal system) (Nagy et al., 2017).

Figure 2.34, An Axoaxonic Synapse The activity of terminal button A can increase or decrease the amount of neurotransmitter released by terminal button B.

~~~.,,.Z'c"T

Terminal "\. button B "\.

spine

Axoaxonic synapse

Structure and Functions of Cells of the Nervous System

N onsynaptic Chemical Communication LO 2.18 Describe examples of nonsyn aptic communication.

Neurotransmitters are released by terminal buttons of neurons and bind with receptors in the membrane of another cell located a very short distance away. The communication at each synapse is private and typically only involves the presynaptic and postsynaptic cell in the synapse. Neuromodulators are chemicals released by neurons that travel farther and are dispersed more widely than are neurotransmitters. Most neuromodulators are peptides, chains of amino acids. Neuromodulators are secreted in larger amounts and diffuse for longer distances, modulating the activity of many neurons in a particular part of the brain. For example, neuromodulators affect general behavioral states such as vigilance, fearfulness, and sensitivity to pain. Chapter 4 discusses the most important neurotransmitters and neuromodulators in greater detail. Hormones are secreted by cells of endocrine glands or by cells located in various organs, such as the stomach, the intestines, the kidneys, and the brain. Cells that secrete hormones release these chemicals into the extracelluJar fluid. The hormones are then distributed to the rest of the body through the bloodstream. Hormones affect the activity of cells (including neurons) that contain specialized receptors located either on the surface of their membrane or deep within their nuclei. Cells that contain receptors for a particular hormone are referred to as target cells for that hormone, and only these cells respond to its presence. Many neurons contain hormone receptors, and hormones are able to affect behavior by stimulating the receptors and changing the activity of these neurons. For example, a sex hormone, testosterone, increases the aggressiveness of most male mammals. Peptide hormones exert their effects on target cells by stimulating metabotropic receptors located in the membrane. The second messenger that is generated travels to the nucleus of the cell, where it initiates changes in the cell's physiological processes. Steroid hormones consist of very small fat-soluble molecules. Examples of steroid hormones include the sex hormones secreted by the ovaries and testes and the hormones secreted by the adrenal cortex. Because steroid hormones are soluble in lipids, they pass easily through the cell membrane. They travel to the nucleus, where they attach themselves to receptors located there. The receptors,

51

stimulated by the hormone, then direct the machinery of the cell to alter its protein production. (See Figure 2.35.) In the past few years, investigators have discovered the presence of steroid receptors in terminal buttons and around the postsynaptic membrane of some neurons. These steroid receptors influence synaptic transmission, and they do so irapidly. Exactly how they work is still not known.

Figure 2.35 Action of Steroid Hormones Steroid hormones affect their target cells by means of specialized receptors in the nucleus. Once a receptor binds with a molecule of a steroid hormone, it causes genetic mechanisms to initiate protein synthesis.

Detail of Cell

Steroid receptor

Cell membrane Hormone binds with steroid receptor, which directs chromosome to initiate protein synthesis

52 Chapter 2

Module Review: Communication Between Neurons Structure of Synapses LO 2.10 Identify the presynaptic structures involved in synaptic communication.

The presynaptic membrane faces the postsynaptic membrane across the synaptic cleft. Presynaptic cells contain synaptic vesicles filled with neurotransmitters. Transport proteins fill vesicles with the neurotransmitters, and trafficking proteins are involved in releasing neurotransmitters and recycling the vesicles.

Effects of Postsynaptic Potentials: Neural Integration LO 2.14 Summarize neural integration of EPSPs and

IPSJPs.

Release of Neurotransmitters

Neurons receive multiple subthreshold EPSPs and IPSPs. The neuron integrates these messages. If the integrated messages result in depolarization beyond the threshold of excitation for the cell, the neuron will fire an action potential. If the messages are IPSPs or do not reach the threshold of excitation, the neuron will not fire an action potential.

LO 2.11 Describe the process of neurotransmitter release.

Terminatiom of Postsynaptic Potentials

Following an action potential, neurotransmitter is released from vesicles in the presynaptic cell that move and dock with the terminal membrane. Docking and creating a fusion pore is triggered by the influx of calcium ions. The neurotransmitter is released into the synaptic gap through the fusion pore. Following release, the membranes of the vesicles are recycled and return to the pool of available vesicles.

Activation of Receptors LO 2.12 Contrast ionotropic and metabotropic receptors.

Ionotropic receptors open ion channels in direct response to the binding of a ligand. Metabotropic receptors can indirectly open ion channels through the use of a G protein. Metabotropic receptors can also activate a second messenger system that can communicate with the nucleus or other regions of the neuron and initiate biochemical changes that affect the functions of the cell. Second messengers can also turn specific genes on or off to initiate or terminate production of particular proteins.

Postsynaptic Potentials LO 2.13 Compare EPSPs and IPSPs in postsynaptic cells. In the postsynaptic cell, an EPSP is a depolarization resulting from the entry of sodium or calcium ions into the cell through a neurotransmitter-dependent ion channel. In the dendrites of the postsynaptic cell, calcium can also bind with enzymes that have a variety of effects. An IPSP is a hyperpolarization resulting from the exit of potassium ions from or the entry of chloride ions into the cell through a neurotransmitter-dependent ion channel.

LO 2.15 Explain how postsynaptic potentials are tem1inated.

Postsynaptic JPOtentials can be terminated by removing a neu rotransmitter from the synapse through reuptake transporters or through enzymatic deactivation.

Autoreceptors LO 2.16 Disttinguish autoreceptors from postsynaptic receptors.

Postsynaptic receptors are located on the postsynaptic membrane arnd serve to convey a message to the postsynaptic cell. Postsynaptic receptors can be ionotropic or metabotropic. Autoreceptors are metabotropic receptors located on the presynaptic membrane that help regulate the amount of neurotransmitter that is released.

Other Types of Synapses LO 2.17 Identify synapses other than those involved in neural integration.

Axoaxonic synapses can modulate the release of neurotransmitters into a synapse via presynaptic inhibition or facilitation . Dendrodendritic synapses likely perform regulatory functions. Gap junctions between neurons permit changes in the membrane potential of one neuron to induce changes in the membrane of the other.

Nonsynaptic Chemical Communication LO 2.18 Describe examples of nonsynaptic com munication.

Neuromodul.ators are chemicals released by neurons that travel farther and are dispersed more widely than are neurotransmitters. Hormones are secreted by cells of endocrine glands or by cells located in various organs.

Structure and Functions of Cells of the Nervous System

The hormones are then distributed to the rest of the body through the bloodstream.

Thought Question

53

drugs block the reuptake of neurotransmitters. Describe the efJfect of blocking reuptake at the synapse. Will the amouint of neurotransmitter available in the synapse increase, decrease, or stay the same? Explain your answer.

Many drugs that change behavior produce their effects by interacting with receptor sites or reuptake sites. For example, some antidepressant drugs and stimulant

Chapter Review Questions 1. Name and describe the parts of a neuron, and explain their functions. 2. Describe the supporting cells of the central and peripheral nervous systems, and explain the bloodbrain barrier. 3. Explain how the forces of diffusion and electrostatic pressure contribute to resting membrane potential. 4. What is the role of ion channels in action potentials, and what are the all-or-none law and the rate law?

5. Describe the structure of synapses, the release of the neurotransmitter, and the activation of postsynaptic receptors. 6. E)(plain postsynaptic potentials: the ionic movements that cause them, the processes that terminate them, and their integration. 7. Describe the regulation of the effects of the neurotransmitters by autoreceptors, presynaptic inhibition, presynaptic facilitation, and nonsynaptic communication.

Chapter 3

Structure of the

Nervous System

The structures of the human nervous system are made up of billions of neurons that make trillions of synapses.

Chapter Outline Basic Features of the Nervous System Anatomical Directions The Meninges and Ventricular System Structure and Function of the Central Nervous System (CNS)

54

The Hindbrain: Metencephalon and Myelencephalon The Spinal Cord Structure and Function of the Peripheral Nervous System (PNS)

The Forebrain: Telencephalon

Cranial Nerves

The Forebrain: Diencephalon The Midbrain: Mesencephalon

Spinal Ne!rves The Autonomic Nervous System

Structure of the Nervous System

m

55

Learning Objectives

LO 3.1

Apply anatomical terms to the nervous system.

LO 3.2

Compare the locations and functions of the meninges and ventricular system.

LO

Identify the locations and functions of the structures of the telencephalon.

LO 3.H

LO 3.3

LO 3.15

3.'7

LO 3.4

Identify the locations and functions of the structures of the diencephalon.

LO

3.!9

LO 3.5

Identify the locations and functions of the structures of the mesencephalon.

LO 3:10

Contrast the locations and functions of the structures of the metencephalon and myelencephalon. Describe the structure and functions of the spinal cord. Identify the functions of the cranial nerves. Differentiate the afferent and efferent axons of the spinal nerves. Compare the sympathetic and parasympathetic divisions of the autonomic nervous system.

Ryan, a first-year college student, had a focal-seizure disorder

several injections of a local anesthetic. He then cut the scalp

and had experienced occasional seizures since childhood. His seizures originated from a region of the brain that contained

ancl injected more anesthetic. Finally, Dr. L. removed a piece of skull. He cut and folded back the thick membrane that covers

some scar tissue, which was probably a result of brain damage that occurred at birth. Periodically, this region would irritate the

the brain, exposing the surface. When removing a seizure focus, the surgeon wants to cut

surrounding areas, triggering seizures- uncontrolled, sustained

away all the scar tissue while sparing healthy brain tissue that

firing of cerebral neurons - that resulted in cognitive disruption

performs important functions, such as speech comprehension

and, sometimes, uncontrolled movements.

ancl production. For this reason, Dr. L. began stimulating parts

His neurologist prescribed a medication to control the seizures, but lately, the medication wasn't helping and his seizures

of tlhe brain to determine which regions he could safely remove. He stimulated the surface of Ryan's brain with a weak electri-

were becoming more frequent. His doctor increased the dose of the medication, but the seizures continued. The drug made

cal current. The stimulation d isrupts the firing patterns of the neurons located near the current, preventing them from carry-

it difficult for Ryan to concentrate. He was afraid he would have to drop out of school. His neurologist eventually recommended

ing out their normal functions. Stimulating parts of the temporal lob13 disrupted Ryan's ability to understand what he was saying.

seizure surgery and referred him to Dr. L., a surgeon.

When Dr. L removed the part of the brain containing the seizure

Ryan was surprised to learn that he would remain awake during his surgery. He was nervous as he was wheeled into the surgery,

focus, he was careful not to damage these regions. The operation was successful. Ryan continued to take his

but after the anesthesiologist gave him a sedative, Ryan relaxed. In preparation for the surgery, Dr. L. shaved Ryan's scalp,

ancl he found it easier to concentrate in class. He went on to

marked where incisions would be made, and then gave Ryan

have a very successful college career.

Ryan's story illustrates the importance of understanding the structures and functions of the nervous system. The overall goal of neuroscience research is to increase our understanding of how the nervous system works. With this knowledge, we may be able to improve health and wellbeing for people like Ryan and many others. To understand the results of this research, you must be familiar with the basic structure of the nervous system. This chapter contains only part of the large body of information about nervous system structures and their associated functions. In Chapter 2, you learned about some of the smallest units of the nervous system: neurons and supporting cells. In this chapter, you'll learn about larger structures of the nervous system that are made up of neurons and supporting cells.

medication but at a much lower dose. His seizures disappeared,

The forst module introduces the basic structures of the nervous system. The second and third modules describe the central and peripheral nervous systems, respectively.

Basic Features of the Nervous System The nervous system is divided into two main parts: the central nervous Stjstem and the peripheral nervous system. The central nervous system (CNS) consists of the brain and spinal cord . The peripheral nervous system (PNS) consists of the cranial nerves:, spinal nerves, and peripheral ganglia. The CNS is encased '.in bone: The brain is covered by the tough, bony skull,

56

Chapter 3

Figure 3.1

The Nervous System

This figure shows the relationship of the nervous system to the rest of the body.

interruption of the blood flow to the brain uses up much of the dissolved oxygen, and a 6-second interruption produces unconsciousness. After only a few minutes without blood flow, permanent brain damage results.

Meninges

Anatomical Directions LO 3.1

Spinal nerves

and the spinal cord is contained within the vertebral column. (See Figure 3.1.) The brain is made up of neurons, glia, and other supporting cells and floats in a pool of cerebrospinal fluid (CSF). The brain requires a large supply of blood and is chemically protected by the blood-brain barrier. The brain continuously receives approximately 20 percent of the blood flow from the heart. Other parts of the body, such as the skeletal muscles or digestive system, receive varying quantities of blood, depending on their needs. In contrast, the brain always receives its share. The brain can store only a small amount of its fuel (primarily glucose), so consistent blood supply is essential. A 1-second

Apply anatomical terms to the nervous system.

Before beginning a detailed description of the nervous system, let's discuss the terms that are used to describe it. Early anatomists named most brain structures according to their similarity to objects they were familiar with: amygdala, or "almond-shaped object"; hippocampus, or "sea horse"; genu, or "knee"; cortex, or "tree bark"; pons, or "bridge"; uncus, or "ho•ok," to give a few examples. Knowing these roots can sometimes make the terms easier to remember. For example, !knowing that cortex means "bark" (of a tree) can help you to remember that the cortex is the outer layer of the brain (and of other structures, like the kidneys, too). When describing features of a structure as complex as the brain, it's helpful to use terms to indicate directions. Directions in the nervous system are usually described relative to the neuraxis, an imaginary line drawn through the length of the central nervous system, ranging from the bottom of the spinal cord up to the front of the brain. First, let's consider an animal with a straight neuraxis. Figure 3.2 shows an alligator and two humans. This alligator is linear, and we can draw a straight line that starts between its eyes and continues down the center of its spinal cord. The front end is anterior, and the tail is posterior. The terms rostral (toward the nose and mouth) and caudal (toward the tail) are also used, especially when referring specifically to the brain. The top of the head and the back are part of the dorsal surface, while the ventral (front) surface faces the ground. (Dorsum means "back," and ventrum means "belly.") These directions are somewhat more complicated in humans because as we stand upright, our neuraxis bends, so the top of the head is pe1cpendicular to the back. Neuroanatomists also use the terms superior and inferior. In the brain, superior means "above," and inferior means "below." For example, the superior colliculi are located above the inferior colliculi. The frontal views of both the alligator and the human illustrate the terms lateral (towardl the side) and medial (toward the middle,). Two other useful anatomical terms are ipsilateral and contralateral. lpsilateral refers to structures on the same side of the body. If we say that the olfactory bulb projects axons to the ipsilateral hemisphere, we mean that axons originating in the left olfactory bulb of the brain terminate in the left hemisphere, and axons originating in the right olfactory bulb terminate in the right hemisphere. Contralateral refers to struc1tures on op posite sides of the body. If we say that a particular region in the left hemisphere of the brain controls movements of the contralateral hand, we mean that the region controls movements of the right hand.

Structure of the Nervous System

Figure 3.2

Anatomical Directions and Planes Dorsal

Coronal plane (frontal section) Horizontal plane

Sagittal plane

Caudal

(a) Transverse plane (cross section)

Caudal

Ventral

Dorsal Dorsal

Dorsal Rostralor ~ anterior ~~

, 1

Dorsal Neuraxis

(b}

Caudal or posterior

Caudal or posterior

57

58 Chapter 3 To see what is in the nervous system, we have to cut it open. To be able to convey information about what we find, researchers slice it in a standard way. Figure 3.2 shows the human nervous system. The nervous system is usually sliced in three standard ways: 1. Coronally, like slicing a loaf of bread, creating cross

sections (also known as frontal sections when referring to the brain). A coronal cut to the middle of the brain would divide the brain into front and back halves. 2. Parallel to the ground, creating horizontal sections. A parallel cut to the middle of the brain would result in cutting off the upper half of the brain. 3. Perpendicular to the ground and parallel to the neuraxis, creating sagittal sections. The midsagittal plane divides the brain into two symmetrical right and left halves. Figure 3.2a shows a midsagittal cut. Note that because of our upright posture, human cross sections of the spinal cord are parallel to the ground.

The Meninges and Ventricular System LO 3.2

Compare the locations and functions of the meninges and ventricular system.

The entire nervous system-brain, spinal cord, cranial and spinal nerves, and peripheral ganglia- is covered by tough connective tissue. The protective sheaths around the brain and spinal cord are referred to as the meninges (from the Greek word for "membrane"). The meninges consist of three layers, which are shown in Figure 3.3. The outer layer, called dura mater, is durable, thick, tough, and flexible but unstretchable. The middle layer of the meninges, the arachnoid membrane, gets its name from the weblike appearance of the arachnoid trabeculae that protrude from it (from the Greek arachne, meaning "spider"; trabecula means "track"). The arachnoid membrane, soft and spongy, lies beneath the dura

mater. Closely attached to the brain and spinal cord, and following every :surface convolution, is the pia mater ("pious mother"). The smaller surface blood vessels of the brain and spinal cord are contained within this layer. Between the pia mater and arachnoid membrane is a gap called the subarachnoid space. This space is filled with cerebrospinal fluid (CSF). The peripheral nervous system is covered with two layers of meninges. Tlhe middle layer (arachnoid membrane), with its associated pool of CSP, covers only the brain and spinal cord. Outside the central nervous system, the outer and inner layers (dura mater and pia mater) fuse and form a sheath that covers the spinal nerves, cranial nerves, and the peripheral ganglia. The ventricular system of the brain consists of a series of hollow, interconnected chambers called ventricles ("little bellies"), which aire filled with CSF. (See Figure 3.4.) The largest two chambers, the lateral ventricles, are connected to the third ventricle. The third ventricle is located at the midline of the brain, and its walls divide the surrounding parts of the brain into symmetrical halves. A bridge of neural tissue called the massa intermedia crosses through the middle of the third ventricle and makes .a convenient landmairk. The cerebral aqueduct, a long tube, connects the third ventricle to the fourth ventricle. The ventricles are more than just empty spaces in the brain. They serve the very importan t function of producing and containing; CSF. CSF is made by special tissue with a rich blood supply called the choroid plexus, which extends into all four of the ventricles. Once CSF is produced by the choroid plexus in the lateral ventricles, it flows into the third ventricle. More CSF is p roduced in this ventricle, and it then flows through the cerebral aqueduct to the fourth ventricle, where still more CSF is produced. The CSF leaves the fourth ventricle through small openings that connect with the subarachnoid space surrounding the brain. The CSF then flows through the subairachnoid space around the CNS, where it is reabsorbed into the blood supply through the arachnoid granulations. The brain. is very soft and jellylike. The considerable weight of a human brain (approximately 1400 g), along with its delicate construction, requires that it be protected

Figure 3.3 Men inges

Dura mater

Layers of { meninges

Arachnoid trabeculae Pia mater Surface of brain (a)

(b)

Structure of the Nervous System

Figure 3 .4

59

The Ventricu lar System and Production of Cerebrospinal Fluid (CSF)

The figure shows (a) a lateral view of the left side of the brain and (b) the production, circulation, and reabsorption of cerebrospinal fluid. CSF is produced within the ventricles by the choroid plexus and circulates through the ventricular system (shown by the arrows), eventually being reabsorbed into the blood supply in the subarachnoid space. Lateral ventricle

Lateral

ventricle

Third ventricle Massa intermedia Cerebral aqueduct

Fourth ventricle

Third ventricle

Cerebral ----aqueduct Fourth ventricle

(b)

(a)

Arachnoid granulation

Choroid plexus olf lateral ventricle Lateral ventricle Third ventricle

Fourth ventricle

Superior sagittal sinus Choroid plexus of third ventricle

s,b.,l,oid·:i~ft·~ space Cerebral aqueduct

(c)

from shock. Fortunately, the intact brain within a living human is very well protected. It floats in a bath of CSF contained within the subarachnoid space. Because the brain is completely immersed in liquid, its net weight is reduced to approximately 80 g. As a result, pressure on the base of the brain is considerably reduced. The CSF surrounding the brain and spinal cord also helps reduce the shock to the CNS that would be caused by sudden head movement. Occasionally, the flow of CSF is interrupted at some point in its route of passage. For example, a brain tumor growing in the midbrain may push against the cerebral aqueduct, blocking the flow of CSF, or an infant may be born with a cerebral aqueduct that is too small to accommodate a normal flow of CSF. This occlusion results in greatly increased pressure within the ventricles,

Third ventricle Choroid plexus of fou rth ventricle

Subarachnoid space Opening into subarachnoid space

(d)

because the choroid plexus continues to produce CSE The walls of the ventricles then expand and produce a condition known as obs tructive h ydrocephalus (hydrocephalus means "waterhead")i. If the obstruction remains and if nothing is done to reverse the increased intracerebral pressure, blood vessels will be occluded, and permanent-perhaps fatal-brain damage will occur. ]Fortunately, a surgeon can usually operate on the person, drilling a hole through the skull and inserting a shunt tube into one of the ventricles. The tube is then placed beneath the skin and connected to a pressure relief valve that is implanted in the abdominal cavity. When the pressure in the ventricles becomes excessiive, the valve permits the CSP to escape into the abdomen, where it is eventually reabsorbed into the blood supply. (See Fi,gure 3.5.)

60

Chapter 3

Module Review: Basic Features of the f\Jervous System Anatomical Directions LO 3.1 Apply anatomical terms to the nervous system. Anterior and rostral refer to the front of the nervous system. Posterior and caudal refer to the back of the nervous system. Dorsal refers to the top of the brain, head, and the back, while ventral refers to the "belly" side of the nervous system. Superior means above, and inferior means below. Medial refers to a position along the midline, and lateral refers to a position to the side. A frontal section is the result of a coronal cut; a horizontal section is the result of a cut parallel to the ground, and a sagittal section results from a cut that is perpendicular to the ground and parallel to the neuraxis in the human brain.

The Meninges and Ventricular System LO 3.2 Compare the locations and functions of the meninges and ventricular system. The meninges protect the nervous system and cover the surface of the brain, extending along the spinal cord, nerves, and peripheral ganglia. The dura mater is the outer layer of the meninges. The arachnoid membrane

Figure 3.5

Hydrocephalus in an Infant

A surgeon places a shunt tube in a lateral ventricle, which permits cerebrospinal fluid to escape to the abdominal cavity, where it is absorbed into the blood supply. A pressure valve regulates the flow of CSF through the shunt.

is the middle layer of the meninges. The pia mater is the inner layier of the meninges. The ventricular system consists of four ventricles filled with cerebrospinal fluid. CSF is generated by the choroid plexus within the ventricles. CSF flows from the lateral ventricles, to the third ventricle, along the cerebral aqueduct, and into the fourth vel!1tricle. CSF then flows into the subarachnoid space arnd is reabsorbed into the blood. CSF functions to proteict the brain by distributing its weight and absorbing shock.

Thought Question When studying the brain, many neuroscientists use a reference tool called a brain atlas. Just like a road atlas can help you find your way to a new location, a brain atlas can help a resiearcher find a location in the brain. Instead of using compass directions like north, south, east, and west, a brain atlas uses anatomical directions, like anterior and posterior, and section directions, like coronal or sagittal. Practice using anatomical direction terms by writing directions for navigating from the center of the brain to the cortex located at the most anterior point of the brain, or from the ventral surface of the brain to the most caudal point in the cortex.

Structt1re and Function of the (=entral Nervous Systerrt (CNS) Understanding the basic features of the central nervous system can make learning about the locations of important structures easier. Table 3.1 summarizes many of the terms introduced in this section and includes some of the major structures found in each part of the brain. The table shows the major divisions (forebrain, midbrain, hindbrain) arnd subdivisions (telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon) of the brain, along with the ventricles and principal brain structures found within them. Figure 3.6 shows the locations of many of the corresponding structures in the adult, human brain. These structures will be described in the remainder of the chapter, and will be organized by subdivisions.

Structure of the Nervous System

Table 3.1 Anatomical Subdivisions of the Brain

61

Figu1re 3.6 Structures of the Human Brain This is a lateral view of the left side of a semitransparent human brain W'ith the brain stem "ghosted in." The colors in Table 3.1 denote corresponding regions.

Cerebral cortex Lateral

Telencephalon

Forebrain

Basal ganglia Limbic system

Third

Diencephalon

Thalamus Hypothalamus

Midbrain

Cerebral aqueduct

Mesencephalon

Tectum Tegmentum

The Forebrain: Telencephalon LO 3.3

Identify the locations and functions of the structures of the telencephalon.

The forebrain contains two subdivisions: the telencephalon and the diencephalon. (See Figure 3.7.) We will begin with the structures of the telencephalon. Oiencephalon structures will be discussion in the following module. The telencephalon includes most of the two symmetrical cerebral hemispheres. These hemispheres make up the cerebrum. The cerebral hemispheres are made up of the cerebral cortex, the limbic system, and the basal ganglia. The limbic system and basal ganglia are primarily in the subcortical regions of the brain, located beneath the cerebral cortex. The cerebral cortex surrounds the cerebral hemispheres like the bark of a tree. In humans, the cerebral cortex appears folded, or convoluted. These convolutions, consisting of su k i (small grooves), fissures (large grooves), and gyri (bulges between adjacent sulci or

CEREBRAL CORTEX

Figure 3.7 Forebrain The forebrain is the most dorsal division of the brain. The forebrain consists of the telencephalon and the diencephalon.

Diencephalon

fissures), help enlarge the surface area of the cortex, compared with a smooth brain of the same size. The presence of these convolutions triples the area of the cerebral cortex. The toital surface area is approximately 2360 cm 2 (2.5 ft. 2), and the thickness is approximately 3 mm. The cerebral cortex consists mostly of glia and the cell bodies, dendrites, and interconnecting axons of neurons. Because cell bodies predominate, giving the cerebral cortex a grayish tan appearance, it is referred to as gray matter. (See Figure 3.8.) Beneath the cerebral cortex are millions of axons that connect the neurons of the cerebral cortex with those located elsewhere in the brain. The large concentration of myelin gives this tissue, called white matter, an opaque white appearance. Lobes of the Cerebral Cortex Discussing the various regions of the cerebral cortex is easier if we have names for them. The cerebral cortex is divided into four areas, or lobes, named for the bones of the skull that cover them: the frontal lobe, parietal lobe, temporal lobe, and occipital lobe. The brain contains two of each lobe, with one lobe in each hemisphere. The frontal lobe (the "front") includes everything in front of the central sulcus. The parietal lobe (the "wall'') is located on the side of the cerebral hemisphere, just behind the central sulcus, caudal to the frontal lobe. The temporal lobe (the " temple") juts forward from the base of the brain, ventral to the frontal and parietal lobes. The occipital lobe (from the Latin ob, "in back of," and caput, "head") lies at the very back of the brain, caudal to the parietal and temporal lobes. Figure 3.9 shows these lobes in three views of the cerebral hemispheres: a ventral view (a view from the bottom), a midsagittal view (a view of the inner surface of the right hemisphere after the left hemisphere has been removed), and a lateral view.

62

Chapter 3

Figure 3.8 Cross Section of Human Brain This brain slice shows fissures and gyri and the layer of cerebral cortex that follows these convolutions. Dorsal White matter

Cerebral cortex (gray matter)

~(

Gyru'

~ Sensory Cortex Three areas of the cerebral cortex receive information from the sensory organs. The primary visual cortex, which receives visual information, is located in the occipital lobe at the back of the brain, on the inner surfaces of the cerebral hemispheres- primarily on the upper and lower banks of the cakarine fissure. (Calcarine means "spur-shaped." See Figure 3.10.) The primary auditory cortex, which receives auditory information, is located in the temporal lobes, on the lower surface of a deep fissure in the side of the brain- the lateral fissu re. (See the inset in Figure 3.10.) The primary somatosensory cortex, a vertical strip of cortex just caudal to the central sukus in the parietal lobe, receives information from the body senses. (See Figure 3.10.) The base of the somatosensory cortex and a portion of the insular cortex, which is normally hidden from view by the frontal and temporal lobes, receive information about taste. Except for olfaction (smell) and gustation (taste), sensory information from the body or the environment is sent to the primary sensory cortex of the contralateral hemisphere. For example, the primary somatosensory cortex of the left hemisphere learns what the right hand is holding, and the left primary visual cortex learns what is happening toward the person's right. Sensory Association Cortex The regions of primary sensory and motor cortex occupy only a small part of the cerebral cortex. The rest of the cerebral cortex accomplishes what is done between sensation and action: perceiving, learning and remembering, planning, and acting. These processes take place in the association areas of the cerebral cortex. The central sulcus provides an important divid ing line between the rostral and caudal regions of the cerebral cortex. (Look once more at Figure 3.10.) The rostral region is involved in movement-related activities, such as

planning and performing behaviors. The caudal region is involved in perceiving and learning. Each primary sensory area of the cerebral cortex sends information to adjacent regions, called the sensory association cortex. Circuits of neurons in the sensory association cortex analyze the information received from the primary sensory cortex, where perception takes place and memories are stored. The regions of the sensory association cortex located closest to the primary sensory areas receive information from only one sensory system. For example, the region closest to the primary visual cortex analyzes visual information and stores visual memories. Regions of the sensory association cortex located far from the primary soensory areas receive information from more than one sensory system and are involved in several kinds of perceptions and memories. These regions make it possible to integrate information from more than one sensory system. For example, we can learn the connection between the sight of a ]particular face and the sound of a particular voice. (Look again at Figure 3.10.) If people sustain damage to the somatosensory association cortex, their deficits are related to somatosensation and the environment in general. For example, they may have difficulty perceiving the shapes of objects that they can touch but not see, they may be unable to name parts of their bodies (see the following case of Mr. M.), or they may have trouble drawing maps or following them. Although people who siustain damage to the visual association cortex will not become blind, they may be unable to recognize objects by sight. People who sustain damage to the auditory association cortex may have difficulty perceiving speech or even producing meaningful speech of their own. People who sustain damage to regions of the association cortex at the jjunction of the three posterior lobes, where

Structure of the Nervous System

Figure 3.9

The Four Lobes of the Cerebral Cortex

This figure shows the location of the four lobes, the primary sensory and motor areas, and the association areas of the cerebral cortex. (a) Ventral view, from the base of the brain. (b) Midsagittal view, with the cerebellum and brain stem removed. (c) Lateral view.

Cross section

Limbic cortex

Temporal Lobe

I

through midbrain

Frontal Lobe

(a)

Frontal Lobe

Occipital Lobe

Occipital Lobe Temporal Lobe

Frontal Lobe

(b)

Primary Primary motor cortex somatosensory cortex Parietal / Lobe Primary visual cortex

63

the somatosensory, visual, and audit ory functions overlap, may have difficulty reading or writing. Some of th ese examples are described in Chapter 13.

Mr. M., a city bus driver, stopped to pick up a passenger. The passonger asked him a question. and Mr. M. suddenly realized that ~1e didn't understand what she was saying. He could hear her, t>ut her words made no sense. He opened his mouth to reply. He made some sounds, but the look on the woman's face told him that she couldn't understand what he was trying to say. He turned off the engine and looked around at the passengers and tried to tell them he needed help. Although he was unable to say anything, they understood that something was wrong, and one of them called an ambulance. 1\n MRI scan showed that Mr. M. had sustained an intra ceret>ral hemorrhage-a kind of stroke caused by the rupture of blood vessels in the brain. The stroke had damaged his left parietal lobe. Mr. M. gradually regained the ability to talk and understand the speech of others, but some deficits remained. A neurologist examined Mr. M. several weeks after his stroke. The dialo~iue went something like this: "Show me your hand." "My hand . .. my hand." Looks at his arms, then touches his left forearm. "Show me your chin." "My chin." Looks at his arms, looks down, puts his hand on his at>domen. "Show me your right elbow." "My right ..." (points to the right with his right thumb) "elbow." Looks up and down his right arm, finally touches his right shoulder. Mr. M. could understand that the physician was asking him to poiint out parts of his body and could repeat the names of the body parts when he heard them, but he could not identify which body parts these names referred to. This deficit, which sometimes follows damage to the left parietal lobe, is called autotopagnosia, or "poor knowledge of one's own topography." The parietal lobes are involved with space: the right primarily with external space and the left with one's body and personal space. You will learn more abou1t disorders such as this one in Chapter 13, which includes brain mechanisms of language.

Motor Cortex

The region of the cerebral cortex that i s

most directly involved in the control of movement is the primary motor cortex, located just in front of the primary somat osensory cortex. Neuron s in different parts of the primary motor cortex are connected to muscles in different parts •Of the body. The connections, like those of the sensory r1egions of the cerebral cortex, are contralateral. This means that the left primary motor cortex controls the right side of the body and vice versa. For example, if a surgeon places an el ectrode on the surface of the primary motor cortex and stimulates the neurons there with a weak elec-

Primary auditory cortex (mostly hidden from view)

trical current, the result will be movement of a particular part of the body. Moving the electrode to a different spot will catUse a different part of the body to move. (Look again

(c) Rostral

Caudal

at Figure 3.10.) You can think of the strip of primary motor

64

Chapter 3

Figure 3.10 The Primary Sensory and Motor Regions of the Brain A lateral view of the left side of a human brain and part of the inner surface of the right side,_ Notice the corresponding functions in the adjacent regions of the primary motor and somatosensory cortex. The inset shows a cutaway of part of the frontal lobe of the left hemisphere, permitting us to see the primary auditory cortex on the dorsal surface of the temporal lobe, which forms the ventral bank of the lateral fissure. Primary somatosensory cortex Cingulate cortex

Insular cortex Right Hemisphere

I

Calcarine fissure

Portion of Left Hemisphere Primary visual cortex Lateral fissure

Primary auditory cortex

cortex as the keyboard of a piano, with each key controlling a different movement. (We will see shortly who is the "player" of this piano.) Motor Association Cortex Just as regions of the sensory association cortex of the posterior part of the brain are involved in perceiving and remembering, the frontal association cortex is involved in the planning and execution of movements. The motor association cortex (also known as the premotor cortex) is located just rostral to the primary motor cortex. Because this region controls the primary motor cortex, it directly controls behavior. If the primary motor cortex is the keyboard of the piano, then the motor association cortex is the piano player. The rest of the frontal lobe, rostral to the motor association cortex, is known as the prefrontal cortex. This region of the brain is less involved with the control of movement and more involved in formulating plans and strategies. (See Figure 3.9c.) Lateralization in the Cerebral Cortex Although the two cerebral hemispheres cooperate, they do not perform

Left Hemisphere

identical functions. Some func tions are lateralizedlocated primarily on one side of the brain. In general, the left hemisphere participates in the analysis of information--the extraction of the elements that make up the whole of an experience. This ability makes the left hemisphere particularly good at recognizing serial events-events whose elements occur one after the other-and controlling sequences of behavior. (In a few people, the functions of the left and right hemispheres are reversed.) The serial functions that are performed by the left hemisphere include verbal activities, such as talking, understanding the speech of other people, reading, and writing. These abilities are disrupted by damage to the various regions of the left hemisphere. (We will say more about language and the brain in Chapter 14.) In contrast, the right hemisphere is specialized for synthesis, whioch means that it is particularly good at putting isolated elements together to perceive things as a whole. For example, our ability to draw sketches (especially of three-dimensional objects), read maps, and construct complex objects out of smaller elements depends heavily on cir·cuits of neurons that are located in the right

Structll'8 o f the Nervous System

65

connections lhat link different regions o f th e t\'\.ro hemi· spheres. Surgically severing the corpus callosum creates a condition called split brain tha t is described in more d etail in C hap ter 14. Figu re 3.11 shows the bundles of axons that constitute the corpus caHosum, obtained using diffu · sion te nsor imaging., a special neuroim agin g method d escribed in Chapter 5.

Figu re 3.11 Bundles of Axons in the Corpus Callosum This figure, obtained by means of diffusion tensor imaging. Shows bundles of axons in the corpus c:allos.um that serve diff&r&nt r&gions o f the c&rebral cortex.

LIM BIC SYSTEM Another fo rm of cerebral cortex, the limbic cortex, is located around the medial edge of the ce· rcbral hemispheres (li111b11s means "border"). The cingulate gyrus, an importan t region of the limb ic cortex, can be seen in Figure 3.12. The limbic cortex, along w ith other parts o f the brain , forms the limbic system. The limb ic system also includ es the h ippocampus ("sea horse") and the amygdala ("almond"), located next to the lateral ventricle in the temporal lobe. The fomix ("arch") is a bundle of axons that connects the hippocampus with other regions of the bra in, including the mammillary bodies ("breast-shaped"), p rotrusions on the b ase o f the brain that contain parts of the hypothalamus. (See Figure 3.12.) We now know that parts of the limbic system (notably, the hippocampal formation a nd the region o f limbic cortex that surrounds it) are in volved in learning and memory. The amygdala and some regions of the limbic cortex are specifi· cally in volved in emotions: feelings and exp ressions o f em-"

hemisp here. Damage to the right hemisph ere disrupts these abiJities. As we go about our d a ily lives, we are not aware o f the fact that each hemisph ere perceives the world diffe r· e ntly. Although the two cerebral h emispheres p erform somewha t d ifferen t functions, o ur perceptions and our memories are uni fied. This un ity is accomp lish ed by the corpus caUosum, a large ban d o f axons tha t connects correspond ing parts of the cerebral cortex o f lh c left and right h emispheres: The le ft and right temporal lobes are connected, the le ft and right parietal Jobes arc connected, and so on. Because o f the corpus callosum, each region of the association cortex knows w ha t is happening in the correspond ing region of the opposite side o f the brain. Th e corpus callosum also makes a few asymmetrical

li.uns, c 11u>li.011a) 111ci nuri.t:s, dHc.1 n.:.'1.:l>g11ilio u of lite ::.ign!:> of

emotions in other people. (See Chapter 11.) BASAL GANGLIA The basal ganglia are a collection o f nudei below the cortex in the forebrain, whid1 lie beneath th e a nterior p ort ion o f th e lateral ventricles. Nuclei a re groups o f ne urons of similar shape. (The word nucleus can refer to the inner portion o f an atom, to the structure of a cell

Figure 3.12 The Major Components of the Limbic System M assa intermecha

- - -= = = .:..--

Cingulate g yrus (region of hrrt>ic

cortex)

Mammitlasy bOdy

Hippocampus of right hemisph&re (ghosted in)

66 Chapter3

Figure 3.13

The Forebrain: Diencephalon

The Basal Ganglia and Oiencephalon

Location of the basal ganglia and diencephak>n (thalamus and hypolhalairus).

LO 3.4

Putainen and

Identify the locations and functions of the s tructures of the diencephalon.

Th e second major d ivision o f the forcb rain, the d icncepha· Ion, is located bctlveen the telencephalon and the mcsen· cephalon and surrounds the third ven tricle. Its hvo most important structu res are the thalamus and the h ypothalamus. (See Figure 3.13 and Figure 3.14.)

gk>bus palhdus caudate nudeus

The thalamus (from the Greek tlinlnmos, " in ner chamber") makes up the d orsal part o f the dien· cepha lo n. It is located near t he m iddle of the cerebral hemispheres, immediately medial and caud al to the basal ga nglia. (Look aga in at Fig ure 3.13 and Figure 3.14.) The Iha Jam us has two lobes, connected by a bridge of g ray matter called the massa intermedin. Most neural inp ut to the cerebral cortex is received from the tha la mus, and much of the cortical surface can be divided in to regions that receive projections from specific parts o f the thalamus. The thalamus is div ided into several nu cle i. Some thalamic nu cle i receive sen sory in fo rmation from the sensory systems . The neurons in lhese n uclei then relay the sensory in for mation to specific sensory projection areas of the cerebral cortex. For example, the lateral geniculate nucleus receives info rmation from the THALAMUS

that contains the chromosomes, and-as in this case- to a collection of neurons located within the b rain.) The major parts o f the basal ganglia are the cnudate nucleus, the pula· men, and the globus pnllidus (the "nucleus w ith a tail," the ha~11I

PYP :.n ti ug11 tht:

capHJarics that supply the muoous membrane that lines the mouth. For example, some drugs used to treat migraine headaches are admin istered this way, resulting in a fas te r onset of the rapeutic effects (compared to oral administra· tion) and less risk of irritatin g the stomach. The lungs provide an other route for drug adminis· tration: inhalation. Nicotine, freebase cocain e, and psy· ch oactive compound s in marijuana are inhaled through smokin g. In addition, many gen eral an esthetics are gases that are administered through inhala tion. The route from the lun gs to the brain is very short and does not in volve first·pass metabolism. Drugs admin istered through inha· lation produce very rapid effects. Some drugs can be absorbed directly through the skin, so they can be given by topical administration. Natu ral o r artificial steroid hormones can be admin istered in this way, and so can nicotine (when used as a treatment to help people stop smoking). The mucous membrane lin ing the nasal passages also provides a route for topical administration. Commonly abused drugs such as cocain e and other stimu· lan ts are often sniffed so that they oome in to contact with the nasal mucosa. Th is route delivers the drug to the brain very rapidly. Note that sniffin g or "snorting" (also called insufflation) is not the same route of administration as inhalation. When powdered drugs are sniffed, they enter circulation through the mucous membrane of the nasal passages, not the lu ngs.

Figure 4.3

Cocaine in Blood Plasma

The graph shows th& concentration of cocaine in blood plasma aftGI' intravenous injection, inhalation, oral administration. and sniff.ng. Source: Jl4japted from Feldman. R. S.• Meyer. J. S.. and Quenzer. L F•• Prlnclples of NeuropsychOphannacolog/. Sunderland. MA: Slnauer As90Cia~es. 1997; after Jones. R. T. NIDA Reseateh Monographs. 1990. 99, 30-41.

Intravenous (0.6 m!Jl of pcpli.c.lt:!:> takL':> pld..:c

so they have no direct effects on the brain. In contrast, many ovcr·thc--countcr sleep aids and allergy medicines contain d iphenh ydramine, which crosses the blood- brain barrier and produces drowsiness. You will read more about the histamine system and its role in sleep in Chapter 9. For a summary of some important drugs that act on monoamine systems, sec Table 4.6.

in the soma, vesicles containing these chemicals must be delivered to the terminal buttons by axoplasmic transport. As we saw in Chapter 2, many terminal buttons con· lain different types of synaptic vesicles, each filled with a different substance. These terminal buttons release pep· tides in conjunction with a classical neurotransmitter. One reason for the co-release of peptides is their ability to regulate the sensitivity of presynaptic or postsynaptic receptors to the neurotransmitter. Many peptides produced in the brain have interesting behavioral effects, as you'H see in subsequent chapters. Peptides are released from all parts of the terminal button, not just from the active zone. This means that only a portion of the molt>eules is released into the synaptic cleft. The rest of Uie molecules presumably act on receptors belonging to other cells in the vicinity. Once released, peptides are deactivated by enzymes. Unlike the other neu· rotransmittcrs in this chapter, there is no mechanism for reuptake and recycling of peptides. Several d ifferent peptides arc released by neurons. Althoug h most peptides appear to serve as neuromodulators, some act as neurotransmitters. One of the bcst·known families of peptides arc the endogenous opioids. Research has revealed that opiates (drugs such as opium, morphine, heroin, and oxycodone) reduce pain because they have direct effects on the brain through their actions in ~ie endogenous opioid system.

Peptides LO 4.13 Contrast th e fea tures of peptide neurotransmitters with classical neurotransmitters.

In addition to amino acids and classical neurotransmit· ters, neurons of the CNS release a large variety of peptides. In contrast to the classical neurotransmitters, peptides consist of hvo or more amino acids Jinked together by peptide bonds. PRODUCTION, STORAGE, AND RELEASE All the peptide neurotransmitters that have been studied so far are produced from precursor molecules. These precursors are large polypeptides that are made into smaller neurotransmitter molecules by special enzymes. Neurons manu· facture both the polypeptides and the enzymes needed to break them apart in the right places. The appropriate sections of the polypeptides arc retained, and the rest are

102 Chapter 4 RECEPTORS Alth ough opiate d rugs like opiu m ha\•e been used for centuries, receptors for opioids were not d is· covered u ntil the 1970s. At that time, no o ne knew about the en dogenous opioids. Soon a fte r the d iscovery of opioid receptors, o lhcr neuroscie ntists discovered th e natura l Ii· gands for these receptors, w hich were cal100 enkephalins. lA'e now know that lhc cnkeph alins arc only two members o f a family o f e ndogenous opioids, all o f w hich are synthesized from one of three large peptides that serve as precursors. Also, we know that there are at least three diffe re nt types o f opioid receptors:µ (mu), & (delta), a nd K (kappa). Several different neu ral systems arc activated when opioid receptors arc stimulated. One type p roduces anal· gesia, another inhibits spcci~typic.al d efensive responses such as fleeing and h iding, and another stimulates a system of neurons in volved in rein forceme nt ("reward"). The last effect explains w hy o pioid s arc o ften abused. (See the case of Christoph er at the beginning of the chapter.) Endogeno us opioid s arc d iscussed in Chapter 7, and brain m echanisms involved in opioid abuse are discussed in Ch apter 16. So far, pharmacologists have developed only two types of drugs that affect neural comm unication u ti)izing op ioid s: direct agonists and antagonists. Many synthetic opioids, in· eluding heroin, methad one, and oxycodone, have been d~ vcloped, and some are used clinically as an algesics. Several opioid receptor an tagonists ha\'e also"""'' developed. One

or "bliss." A few years afte r the discovery of an.and amide, Mechoula m a nd colleagues (1995) d iscovered a nother endocannabinoid, 2-arachid onyl g lycerol (2-AG). NEUROTRANSMITTER PRODUCTION, STORAGE, AND RELEASE Lipid neurotran smitters, such as ananda m id e, a p pear to be synthesized o n demand; that is, Uiey arc pro· duced and released as needed and are not stored in syn· aptic vesicles. Can you think o f an y reason w hy it m ight be difficult to conta in lipid ne urotran s m itters within the lipid·based m embranes of a vesicle? RECEPTORS Two types o f cannabinoid receptors, CB 1 and CB:u are bo th m e tabotropic. Besid es T H C, several drugs affect the actions o f th e e ndocan nabin oids. For ex· ample, CB, receptors arc blocked by the d rug rimonabant. CB1 receptors are found o n terminal buttons o f glutam atergic, GABAergic, acctylcholinergic, nora drene rgic, dopam in ergic, and serotonergic neurons, where they sen 'e as presynaptic heteroreceptors, regulating neu.rotransmit· ter release (Iversen, 2003). When activated, the receptors open potassium channe ls in the tcnninal b uttons, shorten· ing the duration of action pote ntials there and d ecreasing the am ount of neurotrans mitter lhat is released. When ncu· rons release cannabinoid s, the chemicals diffuse a distance of approximately 20 µm in a ll directions, a nd their effects persist fo r several te ns of seconds. The s hort·term m em ory

op iuiU

lmpi1 im tcn t tlldl i.1L't:0111pa n it.'S 111Miju mld u~ i1p pce answer is stereotaxic surgery. Stm!Dlaxis refers to the ab1hty to locate objects in space. A slurol1mc appamtus contains a holder that keeps the animal's head in a standard posibon and an arm that mm-es an electrode or a cannula through measured distances in all three axes of space. HowC\·cr, to perform stereotaxic swgery, a researcher first consults a sttrmta:ric atlas. THESTEREOTAXICATl..AS AstettOtaxi< atlas IS• book, website, or software that contains images that correspond to frontal sections of the brain taken at various di.Stances rostral and caudal to bregma. The skull is composed of several bones that grow together and form sutum (seams). The heads of babies contain a so!t spot at the junction of the coronal and sagillal sutures called the fo11ta11tllt. Once this gap closes,. the junction is called bregma, from the Greek word meaning ,..front of hend." No two brains o( animals o f a given species arc completely identica l, but

there is enough similarity among individuals to predict the location of particular brain structures re lative to external features of th e head. \Ne can find brcgma on.-. r1it's s kull, tnn,

Contrast methods to s tudy the structure of the living human brain.

Although we cannot ethically ask people to submit to lesion studies for the purposes of research, diseases and

118 Chapter 5

accidents do unfortunately occur that damage the human brain. If we know where the damage occurs, we can study the person's behavior and try to make the same sorts of inferences we make with deliberately produced brain lesions in laboratory animals. The problem is, where is the lesion? In the past, a researcher might have studied the behavior of a person with brain damage and never determined exactly where the lesion was located. The only way to be sure was to obtain the patient's brain when they died and examine slices of it under a microscope. But it was often impossible to do this. Sometimes the patient outlived the researcher. Sometimes the patient moved out of town. Sometimes (often, perhaps) the family refused permission for an autopsy. Because of these practical problems, the study of the behavioral effects of damage to specific parts of the human brain made rather slow progress. Advances in X-ray techniques and computers have led to the development of several noninvasive methods for studying the anatomy of the living brain. These advances permit researchers to study the location and extent of brain damage while the patient is still living. The first method developed is called computerized tomog raphy (CT). This procedure, usually referred to as a CT scan, works as follows: The patient's head is placed in a large doughnut-shaped ring. The ring contains an

Figure 5.16

X-ray tube and, directly opposite it (on the other side of the patient's head), an X-ray detector. The X-ray beam passes through the patient's head, and the detector measures the amount of radioactivity that gets through it. The beam scans the head from all angles, and a computer translates the information it receives from the detector into pictures of the skull and its contents. (See Figure 5.16.) Figure 5.17 shows a series of CT scans taken through the head of a patient who sustained a stroke when bleeding occured in the brain. The scans allow a researcher or physician to view the location and extent of an injury. In this case, internal bleeding is indicated by the color blue added to the scan. An even more detailed, high-resolution picture of what is inside a person's head is provided by a process called magnetic resonance imaging (MRI). The MRI scanner resembles a CT scanner, but it does not use X-rays. Instead, it passes an extremely strong magnetic field through the patient's head. When a person's head is placed in this strong magnetic field, the nuclei of spinning hydrogen atoms align themselves with the magnetic field. When a pulse of a radio frequency wave is then passed th rough the brain, these nuclei flip at an angle to the magnetic field and then flip back to their original position at the end of the radio pulse. Different

Computerized Tomography

Within a CT scanner, a beam of X-ray is used to image progressive "slices" through tissues of the body, including the brain and skull. Differences in structure or tissue type, such as tumors or bleeding, can be seen in CT scans. Source: Based on MedlinePlus, U.S. National Library of Medicine http://www.nlm.nih.gov/medlineplus/ency/imagepages/19237.htm

Methods and Strategies of Research

Figure 5.17

119

CT Brain Scans

Computerized tomography (Cl) brain scans (axial view) were taken through the brain of a 38-year-old male stroke patient. The stroke occurred four weeks before the scans were taken. The blue region is an area of internal bleeding, or hemorrhage. SIMON FRASER/NEWCASTLE HOSPITALS NHS TRUST/ Scieince Source

molecules emit energy at different frequencies. The MRI scanner is tuned to detect the radiation from hydrogen atoms. Because these atoms are present in different concentrations in different tissues, the scanner can use the information to prepare pictures of slices of the brain. (See Figure 5.18.) As you can see in Figure 5.18, MRI scans can distinguish between regions of gray matter and white matter, so major fiber bundles (such as the corpus callosum) can be seen. However, small fiber bundles are not visible on these scans. A special modification of the MRI scanner permits the visualization of even small bundles of fibers and the tracing of fiber tracts. Above absolute zero, all molecules move in random directions because of thermal agitation: the higher the temperature, the faster the random movement. Diffusion tensor imaging (DTI) takes advantage of the fact that the movement of water molecules in bundles of white matter will not be random but will tend to be in a direction parallel to the axons that make up the bundles. The MRI scanner uses information about the movement of the water molecules to determine the location and orientation of bundles of axons in white matter. Figure 5.19 shows a sagittal view of some of the axons that project from the thalamus to the cerebral cortex in the human brain, as revealed by DTI. The

computer adds colors to distinguish different bundles of axons. The research methods described in this module are summarized in Table 5.1.

Figure 5.18

MRI Scans of Human Brain

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Figure 5.19

Diffusion Tensor Imaging

Th is image shows a sagittal view of some of the axons that project from the thalamus to the cerebral cortex in the human brain, as revealed by diffusion tensor imaging. Source: From Wakana, S., Jiang, H., Nagae-Poetscher, L. M., van Zijl, P. C., and Mori, S. (2004). Fiber tractbased atlas of human white matter anatomy. Radiology, 230, 77-87. Reprinted with permission.

Thalamus

Table 5.1

Research Methods Related to Ablation

Destroy or inactivate specific brain region

Radio frequency lesion

Dostroys all brain tissue near the tip of the electrode

Excitotoxic lesion; uses excitatory amino acid such as kainic acid

Dnstroys only cell bodies near the tip of the cannula; spares axons passing through the region

Infusion of local anesthetic or drug that produces local neural inhibition

Temporarily inactivates specific brain region; an animal can serve as its own control

Infusion of saporin conjugated with an antibody

Dnstroys neurons that contain the antibody; produces ve·r y precise brain lesions

Place electrode or cannula in a specific region within the brain

Stereotaxic surgery

Consult stereotaxic atlas for coordinates

Rnd the location of a lesion

Perfuse brain; fix brain; slice brain; stain sections

Visualize tissue or cell structures

Light microscopy

Often requires histological methods and staining or immunocytochemical methods to identify cells of interest

Visualize subcellular structures

Electron microscopy

Transmission electron microscopes provide structural information. Scanning electron microscopes provide th1ree-dimensional information

Visualize d etails of cells in thick or living sections of tissue

Confocal laser scanning microscopy

Can be used to see "slices" of tissue in the living brain; requires the presence of fluorescent molecules in the tissue

Identify axons leaving a particular region and the terminal buttons of these axons

Anterograde tracing method, such as PHA-L

Identify location of neurons whose axons terminate in a particular region

Retrograde tracing method, such as ftuorogold

Identify circuits of neurons

TransneuronaJ tracing methods

St1ows series of two or more neurons with serial synaptic connections; often uses herpes simplex (anterograde) or p~;eudorabies (retrograde) viruses

Rnd the location of a lesion in living human brain

Computerized tomography (CT scanner)

St1ows "slice" of the brain; uses X-rays

Magnetic resonance imaging (MRI scanner)

St1ows "slice" of the brain; better detail than CT scan; us:es a magnetic field and radio waves

Diffusion tensor imaging (DTI)

St1ows bundles of myelinated axons; uses an MRI scanner

Find the location of fiber bundles in living human brain

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Module Review: Experimental Ablation Evaluating the Behavioral Effects of Brain Damage LO 5.1 Explain what researchers can learn from

lesion studies. By lesioning a part of the nervous system, a researcher can observe the resulting changes in behavior to determine the function of that portion of the nervous system. The goal is to discover what functions are performed by different regions of the brain and then to understand how these functions are combined to accomplish particular behaviors. No one brain region or neural circuit is solely responsible for a behavior; each region performs a function (or set of functions) that contributes to the performance of the behavior.

Producing Brain Lesions LO 5.2 Compare methods of p roducing brain lesions.

Brain lesions can be produced by passing an electrical current through a wire, or by injecting an excitatory amino acid, selective antibody, or local anesthetic into a specific brain region. Using an electrical current, an excitatory amino acid or a selective antibody produces a permanent

lesion. Using a local anesthetic produces a temporary lesion. Using an electrical current produces a nonselective lesion. The other methods produce lesions based on the type of neuron the lesioning agent selectively binds to.

Stereotaxic Surgery LO 5.3 Describe the process of stereotaxic surgery.

Stereotaxic surgery involves using a stereotaxic atlas to identify a specific location in the brain. Once the location has been identified, the researcher places the head in a stereotaxic apparatus and positions a cannula over the correct location on the head. The researcher makes an incision in the scalp of the anesthetized animal (or human), drills a hole in the skull, and lowers the cannula into place. The researcher makes the lesion (or in some cases implants an electrode or transplants tissue), removes the cannula, and the animal (or human) recovers from the anesthetic.

Histological Methods LO 5.4 Summarize the steps of histological methods.

Brain tissue is perfused and removed from the skull. Then, the tissue to be examined is placed in a fixative. Once the brain is fixed, it is sliced into thin sections on a cryostat or microtome. The slices are placed on a microscope slide. Brain tissue must be stained to reveal cellular and intracellular structures. Cells can be stained for cell

bodies, nuclei, or specific proteins using dyes or specially labeled antibodies. Depending on the characteristics of the ce!U or intracellular structures of interest, light microscopes, transmission electron microscopes, scanning electron microscopes, or confocal laser scanning microscopes may be used to study the tissue samples.

Tracing Neural Connections LO 5.!5 Compare techniques for tracing efferent and

afferent axons. Tracing efferent axons allows researchers to learn about the ta1rget locations of sets of neurons. Using an anterograde labeling method, a chemical is injected into the region containing cell bodies, taken up with the cells, and transported to the terminals. Immunocytochemical methods use antibodies to identify the structures that receive input from the cell bodies. Tracing afferent axons allows resear•chers to learn about neurons that provide input to a regioni of interest. Using a retrograde labeling method, a chemi,cal is injected into the target region and taken up by the terminal buttons. The chemical then travels to the cell body of the neuron. Transneuronal tracing methods can identilfy a series of two or more neurons w ith retrograde (pseudorabies) or anterograde (herpes simplex) viruses.

Studying the Structure of the Living HUinan Brain LO 5.15 Contrast methods to study the structure of the

living human b rain. Computerized tomography (CT) uses X-rays to image the structure of the living human brain. Magnetic resonance imaging (MRI) uses a magnetic field to image the living brain and differentiates among different tissue types. Diffusioni tensor imaging (DTI) uses information about the movement of water molecules to visualize small fiber bundl•es not visible in MRI scans.

Thought Question Henry Molaison (H. M.) became a well-known figure in psychology and neuroscience after undergoing ablation of tiss ue in his temporal lobes to reduce seizures. The surgeiry was performed in 1957. H. M.'s brain and behavior were documented by physicians and researchers until his death in 2008. After his death, researchers at the University of California San Diego carefully preserved, sectioined, and stained his brain to learn more about it. Describe the techniques these researchers would need to use to examine H. M.'s brain after his death.

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Recording and Stimulating Neural Activity The first module of this chapter dealt with the anatomy of the brain and the effects of damage to particular regions.

This module considers a different approach: studying the brain by recording or stimulating the activity of particular regions. Brain functions involve the activity of circuits of neurons. Different perceptions and behavioral responses involve different patterns of activity in the brain. Researchers have devised methods to record these patterns of activity or to artificially produce them.

Recording Neural Activity LO 5.7

Compare methods of recording neural activity.

Axons produce action potentials, and terminal buttons elicit postsynaptic potentials in the membrane of the cells with which they form synapses. These electrical events can be recorded (as we saw in Chapter 2), and changes in the electrical activity of a particular region can be used to determine whether that region plays a role in various behaviors. For example, recordings can be made during stimulus presentations, decision making, or motor activities. Recordings can be made over an extended period of

time after the animal recovers from surgery, for a relatively short period of time during which the animal is kept anesthetized. Short-term recordings, made while the animal is anesthetized, are usually restricted to studies of sensory pathways. Short-term recordings seldom involve behavioral observations, since the behavioral capacity of an anesthetized animal is limited. RECORDINGS WITH MICROELECTRODES Drugs that affect serotonergic and noradrenergic neurons also affect REM sleep. Suppose that, knowing this fact, we wondered whether the activity of serotonergic and noradrenergic neurons would vary during different stages of sleep. To find out, we would record the activity of these neurons with microelectrodes. Microelectrodes, usually made of thin wires, have a very fine tip, small enough to record the electrical activity of individual neurons. This technique is usually called single-unit recording (a unit refers to an individual neuron). Because we want to record the activity of single neurons over a long period of time in unanesthetized animals, we want more durable electrodes. Arrays of very fine wires gathered together in a bundle can simultaneously record the activity of many different neurons. The wires are insulated so that only their tips are bare. Microelectrodes can be implanted in the brains of animals through stereotaxic surgery and bonded to the animals' skull. We can then observe both the animal's behavior during REM sleep and the corresponding activity

of the serotonergic and noradrenergic neurons recorded by the implanted microelectrodes. (See Figure 5.20.) The electrical signals detected by microelectrodes are quite small and must be amplified. Amplifiers used for this purpose work just like the amplifiers in a stereo system, converting the weak signals recorded in the brain into stronger ones. These signals can be displayed and saved on a computer. As you wiill learn in Chapter 9, if we record the activity of these neurons during various stages of sleep, we find their firing rates fall almost to zero during REM sleep, suggesting that these neurons have an inhibitory effect on REM sleep. That is, REM sleep does not occur until these neurons stop firing. RECORDINGS WITH MACROELECTRODES Sometimes, we want to re.cord the activity of a region of the brain as a whole, not the activity of individual neurons. To do this, we would use macroelectrodes. Macroelectrodes do not detect the activity of ili1dividual neurons; rather, the records that are obtained with these devices represent the postsynaptic potentials of mamy thousands-or millions-of cells in the area of the electrode. These electrodes are sometimes implanted into the brain or onto the surface of the brain, but many are temporarily attached to the human scalp with a special paste that conducts electricity. Recordings taken from the scalp, especially, represen t the activity of an enormous number of neurons, who:se electrical signals pass through the meninges, skull, and scalp before reaching the electrodes. The electrical activity of a h uman brain recorded through macroelectrodes is displayed on a polygraph. A polygraph plots the changes in voltage detected by the electrodes along a timeline during recording. The polygraph is displayed on a computer screen. Figure 5.21 illustrates electrical activity recorded from macroelectrodes attached to various locations on a person's scalp. Such records are called

Figure 5.20

Implantation of Electrodes

The drawing shows a set of electrodes in a rat brain. Connecting socket Electrodes

Dental plastic

Methods and Strategies of Research

Figure 5.21

123

Recording Brain Acti vity with Macroelectrodes

Macroelectrodes record the summed electrical activity of many neurons. In this example, an electroencephalogram is created to visually represent the changes in summed postsynaptic poteintials recorded by scalp electrodes.

Left hemisphere

Right hemisphere

An electroencepha1logram (EEG) electroencephalograms (EEGs), or "writings of electricity from the head." They can be used to diagnose epilepsy or to study the stages of sleep and wakefulness, which are associated with characteristic patterns of electrical activity. In addition to their use in research, clinicians use macroelectrodes to help treat patients. Occasionally, neurosurgeons implant macroelectrodes directly into the human brain. The reason for doing so is to detect the source of abnormal electrical activity that is giving rise to frequent seizures. Once the source has been determined, the surgeon can remove the source of the seizures-usually scar tissue caused by brain damage that occurred earlier in life. Similarly, another clinical use of EEG is to monitor the condition of the brain during procedures that could potentially damage it. One of the authors of this book (N. C.) observed such a procedure: Mrs. F. had sustained one mild heart attack, and subsequent tests indicated a considerable amount of atherosclerosis, commonly referred to as "hardening of the arteries." Many of her arteries were narrowed by cholesterol-rich atherosclerotic plaque. A clot formed in a particularly narrow portion of one of her coronary arteries, which caused her heart attack. As the months passed after her heart attack, Mrs. F. had several transient ischemic attacks, brief episodes of neurological symptoms that appear to be caused by blood clots forming and then dissolving in cerebral blood vessels. In her case, they caused numbness in her right arm and difficulty in talking. Her physician referred her to a neurologist, who ordered an angiogram (a recording of heart activity). This procedure revealed that her left carotid artery was almost totally blocked. The neurologist referred Mrs. F. to a neurosurgeon, who urged her to have an operation that would remove the plaque from part of her left carotid artery and increase the blood flow to the left side of her brain. The procedure is called a carotid endarterectomy. I was chatting with Mrs. F. 's neurosurgeon after a conference, and he happened to mention that he would be performing the operation later that morning. I asked whether I could watch, and

he a~1reed. When I entered the operating room, scrubbed and gowned, I found that Mrs. F. was already anesthetized, and the surgical nurse had prepared the left side of her neck for the incision. In addition, several EEG electrodes had been attached to her scalp, and I saw that Dr. L. , a neurologist who specializes in clinical neurophysiology, was seated at his EEG machine. The surgeon made an incision in Mrs. F. 's neck and exposed the carotid artery, at the point where the common carotid, coming from the heart, branched into the external and internal carotid arteries. Hie placed a plastic band around the common carotid artery and clamped it shut, stopping the flow of blood. "How does it look?" he askecl Dr. L. "No good-I see some slowing. You'd better shunt." The surgeon quickly removed the constricting band and askecl the nurse for a shunt, a short length of plastic tubing a little thinnm than the artery. He made two small incisions in the artery well aibove and well below the region that contained the plaque and inserted the shunt. Now he could work on the artery without stopping the flow of blood to the brain. He made a longitudinal cut in the artery, exposing a yellowish mass that he dissected away and removed. He sewed up the incision, removed the shunt, and sutured the small cuts he had made to accommodate it. "Everything still okay?" he asked Dr. L. "Yes, her EEG is fine." Most neurosurgeons prefer to do an endarterectomy by temporarily clamping the artery shut while they work on it. The work goes faster, and complications are less likely. Because the bloodl supply to the two hemispheres of the brain is interconnected (with special communicating arteries), it is often possible to shut down one of the carotid arteries for a few minutes without causiing any damage. However, sometimes the blood flow from one side of the brain to the other is insufficient to keep the other side nourished with blood and oxygen. The only way the surgeon can know is to have the patient's EEG monitored. If the brain is not mceiving a sufficient blood supply, the EEG will show the presence of characteristic "slow waves." That is what happened when Mrs. F. 's artery was clamped shut, and that is why the surgeon had to use a shunt tube. Without it, the procedure might have caused a stroke instead of preventing one. 13y the way, Mrs. F. made a good recovery.

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MAGNETOENCEPHALOGRAPHY When electrical current flows through a conductor, it induces a magnetic field. This means that as action potentials pass down axons or as postsynaptic potentials pass through dendrites or sweep across the somatic membrane of a neuron, magnetic fields are also produced. These fields are very small, but engineers have developed superconducting detectors (called superconducting quantum interference devices, or SQUIDs) that can detect minute magnetic fields. Magnetoencephalography is performed with neuromngnetometers, devices that contain an array of several SQU!Ds, oriented so that a computer can examine their output and calculate the source of particular signals in the brain. These devices can be used clinically-for example, to find the sources of seizures so that they can be removed surgically. They can also be used in experiments to measure regional brain activity that accompanies the perception of various stimuli or the performance of various behaviors or cognitive tasks. (See Figure 5.22.) An important advantage of magnetoencephalography is its temporal resolution (ability to quickly show changes in information). Another technique that you'll read about in this chapter, functional MRI (fMRI) provides excellent spatial resolution of regional activity in the brain, but the process is slow and provides relatively poor temporal resolution. The image produced by magnetoencephalography is not as detailed as an fMRJ image, but it can be acquired much more rapidly and can consequently reveal fast-moving events.

Figure 5.22

Magnetoencephalography

An array of SQUIDS in this neuromagnetometer detects regional changes in magnetic fields produced by the electrical activity of the brain. Source: Phanie/Science Source

Recording the Brain's Metabolic and Synaptic Activity LO 5.8

Compare methods for assessing metabolic and synaptic activity.

Electrica l and magnetic signals are not the only signs of neural activity. If the neural activity of a particular region of the brain increases, the metabolic rate of this region increases, too, largely due to increased operation of ion transporters in the membrane of the cells, which requires an increased use of cellular energy. This increased metabolic rate can be measured. The experimenter injects radioactive 2-deoxyglucose (2-0G) into the animal's bloodstream. Because this chemical closely resembles g lucose (the principal food for the brain), it is taken into cells. This means that the most active cells, which use glucose at the highest rate, will take up the highest concentrations of radioactive 2-DG. But unlike normal glucose, 2-DG cannot be metabolized, so it stays in the cell. After administering 2-DG, the experimenter euthanizes the anim al, removes the brain, slices it, and prepares it for nutorndiogmphy. Autoradit0graphy can be translated roughly as "writing with one's own radiation." Sections of the brain containing the radioactive 2-DG are mounted on microscope slides. The slides are then developed, just like photographic film. The molecules of radioactive 2-DG show themselves as spots of silver grains in the developed images. The most active regions of the brain contain the most radioactivity, showing this radioactivity in the form of dark spots in the developed images of the tissue. Figure 5.:23 shows the distribution of µ opioid receptors (described in Chapter 4) in the rat brain. The researchers modified the autoradiography method described here, by exposing the tissue to a radioactive ligand (the opioid receptor antagonist naloxone) before developing the autoradiographic image. This image shows high concentrations of opioid receptors in the white areas, including the olfactory bulb and hippocampus. Another method of identifying active regions of the brain capitalizes on the fact that when neurons are activated (for example, by the terminal buttons that form synapses with them), particular genes in the nucleus called immedi,ate early genes are turned on, and particular proteins are produced. These proteins then bind with the chromosomes in the nucleus. The presence of these nuclear proteins indicates that the neuron has just been activated. One of the nuclear proteins produced during neural activation is called Fos. You will remember that earlier in this chapter we began an imaginary research project on the

Methods and Strategies of Research

Figure 5.23

Autorad iography

This horizontal section of a rat brain demonstrates autoradiography. A radioactive ligand attached toµ opioid receptor. The brain section was placed on a photographic film. Radiation exposed the film in the white regions, revealing a high concentration of receptors in the olfactory bulb, the cerebral cortex, the hippocampus, the striatum, the thalamus, and the tectum.

Figure 5.24

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Localization of Fos Protein

The photomicrograph shows a frontal section of the brain of a female rat, taken through the medial amygdala. The dark spots indicatEl the presence of Fos protein, localized by means of immunocytochemistry. The synthesis of Fos protein was stimulated by pernnitting the animal to engage in copulatory behavior. Source: Courtesy of Marc Tetel, Skidmore College.

Source: National Institute on Drug Abuse, NATIONAL INSTITUTES OF HEALTH/Miles Herkenham, NIMH/Science Source

neural circuitry involved in the sexual behavior of female rats. Suppose we want to use the Fos method in this project to see what neurons are activated during a female rat's sexual activity. We place female rats with males and permit the animals to copulate. After euthanizing the animals, we remove the rats' brains, slice them, and follow a procedure that stains Fos protein. Figure 5.24 shows the results: Neurons in the medial amygdala of a female rat that has just mated show the presence of dark spots, indicating the presence of Fos protein. Thus, these neurons appear to be activated by copulatory activity-perhaps by the physical stimulation of the genitals that occurs then. As you will recall, when we injected a retrograde tracer (fluorogold) into the VMH, we found that this region receives input from the medial amygdala. The metabolic activity of specific brain regions can be measured noninvasively in a living animal, by means of functional imaging- a computerized method of detecting metabolic or chemical changes within the brain. The first functional imaging method to be developed was positron emission tomography (PET) . First, a person (or another animal) receives an injection of radioactive 2-DG. (The chemical dose is harmless to humans and soon breaks down and leaves the cells.) The person's head is placed in a machine similar to a CT scanner. When the radioactive molecules of 2-DG decay, they emit subatomic particles called positrons, which meet nearby electrons. The particles annihilate each other and emit two photons, which travel in opposite paths. Sensors arrayed around the person's head detect these photons, and the scanner plots the locations from

which these photons are being emitted. From this information, a picture is produced of a slice of the brain, showing the activity level of various regions in that slice. i(See Figure 5.25). One of the disadvantages of PET scanners is their operating cost. For reasons of safety, the radioactive chemicals that are administered have very short half-lives; that is, they decay and lose their radioactivity very quickly. For example, the half-life of radioactive 2-DG is 110 minutes, and the half-life of radioactive water (also used for PET scans) is only 2 minutes. Because these chemicals decay so quickly, they must be produced on-site, in an atomic particle accelerator called a cyclotron. The cost of PET scanning also includes the cost of the cyclotron and the salaries of the personnel who operate it. Another disadvantage of PET scans is the relatively poor s.patial resolution (the blurriness) of the images. The temporal resolution is also relatively poor. The positrons being emitted from the brain must be sampled for a fairly long time, which means that rapid, short-lived events within the brain are likely to be missed. These disadvantages are not seen in functional MRI, described in the next parag1raph. However, PET scanners can do something that functional MRI scanners cannot do: measure the concentration of particular chemicals in various parts of the brain. We will describe this procedure later in this chapter. Ciurrently, the brain-imaging method with the best spatial and temporal resolution is functional MRI (£MRI). Enginieers have devised modifications to existing MRI

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Figure 5.25

PET Scan

Figure 5.26

fMRI Scan

Colored positron emission tomography (PEl) scan of the brain during a speech exercise. The exercise involved reciting synonyms. The PET scan is superimposed onto a black and white three-dimensional magnetic resonance imaging (MRI) scan. The front of the brain is at left. The scan shows the areas of brain activity (color) associated with speech. These areas are in the speech cortex of the brain's frontal lobe. The scan shows increased uptake of radioactive 2-DG in reg ions of the brain that are active in the speech task, which indicates an increased metabolic rate in these areas. Different computer-generated colors indicate different rates of uptake of 2-DG, with "warmer" color indicating increased activity.

This frontal section from a functional magnetic resonance image (fMRI} shows inc:reased blood flow to brain regions active during a motor task involving feet and toes. The "warmer" colors represent higher blood oxygen level-dependent (BOLD) activation in regions of the motor cortex and cerebellum. SMA =supplementary motor area

scanners and their software that permit the devices to acquire images that indicate regional metabolism. Brain activity is measured indirectly, by detecting levels of oxygen in the brain's blood vessels. Increased activity of a brain region stimulates blood flow to that region, which increases the local blood oxygen level. The formal name of this type of imaging is BOLD: blood oxygen level-dependent signal. Functional MRI scans have a higher resolution than PET scans do and reveal more detailed information about the activity of particular brain regions. (See Figure 5.26.) You will read about many functional imaging studies that employ fMRI in subsequent chapters of this book.

we remove the rats' ovaries, the loss of these hormones will abolish the rats' sexual behavior. We found in our earlier studies that VMH lesions disrupt this behavior. Perhaps if we activate the VMH, we will make up for the lack of femal1~ sex hormones, and the rats will copulate again.

Stimulating Neural Activity LO 5.9

Compare methods of neural stimulation.

So fa r, this module has focused on research methods that measure the activity of specific regions of the brain. But sometimes we may want to artificially change the activity of these regions to see what effects these changes have on behavior. For example, female rats will copulate with males only if certain female sex hormones are present. If

ELECTRIC AL A ND C HEMICAL STIMULATION How do we activate neurons? We can do so by electrical or chemical stimulation. Electrical stimulation involves passing an electrical current through a wire inserted into the brain usiing stereotaxic surgery. Chemical stimulation is usually accomplished by injecting a small amount of excitatory amino acid, such as kainic acid (which in small doses s:timulates neurons) or g lutamic acid, into the brain. As you learned in Chapter 4, the principal excitatory neurotransmitter in the brain is glutamic acid (glutamate), and both of these substances stimulate glutamate receptors, activating the neurons on which these receptors are located. Injections of chemicals into the brain can be done through an apparatus that is permanently attached to the skull so that the animal's behavior can be observed several

Methods and Strategies of Research

times. A researcher can place a cannula (a guide cannula) in an animal's brain using stereotaxic surgery and cement its top to the skull. A smaller cannula of measured length can be placed inside the guide cannula and used to inject a chemical into the brain. Because the animal is free to move about, it is possible to observe the effects of the injection on its behavior. (See Figure 5.27.) The principal disadvantage of chemical stimulation is that it is slightly more complicated than electrical stimulation because chemical stimulation requires cannulas, tubes, special pumps or syringes, and sterile solutions of excitatory amino acids. However, it has a distinct advantage over electrical stimulation: It activates cell bodies but not axons. Because only cell bodies (and their dendrites) contain glutamate receptors, we can be assured that an injection of an excitatory amino acid into a particular region of the brain excites the cells there but not the axons of other neurons that happen to pass through the region. This means that the effects of chemical stimulation are more localized than are the effects of electrical stimulation. You might have noticed that we just said that kainic acid, which we described earlier as a neurotoxin, can be used to stimulate neurons. These two uses are not really contradictory. Kainic acid produces excitotoxic lesions by stimulating neurons to death. Whereas large doses of a concentrated solution kill neurons, small doses of a dilute solution simply stimulate them.

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When chemicals are injected into the brain through cannulas, molecules of the chemicals diffuse over a region that includes many different types of neurons: excitatory neurons, inhibitory neurons, interneurons that participate in loceidase. Area V1 shows spots (blobs), and area V2 shows three types of stripes: thick, thin (both dark), and pale. (b) Neurons located in CO blobs of V1 project to thin stripes in V2. Neurons in the interblob reg ions of V1 project to pale and thick stripes of V2. Source: From Sincich, L. C., and Horton, J.C. (2005). The circuitry of V1 and V2: Integration c>f color, form, and motion, Annual Review of Neuroscience, 28, 303326. www.annualreviews.org

V2

(a)

V1 Smm

Thin

Pale stripe

Thick stripe

Neurons in the thin stripes receive information concerning color

(b)

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Extrastriate Cortex LO 6.11 Describe the structures and functions of the pathways of the extrastriate cortex. The striate cortex is necessary for visual perception, but the perception of objects and of entire visual scenes does not take place there. Each of the thousands of modules of the striate cortex sees only what is happening in one tiny part of the visual field. For us to perceive objects and entire visual scenes, the information from these individual modules must be combined. That combination takes place in the extrastriate cortex. STRUCTURES OF THE EXTRASTRIATE CORTEX In primates, extrastriate contains multiple regions (for example, V2-V4) arranged in a hierarchy from closest (V2) to farthest (V4) from the striate cortex (Grill-Spector & Malach, 2004; Wandell et al., 2007). So far, investigators have identified over two dozen distinct regions and subregions

Figure 6.14

of the visual cortex of the rhesus monkey. Each region of the extrastriatc~ cortex contains maps of the visual field and is specialized to respond to features of visual information, such as orientation, movement, spatial frequency, retinal disparity, or color. Most of this specialized information passes up the: hierarchy. Lower regions in the hierarchy (such as V2) analyze the information and pass the results on to "higher" regions (such as V3) for further analysis. Some information is also transmitted in the opposite direction, but fewer axons descend the hierarchy than ascend it. PATHWAYS O F THE EXTRASTRIATE CORTEX Visual processing in the extrastriate cortex divides into two pathways: the do rsal stream and the ven tral stream. The pathways begin to diverge after area V2. The dorsal stream begins with the neurons in the thick stripes of area V2 and ascends into regions of the posterior parietal cortex. The ventral stream begins with the neurons in the pale and thin

Pathways of the Extrastriate Cortex: The Dorsal and Vent ral Streams

Processing visual information involves connections across a hierarchy of cortical areas (represented by the blue arrows) beginning in the primary visual cortex (V1), which receives input from the lateral geniculate nucleus (LGN). Tl1e connections extend through a ventral stream into the temporal lobe and a dorsal stream into the parietal lobe and prefrontal cortex. This figure depicts some of the many cortical regions that are involved in extrastriate visual processing. Regions within the intraparietal sulcus (anterior/AIP, lateral/LIP, ventralNIP, and medial/MIP) are described in detail in the section on the role of the extrastriate cortex in perceiving spatial location. Source: Gilbert, C., Li, W. (2013) Top-down influences on visual processing. Nat Rev Neurosci 14, 350-363. https://doi.org/10.1038/nrn3476

-----+-

•• ••

Dorsal Stream Where an object is (motion processing) Ventral Stream What an object is (object recognition) parietal lobe frontal lobe occipital lobe temporal lobe

MT

middle temporal area

PFC

prefrontal cortex

LGN

lateral geniculate nucleus

TEO

temporo-occipital cortex

IT

inferior temporal cortex

MST medial superior temporal cortex

Vision 153 stripes of area V2, continues forward to area V4, and then projects to a variety of subareas of the inferior temporal cortex. Some axons conveying information received from the magnocellular system bypass area V2: They project from area Vl d irectly to area VS (also called area MT for medial temporal), a region of the dorsal stream devoted to the analysis of movement. (See Figure 6.14.) The dorsal and ventral streams play different roles in visual processing. The dorsal stream provides visual information that guides navigation and skilled movements directed toward objects. The ventral stream provides visual information about the size, shape, color, and texture of objects (including, as we shall see, other people). In other words, the dorsal stream recognizes where an object is, and the ventral stream recognizes what an object is. Usually, the dorsal and ventral streams communicate with each other through the vertical occipital Jasciculus, a tract of white matter found in many species (Takemura et al., 2018). Communication between these streams helps to seamlessly convey where and what in visual perception.

A fascinating study with young children demonstrates the importance of communication between the dorsal and ventral streams of the visual system in perception of form (DeLoache et al., 2004). The experimenters let children play with large toys: an indoor slide that they could climb and slide down, a chair that they could sit on, and a toy car that they could enter. After the children played in and on the large toys, the children were taken out of the room, the large toys were replaced with identical miniature versions, and the children were then brought back into the room. When the children played with the miniature toys, they acted as if they were the large versions: They tried to climb onto the slide, dimb into the car, and sit on the chair. One child said "In!" several times and turning to his mother, apparently asked her to help him. The authors suggest that this child's behavior reflects incomplete maturation of connections between the dorsal and ventral streams. The ventral stream recognizes the identity of the objects, and the dorsal stream recognizes their size, but in the developing brain, the information is not adequately shared between these two streams.

Module Review: Brain Regions Involved in Visual Processing Lateral Geniculate Nucleus LO 6.9

Describe the structure of the lateral geniculate nucleus.

Of the six cell layers in the LGN, layers 1, 4, and 6 receive inpu t from the retinal ganglion cells of the contralateral eye, and layers 2, 3, and 5 receive input from the ipsilateral eye. The two inner layers of the LGN are the magnocellular layers, an d the four outer layers are the parvocellular layers. The koniocellular sublayers are found beneath each of the six layers.

Striate Cortex LO 6.10 Identify the functions and organization of the

striate cortex. The striate cortex is the first cortical region involved in combining visual information from several sources. It receives visual input from the LGN and performs additional processing of this information, which it then transmits to the extrastriate cortex. The striate cortex contains six layers. Layer 4 contains four sublayers (4A, 4B, 4Ca, and 4Cl3). CO blobs are groups of cells that receive information about color from the parvocellular and koniocellular layers of the LGN. The striate cortex is divided into many modules, each containing thousands of neurons devoted to the analysis of specific features of a portion of the visual field . Neurons in CO blobs of the striate cortex project to thin stripes, and neurons outside the blobs (in interblob areas) p roject to thick stripes and pale

stripes: of the extrastriate cortex. Neurons in the thin stripes receive information concerning color, and those in the thick stripe~; and pale stripes receive information about orientation, spatial frequency, movement, and retinal disparity.

Extrastriate Cortex LO 6.111 Describe the s tructures and functions of the

pathways of the extrastriate cortex. The extrastriate cortex is responsible for hierarchically combining information from individual modules of the striate cortex to allow an individual to perceive objects and entire visual scenes. Each region of the extrastriate cortex is specialized, containing neurons that respond to particu lar fea tures of visual information, such as orientation,. movement, spatial frequency, retinal disparity, or color. The dorsal stream terminates in the posterior parietal cortex and is responsible for processing where the object is located. The ventral stream terminates in the inferior temporal cortex and is responsible for p rocessing what an object is.

Thought Question Take at moment to look at the scene in front of you right now a:nd imagine how its features are encoded by neurons in your striate and extrastriate cortex. Describe one object or aspect of your current visual scene and summarize where this information is processed in your visual cortex.

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1. ON cells are excited by light falling in the central field (center) and inhibited by light falling in the surrounding field (surround).

Perceiving Color With a basic understanding of the visual system, we will now turn our attention to understanding the roles these structures play in more specific visual functions. Not all components of the visual system have the same amount of involvement in different visual functions. For example, the retina is highly involved in basic functions such as perceiving light and dark, while both retinal and cortical processing are required for perceiving faces (see the case at the beginning of the chapter). The following sections will investigate the role of the visual system in perceiving color, form, spatial location, orientation, and movement. The sections on perceiving color and form focus on the "what" of ventral stream processing. The sections on perceiving spatial location, orientation, and movement focus on the "where" of dorsal stream processing.

2. OFF cells are excited by light falling in the surround and inhibited by light falling in the center. 3. ON/OFF ganglion cells are briefly excited when light is turned ion or off. In primates most of these ON/OFF cells project mainly to the superior colliculus, which is primarily involved in visual reflexes in response to moving or suddenly appearing stimuli (Schiller & Malpeli, 1977). (See Figure 6.15.) Figure 6.15 also illustrates a rebound effect that occurs when the light is turned off again. Neurons whose firing is inhibited while the light is on will show a brief burst of excitation when it is turned off. In contrast, neurons whose firing is increased will show a brief period of inhibition when the ligh1t is turned off. Ganglion cells normally produce action potentials at a relatively low rate. Then, when the level of illumination in the center of their receptive field increases or decreases (for example, when an object moves or the eye makes a saccade), the ganglion cells signal the change in illumination. ON cells signal increases in illumination and OFF cells signal decreases, but both convey changes in illumination through an increased rate of firing action potentials.

Role of the Retinal Ganglion Cells LO 6.12 Compare the activity of retinal ganglion cells in perceiving light and d ark. Perceiving light is required for perceiving color. As you read in the section on Transduction, ON and OFF bipolar cells initiate signals to retinal ganglion cells that are important in perceiving light and dark. Mammalian ganglion cells have a receptive field that consists of a roughly circular center, surrounded by a ring. There are three types of ganglion cells:

Figure 6.15

ON and OFF Ganglion Cells

This figure shows responses of ON and OFF ganglion cells to stimuli presented in the center or the surround of the receptive field. Source: Adapted from Kuttler, S. W. (1952). Neurons in the retina: Organiza1tion, inhibition and excitation problems. Cold Spring Harbor Symposium for Quantitative Biology, 17, 281-292.

OFF ganglion cell

ON ganglion cell ON area

OFF area

OFF area

ON area

Light

Spot of light in center

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(s)

Time ~

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0.5

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0.5

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Vision

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Role of the Retina

Figure 6.16 Absorbance of Light by Rods and Cones

LO 6.13 Differentiate between the trich romatic and opponent-color system theories.

The graph shows the relative absorbance of light of various wavelengths by rods and the three types of cones in the human retina.

Various theories of color vision have been proposed for many years-long before it was possible to disprove or validate them by physiological means. The trichromatic (three-color) theon; was proposed in 1802 and suggested that the eye detected different colors because it contained three types of cones, each sensitive to a single hue. An alternative explanation, the opponent-color system theory, suggested that color might be represented in the visual system as opponent colors: red versus green and yellow versus blue. Many people consider yellow, blue, red, and green as primary colors-colors that seem unique and do not appear to be blends of other colors. (Black and white are primary, too, but we perceive them as colorless.) All other colors can be described as mixtures of these primary colors. The trichromatic system cannot explain why yellow is included in this group-why it is perceived as a pure color. In addition, some colors appear to blend, whereas others do not. For example, one can speak of a bluish green or a yellowish green, and orange appears to have both red and yellow qualities. Purple resembles both red and blue. But try to imagine a reddish green or a bluish yellow. It is impossible; these colors seem to be opposite to each other. Again, these facts are not explained by the trichromatic theory. As we shall see in the following sections, the visual system uses both trichromatic and opponent-color systems to encode information related to color.

(1983). Proceedings of the Royal Society of London, B, 220, 115-130.

Source: Based on data from Dartnall, H. J. A., Bowmaker, J. K., and Mellon, J. D.

PHOTORECEPTORS: TRICHROMATIC CODING Physiological investigations of retinal photoreceptors in higher primates support the trichromatic theory: Three different types of photoreceptors (three different types of cones) are responsible for color vision. Figure 6.16 demonstrates light absorbance by blue, green, and red light-sensitive cones. Investigators have studied the absorption characteristics of individual photoreceptors, determining the amount of light of different wavelengths that is absorbed by the photopigments. These characteristics are controlled by the particular opsin a photoreceptor contains; different opsins absorb particular wavelengths more readily. Changes in color vision can result from anomalies in one or more of the three types of cone (Wissinger & Sharpe, 1998; Nathans, 1999). The first two kinds of color blindness described here involve genes on the X chromosome. Because most men have only one X chromosome, they are more likely to have this disorder. (Women are likely to have an unaffected gene on one of their X chromosomes, which compensates for the defective one.) People with protanopia ("first-color defect") confuse red and green.

"Blue"

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They see the world in shades of yellow and blue; both red and green look yellowish to them. Their visual acuity is normal, which suggests that their retinas do not lack "red" or "green" cones. This fact and their sensitivity to lights of diff.erent wavelengths suggest that their "red" cones are filled with "green" cone opsin. People with d euteran.opia ("second-color defect") also confuse red and green and have normal visual acuity. Their "green" cones appear to be filled with "red" cone opsin. (In other words, their vision is dichro•matic, or "two color," like that of our ancestors and most present-day mammals.) Mancuso and colleagues (2009) attempted to perform gene !therapy on adult squirrel monkeys whose retinas lacked! the gene for "red" cone pigment. Although most female squirrel monkeys have trichromatic color vision, males have only dichromatic vision and cannot distinguish red from green. Mancuso and her colleagues used a genetically modified virus to insert a human gene for the pigment of that "red" cone into the retinas of male monkeys. Color vision tests before and after surgery confirmed that the gene insertion converted the monkeys from dichromats into trichromats: They could now distinguish between red and green. Tritanopia ("third-color defect") is rare, affecting fewer than 1 in 10,000 people. This disorder involves a faulty gene that is not located on an X chromosome and is equally prevalent in men and women. People with tritanopia have difficulty with hues of short wavelengths and see the world in greens and reds. To them a clear blue sky is a bright green, and yellow looks pink. Their retinas lack "blue" cones. Because the retina contains so few of these cones, their absence does not noticeably affect visual acuity.

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Finally, some people possess a very rare genetic condition in which the retina completely lacks cones. These individuals have monochromatic vision and see the visual world in black and white and shades of grey. For an example of the stimuli used to assess color blindness, see Figure 6.17. RETINAL GANGLION CELLS: OPPONENT-PROCESS CODING Unlike cones, retinal ganglion cells use an

opponent-color system. These neurons respond specifically to pairs of primary colors, with red opposing green and blue opposing yellow (Daw, 1968; Gouras, 1968). This means the retina contains two kinds of color-sensitive ganglion cells: red-green and yellow-blue. Some colorsensitive ganglion cells respond in a center-surround fashion. For example, a cell might be excited by red and inhibited by green in the center of their receptive field while showing the opposite response in the surrounding ring.

Figure 6.17

Testing for Color Vision

Special images are used to assess protanopia, deuteranopia, and tritanopia. The tester shows the individual the images and asks them to identify the number in the circle. In protanopia, people have difficulty seeing the color red because their "red" cones are filled with "green" cone opsin. In deuteranopia, people have difficulty seeing green because their "green" cones appear to be filled with "red" cone opsin. In tritanopia, people have difficulty seeing blue

because their retinas lack "blue" cones.

Test for protanopia:

Test for deuteranopia:

Figure 6.18

Receptive Fields of Color-Sensitive

Gang lion Cells When a portion of the receptive field is illuminated with the color shown, the cell's rate of firing increases. When a portion is illuminated with the complementary color, the cell's rate of firing decreases.

O®®O Yellow on, blue off

Blue on, yellow off

Red on, green off

Green on red off

(See Figure 6.18.) Other ga nglion cells that receive input from cones do not respond differently to different wavelengths but simply encode relative brightness in the center and surround. These cells serve as "black-andwhite detecto1rs." The response characteristics of retinal ganglion cells to light of different wavelengths are determined by the particular circuits that connect the three types of cones with the two types of ganglion cells. Figure 6.19 helps to explain how hues are detected by "red," "green," and "blue" cones and translated into excitation or inhibition of the red-green and yellow-blue ganglion cells. The diagram does not show the actual neural circuitry, which includes the retinal neurons that connect the cones with the ganglion cells. The arrows in Figure 6.19 refer to the effects of the light falling on the retina. Detection and coding of pure red, green, or blue light is the easiest to understand. For example, red light excites "red" cones, which causes the excitation of red-green ganglion cells. (See Figure 6.19a.) Green light excites "green" cones, which causes the inhibition of red-green cells. (See Figure 6.19b) But consider the effect of yellow light. Because the wavelength that produces the sensation of yellow is intermediate between the wavelengths that produce red and green, it will stimulate both "red" and "green" cones about equally. Yellow-blue ganglion cells are excited by both "red" and "green" cones, so their rate of firing increases. However, red-green ganglion cells are excited by red and inhibited by green, so their firing rate does not change. The brain detects an increased firing rate from the axons of yellow-blue ganglion cells, which it interprets as yellow. (Se1e Figure 6.19c.) Blue light inhibits the activ-

ity of yellow..:blue ganglion cells. (See Figure 6.19d.) The

Test for tritanopia:

opponent-color system used by the ganglion cells explains why we cannot perceive a reddish green or a bluish yellow: An axon that signals red or green (or yellow or blue) can either increas1~ or decrease its rate of firing; it cannot do both at the same time. A reddish green would have to be signaled by a :ganglion cell firing slowly and rapidly at the same time, which is impossible.

Vision

Figure 6.19

157

Color Coding in the Retina

{a) Red light stimulating a "red" cone, which causes excitation of a red-!~reen ganglion cell. (b) Green light stimulating a "green" cone, which causes inhibition of a red-green ganglion cell. {c) Y•ellow light stimulating "red" and "green" cones equally but not affecting "blue" cones. The stimulation of "red " and "gmen" cones causes excitation of a yellow-blue ganglion cell. {d) Blue light stimulating a "blue" cone, which causes inhilbition of a yellow-blue ganglion cell. The arrows labeled E and I represent neural circuitry within the retina that translates; excitation of a cone into excitation or inhibition of a ganglion cell. For clarity, only some of the circuits are shown. Red light stimulates "red" cone

Green light stimulates "green" cone

i

Yellow light stimulates " red" and "green" cones equally

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Figure 6.20 demonstrates an interesting property of the visual system: the formation of a negative afterimage. Stare at the cross in the center of the image on the left for approximately 30 seconds. Then quickly look at the cross in the center of the white rectangle to the right. You will have a fleeting experience of seeing the red and green colors of an applecolors that are complementary, or the opposite, to the ones on the left. Complementary items go together to make up a whole. In this context complementary colors are those that make white (or shades of gray) when added together. The most important cause of negative afterimages is adaptation in the rate of firing of retinal ganglion cells. When ganglion cells are excited or inhibited for a prolonged period of time, they later show a rebound effect, firing faster or slower than normal. For example, the green of the apple in Figure 6.20 inhibits some red-green ganglion cells. When this region of the retina is then stimulated with the neutral-colored light reflected off the white rectangle, the red-green ganglion cells-no longer inhibited by the green light- fire faster than normal and we see a red afterimage of the apple.

Role of the Striate and Extrastriate Cortex LO 6.114 Describe the role of the striate and extrastriate cortex in color perception. The retinal ganglion cells encode information about the relative amounts of light falling on the center and surround regionis of their receptive field and, in many cases, about the wavelength of that light. This information is then relayed to the LGN, then on to the striate cortex, and finally to the extrastriate cortex. The parvocellular, koniocellular, and magnocellular systems provide different kinds of information to the striate cortex. (See Figure 6.11.) Only the cells in the parvocellular and koniocellular systems receive information about wavelength from cones. These systems provide information concerning color. The parvocellular system receives information only from "red" and "green" cones; additional information from "blue" cones is transmitted through the koniocellular system (Chatterjee & Callaway, 2003; Hendry

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Figure 6.20

A Negative Afterimage

Stare for approximately 30 seconds at the plus sign in the center of the left figure; then quickly transfer your gaze to the plus sign in the center of the right figure. You will see colors that are complementary to the originals.

+

& Yoshjoka, 1994). Cells in the parvocellular system also show hlgh spatial resolution and low temporal resolution; that is, they are able to detect very fine details, but their response is slow and prolonged. In the koniocellular system, the "blue" cones are much less numerous than "red" and "green" cones and do not provide information about fine details. In contrast, neurons in the magnocellular system are color-blind. They are not able to detect fine details, but they can detect smaller contrasts between light and dark. They are also especially sensitive to movement. (See Table 6.2.) In the extrastriate cortex, the dorsal ("where") stream receives mostly magnocellular input to process light/dark contrast and movement. The ventral stream ("what") receives approximately equal input from the magnocellular and the parvocellular/koniocellular systems, helping to process color and details relevant to object recognition.

STUDIES WITH LABORATORY ANIMALS In the monkey brain, color-sensitive neurons in the CO blobs of the striate cortex send color-related information to the thin stripes in area V2. Neurons in V2 send information to an adjacent region of the extrastriate cortex, called V4. (See Figure 6.21.) Zekj (1980) found that neurons in thls region respond selectively to colors, but their response characteristics are much more complex than those of neurons in Vl or V2. Unlike the neurons we have encountered so far, these extrastriate

neurons respond to a variety of wavelengths, not just the wavelengths that correspond to red, green, yellow, and blue. Schein and Desimone (1990) performed a careful study of the response characteristics of neurons in area V4 of the monkey extra:striate cortex, which receives input from the pale and thin stripes of area V2. They found that these neurons responded to specific colors. Some also responded to colored bars of specific orientation. Thls inrucates that area V4 seems to be involved in the analysis of form as well as color. The col.or-sensitive neurons had a rather unusual secondary receptive field: a large region surrounding the primary field. When stimuli were presented in the secondary receptive :field, the neuron rud not respond. However, stimuli presented there could suppress the neuron's response to a sltimulus presented in the primary field. For example, if a cell would fire when a red spot was presented in the primary field, it would fire at a slower rate (or not at all) when an atdditional red stimulus was presented in the surrounding secondary field. In other words, these cells responded to particular wavelengths of light but subtracted out the amow1t of that wavelength that was present in the background. As Schein and Desimone point out, thls subtraction could serve as the basis for color constancy (see section The Stimulus: Light).

Table 6.2 Properties of the Magnocellular, Parvocellular, and Koniocellular Divisions of the Visual System Color

No

Yes (from "red" and "green" cones)

Yes (from "blue" cones)

Sensitivity to contrast

High

Low

Low

Spatial resolution (ability to detect fine details)

Low

High

Low

Temporal resolution

Fast (transient response)

Slow (sustained response)

Slow (sustained response)

Vision 159

Figure 6.21 Color Processing via Parvocellu1lar and Koniocellular Systems

The dorsal stream receives mostly magnocellular input (light/dark contrast and movement).

Color processing: The ventral stream receives approximately equal input from the magnocellular, parvocellular ("red" and "green" cones) and koniocellular ("blue" cones) systems.

Walsh and colleagues (1993) confirmed this prediction; damage to area V4 does disrupt color constancy. The investigators found that, although monkeys could still discriminate between d ifferent colors after area V4 had been damaged, their performance was impaired when the color of the overall illumination was changed.

strongly sensitive to colors or to shape but not to both. The fact that color-sensitive globs are spread across a wide area of visiual association cortex probably explains why only rather large brain lesions cause severe disruptions in perceiving color.

But the fact that the monkeys could still perform a color

STUDIES WITH HUMANS Lesions of a restricted region of the human extrastriate cortex can cause loss of color vision withoiut disruption of visual acuity. Some patients describe their vision as resembling a black-and-white film. In addition, they may not be able to imagine colors or remember the colors of objects they saw before their brain damage occurred (Damasio et al., 1980; Heywood & Kentridge, 2003). The condition is known as cerebral achromatopsia. If the brain damage is unilateral, people will lose color vision in only half of the visual field. The case of Mrs. D. illustrates a unique example of cerebral achromatopsia.

discrimination task under constant illumination means that some region besides area V4 must be involved in color vision. A study by Heywood and colleagues (1995) suggested that a portion of the inferior temporal cortex just anterior to area V4-a region of the monkey brain that is usually referred to as area TEO- plays a critical role in visual discrimination. (See Figures 6.14 and 6.21.) The investigators destroyed area TEO, leaving area V4 intact, and observed severe impairment in color discrimination. The monkeys had no difficulty in discriminating shades of gray, so the deficit was restricted to impaired color perception. Conway and colleagues (2007) performed a detailed analysis of the responsiveness of neurons in a large region of the visual association cortex in monkeys, including areas V4 and TEO. Using fMRI, the investigators identified color "hot spots"-small scattered regions that were strongly activated by changes in the color of visual stimuli. Next, they recorded the response characteristics of neurons inside and outside these spots, which they called globs. (It's likely the similarity between the terms "blobs" and "globs" was intentional.) They found that glob neurons were indeed responsive to colors but also had some weak sensitivity to shapes. In contrast, interglob neurons (those located outside globs) did not respond to colors but were strongly selective to shape. This means that within a large region of the visual association cortex, patches of neurons were

Mrs. D. was a 74-year-old woman who loved oil painting as a hobby. She suffered two strokes that affected her occipital cortex, one in each hemisphere. After the strokes. testing revealed that she had a full visual field; however, Mrs. D. reported seeing the world in shades of grey. Several months later, she described seein!;:J the world in reddish-brownish shades, and occasionally perce,ived bright, saturated colors (Bartolomeo et al., 1997). Researchers located a region of the inferior temporal co1rtex of the monkey brain whose damage disrupted the ability to make color discriminations. The analogous regiont in humans appears to play a critical role in color perception as well. An fMRI study by Hadjikhani and colleagues (1998) found a color-sensitive region that included the lingual and fusiform gyri, in a location corresponding to area TEO in the monkey's cortex, which they called area V8. An analysis of 92 cases of achromatopsia

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by Bouvier and Engel (2006) confirmed that damage to this region (which is adjacent to and partly overlaps the fusiform face area, discussed later in this chapter) disrupts color vision. The function of our ability to perceive different colors is to help us perceive different objects in our environment. To perceive and understand what is in front of us, we must have information about color combined with other forms of information. Some people with brain damage lose the ability to perceive shapes but can still perceive colors. For example, Zeki and colleagues (1999) described a patient who could identify colors but was otherwise blind. Patient P. B. received an electrical shock that caused both cardiac and respiratory arrest. He was revived, but the period of anoxia caused extensive damage to his extrastriate cortex. As a result, he lost all form perception. However, even though he could not recognize objects presented on a video monitor, he could still identify their colors. (See Figure 6.22.)

Figure 6.22'. Case of Damage to the Extrastriate Cortex That Resulted in Loss of Form, but Not Color, Perception Patient P. B. exp1erienced damage to the extrastriate cortex. Structural and functional MRI data from the patient P. B. show activation in area V1 (white area on the MRI scan) when correctly identifying colors, though he could not perceive the form or shape of the stimulus. Source: Zeki , S., A!~lioti, S., McKeefry, D., and Berlucchi, G. (1999). The neurological basis of conscious color perception in a blind patient. Proceedings of the National Academy of Sciences, USA, 96, 13594-13596.

calcarine fissure

Module Review: Perceiving Color Role of the Retinal Ganglion Cells LO 6.12 Compare the activity of retinal ganglion cells in perceiving light and dark.

ON, OFF, and ON/OFF retinal ganglion cells contain center and surround portions of their receptive fields. In ON cells, light stimulating the center (but not the surround) portion of the receptive field results in a burst of action potentials. In OFF cells, light stimulating the surround (but not the center) portion of the receptive field results in a burst of action potentials. ON/OFF cells respond when the light goes on and again when it goes off. These cells project mainly to the superior colliculus, which is involved in visual reflexes in response to moving or suddenly appearing stimuli.

Role of the Retina LO 6.13 Differentiate between the trichromatic and opponent-color system theories.

The trichromatic theory explains that the eye detects different colors because it contains three types of receptors,

each sensitive to a single hue (blue, green, or red). The opponent-color system theory explains that color is represented in the visual system as opponent colors: red versus green and yellow versus blue. Research has revealed that cones are sensitive to blue, green, and red light, in support of the trichromatic theory and that retinal ganglion cells respond specifically to pairs of colors, with red

opposing green and blue opposing yellow, in support of the opponent-color system theory.

Role of the Striate and Extrastriate Cortex LO 6.14 Describe the role of the striate and extr.astriate cortex in color perception.

In the striate cortex, the parvocellular system receives information from "red" and "green" cones. Additional information from "blue" cones is transmitted through the koniocellular system and relayed to the extrastriate cortex. Extrastriate cortex region V4 adds complexity to the color processing begun in the striate cortex and is likely involved in the analysis of form as well as color. Area TEO in the primate extrastriate cortex is responsible for additional color and shape perception. Research with human volunteers revealed a region for color perception, V8, that is analogous to TEO. Damage to this region results in achromatopsia. Damage to other regions of the extrastriate cortex can selectively impair form recognition, leaving the ability to dliscriminate between colors intact.

Thought Question Imagine that you have been asked to create a figure that would produce a negative afterimage. Describe how you would constriuct the image to produce a negative afterimage and wli1at directions you would give to viewers to help them experience the negative afterimage. For review, refer to IFigure 6.20.

Vision

Perceiving Form The analysis of visual information that leads to the perception of form begins with neurons in the striate cortex that are sensitive to spatial frequency. These neurons send information to area V2 and then on to the ventral stream of the extrastriate cortex. (See Figure 6.14.) Let's look at this process in closer detail.

Role of the Striate Cortex LO 6.15 Outline the benefit of neural circuits that analyze spatial frequency in the striate cortex. Early studies by Hubel and Wiesel suggested that neurons in the primary visual cortex detected lines and edges, and subsequent research found that cells in the striate cortex actually responded strongest to sine-wave gratings (De Valois et al., 1978). Figure 6.23 compares a sine-wave grating with a square-wave grating. A square-wave grating consists of a simple set of rectangular bars that vary in brightness; the brightness along the length of a line perpendicular to them would vary in a stepwise (square-wave) fashion. (See Figure 6.23a.) A sine-wave grating looks like a series of fuzzy, unfocused parallel bars. Along any line perpendicular to the long axis of the grating, the brightness varies according to a sine-wave function. (See Figure 6.23b.) A sine-wave grating is designated by its spatial frequency. Frequencies (for example, of sound waves or radio

Figure 6.23

waves.) are often expressed in terms of time or distance (such as cycles per second or wavelength in cycles per meter). But because the image of a stimulus on the retina varies in size according to how close it is to the eye, the visual angle is generally used instead of the physical distance lbetween adjacent cycles. This means that the spatial frequimcy of a sine-wave grating is its variation in brightness measured in cycles per degree of visual angle. Most neuroins in the striate cortex respond best when a sinewave grating of a particular spatial frequency is placed in the appropriate part of the visual field. Different neurons detect different spatial frequencies. What is the point of having neural circuits that analyze spatial frequency? Consider the types of information provided by high and low spatial frequencies. Small objects, details within a large object, and large objects with sharp edges provide a signal rich in high frequencies, whereas large areas of light and dark are represented by low frequencies. An image that is deficient in high-frequency infomrntion looks fuzzy and out of focus, like the image seen by a nearsighted person who is not wearing corrective lenses. This image still provides much information about forms and objects in the environment. The most important visual information is contained in low spatial frequencies. When low-frequency information is removed, the shapes of images are very difficult to perceive. (The evolutionarily older magnocellular system provides low-frequency infomrntion.)

Spatial Frequency

This figure compares two kinds of gratings: (a) square-wave grating, and (b) sine-wave grating. (c) Angles are drawn between the sine waves, with the apex at the viewer's eye. The visual angle between adjacent sine waves is smaller when the waves are closer together.

(a)

(b)

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162 Chapter 6 Many experiments have confirmed that the concept of spatial frequency analysis plays a central role in visual perception, and mathematical models have shown that the information present in a scene can be represented very efficiently if it is first encoded in terms of spatial frequency. This means that the brain probably represents the information in a similar way. Here we will describe an example to help show the validity of the concept. Look at the two pictures in Figure 6.24. You can see that the picture on the right looks much more like the face of Abraham Lincoln than the one on the left does. Yet the two pictures contain the same information. The creators of the pictures, Harmon and Julesz (1973), constructed the figure on the left, which consists of a series of squares, each representing the average brightness of a portion of a picture of Lincoln. The one on the right is simply a transformation of the first one in which high frequencies have been removed. Sharp edges contain high spatial frequencies, so the transformation eliminates them. In the case of the picture on the left, these frequencies have nothing to do with the information contained in the original picture, and they can be seen as visual "noise." The filtration process removes this noise-and makes the image much clearer to the human visual system. Presumably, the high frequencies produced by the edges of the squares in the left figure stimulate neurons in the striate cortex that are tuned to high spatial frequencies. When the visual association cortex receives this noisy information, it has difficulty perceiving the underlying form. If you want to watch the effect of filtering the extraneous high-frequency noise, try the following demonstration. Look at the pictures in Figure 6.24 from across the room. The distance "erases" the high frequencies, because they exceed the resolving power of the eye, and the two pictures look identical Now walk toward the pictures, focusing on the left

Figure 6.24

Spatial Filtering

The two pictures contain the same amount of low-frequency information, but extraneous high-frequency information has been filtered from the picture on the right. If you look at the pictures from across the room, they look identical. Source: From Harmon, L. D.. and Julesz, B. (1973). Masking in visual recognition: Effects of two-dimensional filtered noise, Science, 180, 11911197. Copyright 1973 by the American Association for the Advancement of Science. Reprinted with permission.

figure. As you get closer, the higher frequencies reappear, and this picture looks less and less like the face of Lincoln.

Role of the Extrastriate Cortex LO 6.16 Describe the roles of the ventral stream and

fusiform face area in perceiving form. Much of our understanding about the role of the extrastriate cortex in form perception has come from research in humans and other animals. The following sections describe research supporting the role of the extrastriate cortex in recognizing; objects, patterns, and categories. STUDIES WllrH LABORATORY ANIMALS In primates, recognizing visual patterns and identifying objects take place in the inferior temporal cortex, located in the ventral part of the temporal lobe. This region of extrastriate cortex is located at the end of the ventral stream. It is here that analyses of form and color are put together, and perceptions of three-dimensional objects and backgrounds are achieved. The inferior temporal cortex consists of two major regions: a posterior area (TEO) and an anterior area (TE). Damage to these regions causes severe deficits in visual discrimination (Dean, 1976; Gross, 1973; Mishkin, 1966). (See Figure 6.14.) As we saw earlier, the analysis of visual information is hierarchical: Area Vl is concerned with the analysis of elementary aspects of information in very small regions of the visual field, and successive regions (V2, etc.) analyze more complex characteristics. The size of the receptive fields also grows a~; the hierarchy is ascended. The receptive fields of neurons in area TEO are larger than those in area V4, and the receptive fields of neurons in area TE are the largest of all, often encompassing the entire contralateral half of the visual field (Boussaoud et al., 1991). In general, these neurons respond best to three-dimensional objects (or photographs of them). They respond poorly to simple stimuli such as spots, lines, or sine-wave gratings. Most of them conti1nue to respond even when complex stimuli are moved to different locations, are changed in size, are placed against a different background, or are partially occluded by othier objects (Kovacs et al., 1995; Rolls & Baylis, 1986). Th ese cells appear to participate in the recognition of objects rather than the analysis of specific features. The fact tlhat neurons in the primate inferior temporal cortex respond to very specific complex shapes suggests that the devek>pment of the circuits responsible for detecting them mus.t involve learning. Indeed, that seems to be the case. For e:xample, several studies have found neurons in the inferior temporal cortex that respond specifically to objects that the monkeys have already seen many times but not to unfamiliar objects (Baker et al., 2002; Kobatake et al., 1992; Logothetis et al., 1995). STUDIES WITH HUMANS Study of people who have sustained braiin damage to the extrastriate cortex has told

Vision 163 us much about the organization of the human visual system. In recent years our knowledge has been greatly expanded by functional imaging studies. Visual Agnosia Damage to the human extrastriate cortex can cause a category of deficits known as visual agnosia. Mrs. R., whose case was described in the opening of this chapter, had visual agnosia caused by damage to the ventral stream of her extrastriate cortex. She could not identify common objects by sight, even though she had relatively normal visual acuity. However, she could still read, even small print, which indicates that reading involves different brain regions than object perception does. (Chapter 14 discusses research that has identified brain regions involved in visual recognition of letters and words.) When she held an object that she could not recognize visually, she could immediately recognize it by touch and say what it is, which demonstrates that she had not lost her memory for the object or simply forgotten how to say its name. Recognizing Categories Visual agnosia is caused by damage to the parts of the extrastriate cortex that contribute to the ventral stream. This is vividly illustrated by a case report of patient J. S. by Karnath and colleagues (2009). Patient J. S. sustained a stroke in which the ventral stream was seriously damaged, but the dorsal stream was intact. He was unable to recognize objects or faces and could no longer read. He could not recognize shapes or orientations of visual stimuli (ventral stream functions). However, his ability to reach for and pick up objects was preserved, and if he knew in advance what they were, he could pick them up and use them appropriately (dorsal stream functions). For example, if he knew where his clothes were, he could pick them up and get dressed. He could shake hands when someone else extended his hand to him. He could walk around his neighborhood, enter a store, and give a wrrtten list to an employee. With the advent of functional imaging, investigators have studied the responses of the typical human brain and have discovered several regions of the ventral stream that are activated by the sight of particular categories of visual stimuli. For example, researchers have identified regions of the inferior temporal and lateral occipital cortex that are specifically activated by categories such as animals, tools, cars, flowers, letters and letter strings, faces, bodies, and scenes. (See Grill-Spector & Malach, 2004, and Tootell et al., 2003 for a review.) However, not all of these findings have been replicated, and general-purpose regions contain circuits that can learn to recognize shapes that do not fall into these categories. A relatively large region of the ventral stream of the visual association cortex, the lateral occipital complex (LOC), appears to respond to a wide variety of objects and shapes. A functional imaging study by Downing and colleagues (2006) suggests that there are few regions of the extrastriate cortex devoted to the analysis of specific categories of

stimuli. The investigators presented images of objects from 19 difJferent categories to a control group and found only three regions that showed the greatest activation to the sight of specific categories: faces, bodies, and scenes. Bell and colleagues (2009) found that in both the human and the monkey brain, regions that responded to faces and body parts were atdjacent to each other, as were those that responded to objects and scenes of places. (See Figure 6.25.) Recog1nizing Faces A common symptom of visual agnosia is prosop agnosia, inability to recognize particular faces (prosopon is Greek for "face"). That is, patients with this d isorder •Can recognize that they are looking at a face, but they cannot say whose face it is-even if it belongs to a relative or clos:e friend. They see eyes, ears, a nose, and a mouth, but they cannot recognize the particular configuration of these featun?s that identify an individual face. They still remember who these people are and will usually recognize them when they hear the person's voice, like the case of Mrs. R.

Figure 6.25 Category-Selective Regions in Monkeys and Humans Views of the temporal lobes of monkeys E and J as well as the groupe1d human dataset showing category-selective regions throughout the brain. Voxels are colored according to their prefere1nce for one of the four categories tested. Source: Bell, A. H., Hadj-Bouziane, F., Frihauf, J. B., Tootell, R. B. H., et al. (2009'). Object representations in the temporal cortex of monkeys and humans as revealed by functional magnetic resonance imaging. Journal of Neuropt.1ysiology, 101, 688-700.

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Chapter 6

As one patient said, "I have trouble recognizing people from just faces alone. I look at their hair color, listen to their voices ... I use clothing, voice, and hair. I try to associate something with a person one way or another ... what they wear, how their hair is worn" (Buxbaum et al., 1999, p. 43). Studies with people who have experienced brain damage and functional-imaging studies suggest that these special face-recognizing circuits are found in the fusiform face area (FFA), located in the fusiform gyrus on the base of the temporal lobe. For example, Grill-Spector and colleagues (2004) obtained fMRI scans of the brains of people who looked at pictures of faces and several other categories of objects and found that regions of the fusiform cortex were selectively activated by viewing faces. (See Grill-Spector et al., 2017 for a review of the FFA and its associated circuits.) Perhaps the most unusual piece of evidence for a special face-recognition region comes from a report by Moscovitch and colleagues (1997), who studied a man with a visual agnosia for objects but not for faces. For example, he recognized the face shown in Figure 6.26 but not the flowers, fruits, and vegetables that compose it. Presumably, some regions of his visual association cortex were damaged, but the fusiform face region was not. Some people have congenital prosopagnosia-the inability to recognize faces without having obvious damage to the FFA. Behrman and colleagues ( 2007) found that the

anterior fusiform gyrus is smaller in people with congenital prosopagn1Jsia, and a diffusion tensor imaging study by Thomas and colleagues (2009) found evidence that people with congenital prosopagnosia show decreased connectivity within the occipito-temporal cortex. Another interesting region of the ventral stream is the extrastriate b01dy area (EBA), which is just posterior to the FFA and partly overlaps it. Downing and colleagues (2001) found that this region was specifically activated by photographs, silhouettes, or stick drawings of human bodies or body parts and not by control stimuli such as photographs or drawings of tools, scrambled silhouettes, or scrambled stick drawings of human bodies. Figure 6.27 shows the magnitude of the fMRI response in the nonoverlapping regions of the FFA and EBA t:o several categories of stimuli (Schwarzlose et al., 2005). As you can see, the FFA responded to faces more than any of the other categories, and the EBA showed the greatest response to headless bodies and body parts. Urgesi and colleagues (2004) used transcranial magnetic stimulation (TMS) to temporarily disrupt the normal neural activity of the EBA. (As we saw in Chapter 5, the TMS procedure applies a strong localized magnetic field to the brain by passing an electrical current through a coil of wire placed on the scalp.) The investigators found that the disruption temporarily impaired people's ability to recognize photographs of body parts, but not parts of faces or motorcycles.

Figure 6.26

Figure 6.27'

Visual Object Agnosia Without

Prosopagnosia A patient could recognize the face in this painting but not the flowers, fruits, and vegetables that compose it. Source: Giuseppe Arcimboldo. 1527-1593. Vertumnus. Erich Lessing/Art Resource, New York.

Perception of Faces and Bodies

The fusiform fac13 area (FFA) and extrastriate body area (EBA) were activated by images of faces, headless bodies, body parts, and assorted objects.. Source: Adapted from Schwarzlose, R. F., Baker, C. I., and Kanwisher, N. (2005). Separate face and body selectivity on the fusiform gyrus. Journal of Neuroscience, 23, 11055-11059.

Faces

Assorted objects

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Body parts

oo rm Extrastriate Body Area (EBA)

Vision

As we will see in Chapter 13, the hippocampus and nearby regions of the medial temporal cortex are involved in spatial perception and memory. Several studies have identified a parahippocampal place area (PPA), located in a region of limbic cortex bordering the ventromedial temporal lobe, that is activated by the sight of scenes and backgrounds. For example, Steeves and colleagues (2004) studied Patient 0. F., a 47-year-old woman who had sustained brain damage caused by accidental carbon monoxide poisoning 14 years earlier. Bilateral damage to her lateral occipital cortex (an important part of the ventral stream) caused profound visual agnosia for objects. However, she was able to recognize both natural and human-made scenes (beaches, forests, deserts, cities, markets, and rooms). Functional imaging showed activation of her intact PPA. These results suggest that scene recognition does not depend on recognition of particular objects found within the scene, because D. F. was incapable of recognizing these objects. Figure 6.28 shows the activation in her brain and that of a control participant. Expert Recognition As we just saw, the ability to recognize faces by sight depends on a specific region of the fusiform gyrus. But must we conclude that the development of this region is a result of natural selection and that the FFA comes prewired with circuits devoted to the analysis of faces? Several kinds of evidence suggest that the answer is no-that the face-recognition circuits develop as a result of the experience we have of seeing people's faces. Because of the extensive experience we have of looking at faces, we can become expert at recognizing them. It appears that recognizing specific complex stimuli by experts, too, is disrupted by lesions that cause prosopagnosia: inability of a farmer to recognize his cows, inability

Figure 6.28 The Parahippocampal Place Area The scans show activation of the parahippocampal cortex in Patient D. F., a woman with a profound visual agnosia for objects, in response to viewing scenes (a) and similar responses in a control subject (b). Source: From Steeves, J. K. E., Humphrey, G. K., Culham, J. C. , et al. (2004). Behavioral and neuroimaging evidence for a contribution of color and texture information to scene c lassification in a patient with visual form agnosia. Journal of Cognitive Neuroscience, 16, 955-965. Reprinted by permission.

(a)

(b)

165

of a bird expert to recognize different species of birds, and inability of a driver to recognize his own car except by reading its license plate (Bornstein et al., 1969; Damasio et al., 1982). Two functional imaging studies (Gauthier et al., 2000; Xu, 2005) found that when bird or car experts (but not nonexperts) viewed pictures of birds or cars, the fusiform face area was activated. Another study (Gauthier et al., 1999) found that when people had spent a long time becoming familiar with computer-generated objects they called "greebles," viewing the greebles activated the fusiform face area. Tarr and Gauthier (2000) suggested we should relabel the FFA as the flexible fusiform area. A functional imaging study (Golby et al., 2001) found higher activation of the fusiform face area when people viewed pictures of faces of members of their own race (African Americans or European Americans). Participants in this. study recognized faces of people of their own race more accurately than faces of people of another race. Presumably, this difference reflected the fact that the people in the study had more experience seeing members of their own race, which indicates that expertise does appear to play a role in face recognition. There is no doubt that a region of the fusiform gyrus plays an essential role in the analysis of particular faces. In fact, a face-responsive area exists in a similar location in the monkt~y brain, and this area contains neurons that respond to the faces of both monkeys and humans (Tsao et al., 2006). Two issues are still disputed by investigators interested in the FFA. First, is an analysis of faces the sole function of this region, or is it really a "flexible fusiform area" involved in visual analysis of categories of very similar stimuli that can be discriminated only by experts? The activation of the FFA by greebles in the brains of greeble experts suggests that the FFA is an expertise area rather than an exclusively face area. However, perhaps a more important issue is the relative roles of genetic programming and experience in the development of a brain region critically involved in face perception. Developmental Aspects of Recognition A functional imaging study indicates that although the relative size of the LOC, which responds to objects other than faces and bodies, is the same in children and adults, the left FFA does not reach its eventual size until adulthood, and the ability to 1recognize faces is directly related to the expansion of the FFA (Golarai et al., 2007). These findings are consistent with the suggestion that the ability to recognize faces is a learned skill that grows with experience. Figure 6.29 shows the regions on the left and right fusiform cortex of an 8-year-old child and an adult. You can see the age-related size difference and also the difference between the size of this region in the left and right hemispheres. Newborn babies prefer to look at stimuli that resemble faces, which suggests the presence of prewired circuits in the human brain that dispose babies to look at faces and learn to recognize them. Farroni and colleagues (2005) presented

166 Chapter 6

Figure 6.29

Fusiform Gyrus Responses to Faces

This "inflated" ventral view of the brain of an 8-year-old child and an adult from the study by Golarai and colleagues (2007) shows the regions of the fusiform gyrus that responded to the sight of faces. The FFA is much larger in adults. Source: Courtesy of Golijeh Golarai, Department of Psychology, Stanford

University.

newborn babies (between 13 and 168 hours old) with pairs of stimuli and found that they preferred to look at the ones that bore the closest resemblance to faces viewed in their normal, upright orientation, with the lighting coming from above, as it normally does. Figure 6.30 illustrates the stimuli that Farroni and her colleagues used. An asterisk above a stimulus indicates that the babies spent more time looking at it than at the other member of the pair. If neither stimulus is marked with an asterisk, that means that the baby indicated no preference-and as you can see, these pairs of stimuli bore the least resemblance to a face illuminated from above. An imaging study by Deen and colleagues (2017) confirmed that brain areas sensitive to faces and scenes show adult-like spatial organization in the ventral streams by four to six months of age. However, this organization is further refined throughout development. Similar to other lines of research, face-sensitive regions in the infants included the fusiform gyrus, lateral occipital cortex, superior temporal sulcus (STS) and medial prefrontal cortex, while the

Figure 6.30 Preference of Newborn Babies for Viewing Stimuli That Resemble Faces An asterisk above a stimulus indicates that the babies spent more time looking at it than the other member of the pair. If neither stimulus is marked with an asterisk, the baby indicated no preference. Source: Adapted from Farroni, T., Johnson, M. H., Menon, E., Zulian, L., Faraguna, D., and Csibra, G. (2005). Newborns' preference for face-relevant stimuli: Effects of contrast polarity. Proceedings of the National Academy of Sciences, USA, 102, 17245- 17250.

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parahippocampal gyrus and lateral occipital cortex selectively responded to scenes (Deen et al., 2017). (See Figure 6.31.) A review of the literature by Johnson (2005) suggests that a baby's preference for faces is controlled by a fast, lowspatial-frequency, subcortical pathway that is present in newborn infants. This circuit survives in many adults with prosopagnosia caused by cortical damage, who are aware that they are looking at a face even though they cannot recognize it and .can even recognize facial expressions such as happiness, fear, or anger. (This phenomenon is discussed in more detail in Chapter 11, which deals with emotion.) In babies, the subcortical pathway helps facilitate looking at faces, which increases social bonding with other humans and facilitates developing face-sensitive circuits in the cerebral cortex. A s tudy by Le Grand and colleagues (2001) discovered that the experience of seeing faces very early in life plays a critical role in the development of the s kills necessary for recognizing them later in life. The investigators tested the ability of people (aged 9-21 years) who had been born with congenital cataracts to recognize subtle differences between pairs of faces. The participants in the study had been

Figure 6.31. Category-Sensitive Responses to Faces and Scenes in Infants Show Adult-Like Spatial Organization Regions preferring faces over scenes are reported in red/yellow, and regions pref1erring scenes over faces in blue. The top two rows of whole-brain activation maps show results from the two individual infants with the largest amount of usable data, while the third shows a group map witlh statistics across infants.

Vision

unable to see more than light and dark until they received eye surgery at 62-187 days of age that made detailed vision possible. The early visual deprivation resulted in a severe deficit, compared with the performance of control participants, in recognizing the facial differences. A follow-up study by Le Grand and colleagues (2003) tested people who were born with cataracts in only one eye. Because of the immaturity of the newborn brain, visual information received by one eye is transmitted only to the contralateral visual cortex. (You may recall that we said earlier in this chapter that it is not correct to say that each hemisphere receives visual information solely from the contralateral eye. However, our admonition does not apply to newborn babies.) This means that the right hemisphere of a person born with a cataract in the left eye does not receive patterned visual information until the cataract is removed. Le Grand and his colleagues predicted that because the right fusiform gyrus is critical for facial recognition, people born with cataracts in their left eye would have difficulty recognizing faces but that people born with cataracts in the right eye would show expected facial discrimination-and that is exactly what they found. As we will see in Chapter 18, people diagnosed with autism spectrum disorder (ASD) may find it more challenging to develop close social relationships. Grelotti and colleagues (2002) found that a sample of people with this disorder had difficulty recognizing faces and that looking at faces did not activate the fusiform gyrus. (See Figure 6.32.) The authors speculate that features associated with this change in fusiform

Figure 6.33

Figure 6.32

fMRI of the Brain During Facial Recognition

fMR I maps of the brain during face perception. Activation of the fusiform gyrus to faces is shown in red/yellow and identified by arrows in a typically developing young adult (a). Note the clear focus of face··related activation bilaterally in the fusiform gyrus. In contrast, a youn!~ adult with autism shows a lack of activation (b). Source: Grelotti, D. J., Gauthier, I., and Schultz, R. T. (2002). Social interest and the ·development of cortical face specialization: What autism teaches us about face processing. Developmental Psychobiology, 40(3), 213-225.

(a)

activation could be related differences in recognizing faces as a childl grows up. Additional research revealed reduced connectivilty between the FFA and other areas of the visual cortex, which may also be related to the social processing differences associated with ASD (Lynn et al., 2018). Another frequent feature of ASD can be intense interest and expertise in a specific topic or hobby, such as cars or characters. Functional imaging ha:s revealed that viewing stimuli related to an area of expertise produced a response in the FFA of people without an ASD diagnosis, with an enhanced response associated with ASD (Foss-Feig et al., 2016). (See Figure 6.33 for examples of

Sample Stimuli Related to Areas of Expertise

More robust activity in the fusiform regions was recorded from brains of people diagnosed with ASD when viewing images related to an area of expertise or interest.

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168 Chapter 6

stimuli used in this study.) Chapter 17 discusses autism spectrum disorder in more detail. Williams syndrome is a genetic condition caused by a mutation on chromosome 7. People with this disorder tend to be very sociable, charming, and kind. People with Williams syndrome often show a lot of interest in other people, spend a great deal of time looking closely

at their faces, and are generally better at recognizing faces than people without the syndrome. A functionalimaging study by Golarai and colleagues (2010) found that the fusiform face area was enlarged in people with Williams syndrome and that the size of the FFA was positively correlated with a person's ability to recognize faces.

Module Review: Perceiving Form Role of the Striate Cortex LO 6.15 Outline the benefit of neural circuits that

analyze spatial frequency in the striate cortex. Small objects, details within a large object, and large objects with sharp edges provide a signal rich in high frequencies, whereas large areas of light and dark are represented by low frequencies. Possessing neural circuits that can differentiate between these types of stimuli is beneficial in filtering noise from a visual stimulus, making the image more clear in the human visual system, and allowing an individual to perceive the underlying form.

three-dimensional objects and backgrounds are achieved. Damage to the human extrastriate cortex can cause a category of deficits known as visual agnosia, a failure to recognize familiar objects or categories of objects, including faces. The fusiform face area is specifically devoted to facial recognition. Development of this region may be a result of extensive experience looking at faces; expertise with other complex stimuli such as artificial creatures (greebles) causes the development of circuits devoted to the perception of these stimuli as well. Development of the fusiform face area may be involved in symptoms of autism spectn.un disorder, possibly related to developing experience in recognizing faces.

Role of the Extrastriate Cortex LO 6.16 Describe the roles of the ventral stream and

fusiform face area in p erceiving form. Recognizing visual patterns and identifying particular objects take place in the inferior temporal cortex (part of the ventral stream) in primates. It is here that analyses of form and color are put together, and perceptions of

Thought Question A classmate is. having trouble remembering the locations and functions of the dorsal and ventral visual processing pathways. To help your peer, devise a strategy for remembering these important pathways, the brain regions they involve, and their functions.

Perceiving Spatial Location

know what we mean. Stereopsis is particularly important to visually guide fine movements of the hands and fingers.

Perceiving spatial location involves the retina, striate, and extrastriate cortex. Together, these structures contribute to depth perception, perceiving and remembering the locations of objects, and controlling movements of the eyes and the limbs.

Role of the Striate and Extrastriate Cortex LO 6.18 Desc:ribe th e role of the striate and extrastriate

Role of the Retina LO 6.17 Identify the retina's contributions to perceiving

spatial location. We perceive depth by many means, most of which involve cues that can be detected monocularly-that is, by one eye alone. For example, perspective, relative retinal size, loss of detail through the effects of atmospheric haze, and relative apparent movement of retinal images as we move our heads all contribute to depth perception and do not require binocular vision. However, binocular vision provides a vivid perception of depth through the process of stereoscopic vision, or stereopsis. If you have seen a three-dimensional movie, you

corte~x

in p erceiving spatial location.

Most neurons in the striate cortex are binocular-that is, they respond to visual stimulation of either eye. Many of these binocular cells, especially those found in a layer that receives information from the magnocellular system, have response patterns that appear to contribute to the perception of depth (Poggio & Poggio, 1984). In most cases the cells respond most vigorously (by firing action potentials) when each eye sees a stimulus in a slightly different location. That is, the neurons respond to retinal disparity, a stimulus that produces images on slightly different parts of the retina of each eye. This is exactly the information that is needed for stereopsis: Each eye sees a three-dimensional scene slightly

Vision

differently, and the presence of retinal disparity indicates differences in the distance of objects from the observer. Many neurons throughout almost all regions of the visual cortex are responsive to binocular disparity, which serves as the basis for stereoscopic depth perception (Parker, 2007; Roe et al., 2007). The disparity-sensitive neurons found in the dorsal stream, which is involved in spatial perception, respond to large, extended visual surfaces, whereas those found in the ventral stream, which is involved in object perception, respond to the contours of three-dimensional objects. A phenomenon called "flat vision" illustrates the role of the dorsal stream in perceiving spatial location.

intraparietal sulcus (IPS) are of particular interest: AIP, LIP, VIP, CIP, and MIP (anterior, lateral, ventral, caudal, and medial IPS).

Figure 6.35

The Posterior Parietal Cortex

An "inflated" dorsal view of the left hemisphere of a human brain shows the anatomy of the posterior parietal cortex. Source: Adapted from Astafiev, S. V., Shulman, G. L., Stanley, C. M., et al. (2003). Functional organization of human intraparietal and frontal cortex for attendin•g, looking, and pointing. Journal of Neuroscience, 23, 4689-4699.

Rostral

Frontal Patient E. H. experienced a stroke that impacted the area between the parietal and occipital lobes on the right side of the brain, areas involved in processing retinal disparity information. Although he had normal stereopsis, E. H. lost his ability to perceive depth and described his experience of "flat vision" as seeing all objects appearing as equidistant to him. This made behaviors that required depth perception, such as walking on stairs or uneven ground, difficult. With visual training, E. H. recovered depth perception (Schaadt et al., 2015). (See Figure 6.34.)

lobe~

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Temporal IObEl

The parietal lobe is involved in spatial and somatosensory perception, and it receives visual, auditory, somatosensory, and vestibular information to perform these tasks. Damage to the parietal lobes disrupts performance on a variety of tasks that require perceiving and remembering the locations of objects and controlling movements of the eyes and the limbs. The dorsal stream of the visual association cortex terminates in the posterior parietal cortex. The anatomy of the posterior parietal cortex is shown in Figures 6.14 and 6.35. Five regions within the

Figure 6.34

169

Medial AIP

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Damage to the Parieto-Occipital Cortex Produces Flat Vision

A representation of the stroke lesion in the case of E. H. showing dama!~e to the right occipital-parietal area surrounding the calcarine sulcus and impacting the dorsal stream. E. H. lost the ability to view visual stimuli in three dimensions and experienced "flat vision" as a result.

Region of intraparietal sulcus

170 Chapter 6

Single-unit studies with monkeys and functionalimaging studies with humans indicate that neurons in the IPS are involved in visual attention and control of saccadic eye movements (LIP and VIP), visual control of reaching and pointing (VIP and MJP), visual control of grasping and manipulating hand movements (AIP), and perception of depth from stereopsis (CIP) (Astafiev et al., 2003; Culham & Kanwisher, 2001; Frey et al., 2005; Snyder et al., 2000; Tsao et al., 2003). Goodale and his colleagues (Goodale & Milner, 1992; Goodale & Westwood, 2004; Goodale et al., 1994) suggest that the primary function of the dorsal stream of the visual cortex is to guide actions rather than simply to perceive spatial locations. Ungerleider and Mishkin (1982) originally said the ventral and dorsal streams tell us "what" and "where." Goodale and his colleagues suggested that better terms are "what" and "how." First, they noted that the visual cortex of the posterior parietal lobe is extensively connected to regions of the frontal lobe involved in controlling eye movements, reaching movements of the limbs, and grasping movements of the hands and fingers. Second, they noted that damage to the dorsal stream can produce deficits in visually guided movements. (Chapter 8 discusses in more detail the role of the posterior parietal cortex in control of movements.) They cited the case of a woman with damage to the dorsal stream who had no difficulty recognizing line drawings (that is, her ventral stream was intact) but who had trouble picking up objects Gakobson et al., 1991). The patient could easily perceive the difference in the size of wooden blocks that were set out before her, but she failed to adjust the distance between her thumb and forefinger to the size of the block she was about to pick up. In contrast, a patient with profound visual agnosia caused by damage to the ventral stream could not distinguish between wooden blocks of different sizes but could adjust the distance between her thumb and forefinger when she picked them up. She made this adjustment by means of vision before she actually touched them (Goodale et al., 1994; Milner et al., 1991). A functional-imaging study of

this patient Games et al., 2003) showed the expected activity in the dorsal stream while she was picking up objects-especially in the anterior intraparietal sulcus (AIP), which is involved in manipulating and grasping. The suggestion by Goodale and his colleagues seems a reasonable one. Certainly, the dorsal stream is involved in perception of the location of object's space-but then, if its primary role i:s to direct movements, it must be involved in location of these objects, or else how could it direct movements toward them? In addition, it must contain information about the size and shape of objects, or else how could it control the distance between thumb and forefinger? Two functional-imaging studies provide further evidence that the dorsal stream is involved in visual control of movement. Va1lyear and colleagues (2006) presented photographs of pairs of elongated stimuli, one after the other, and noted which regions of the brain responded to the difference between the two stimuli. They found that a region of the ventral stream responded differentially to pairs of stimuli that differed in their form (for example, a fork versus a clarinet) but did not distinguish between the same object shown in different orientations (for example, one tipped 45 degrees to the right of vertical and the other tipped 45 degrees to the left). In contrast, a region of the dorsal stream distingujshed between diffe1~ent orientations but ignored changes in the identity of tht? two objects. A follow-up study published the next year (Rice et al., 2007) showed volunteers photographs of two different types of objects: graspable ones, such as forks and hammers, and ungraspable ones, such as tractors and pieces of furruture. The investigators found that, as before, the region of the dorsal stream ignored changes in the identi~y of the objects but distinguished between orientations. However, the region distinguished between the orientations only of stimuli that a person could grasp. This region did not distinguish between the orientations of photos of stimuli that could not be picked up, such as tractors and pieces of furruture.

Module Review: Perceiving Spatial Location Role of the Retina

Role of the Striate and Extrastriate Cortex

LO 6.17 Identify the retina's contributions to p erceiving spatial location.

LO 6.18 Describe the role of the striate and extr.astriate cortex in perceiving spatial lo ca.ti on.

The retina contributes to perspective, relative retinal size, loss of detail through the effects of atmospheric haze, and relative apparent movement of retinal images as we move our heads as monocular features that contribu te perception of depth and spatial location. Binocular vision provides a vivid perception of depth through the process of stereopsis involving information from both retinas.

Most neurons iin the striate cortex are binocular and contribute to depth p1erception via retina] disparity. The disparitysensitive neu1rons found in the dorsal stream, which is involved in spatial perception, respond to large, extended visual surfaces, whereas those found in the ventral pathway, which is iinvolved in object perception, respond to the contours of three-dimensional objects. Damage to regions

Vision

of the dorsal stream can impair three-dimensional spatial perception, producing "flat vision." The dorsal stream of the extrastriate cortex terminates in the parietal cortex, which is involved in spatial and somatosensory perception. The parietal cortex receives visual, auditory, somato-

sensory, and vestibular information to perform these tasks. Single-unit studies with monkeys and functional-imaging studies with humans indicate that neurons in the intraparietal sulcus (IPS) are involved in visual attention and control of saccadic eye movements (LIP and VIP), visual control of reaching and pointing (VIP and MIP), visual control of grasping and manipulating hand movements (AIP), and perceiving depth from stereopsis (CIP).

Perceiving Orientation and Movement We need to know not only what things are and where they are located, but also where they are going. Without the ability to perceive the direction and velocity of the movement of objects, we would have no way to predict where they will be. We would be unable to catch the objects (or avoid letting them catch us). This module examines the perception of movement.

Role of the Striate Cortex LO 6.19 Explain the role of the striate cortex in perceiving orientation. Most neurons in the striate cortex are sensitive to orientation. That is, if a line or an edge (the border of a light and a dark region) is positioned in the cell's receptive field and rotated around its center, the cell will respond only when the line is in a particular position-a particular orientation. Some neurons respond best to a vertical line, some to a horizontal line, and some to a line oriented somewhere in between. Figure 6.36 shows the responses of a neuron in the striate cortex when lines were presented at various orientations. As you can see, this neuron responded best when a vertical line was presented in its receptive field. Information about orientation is conveyed to the extrastriate cortex, where it is used to aid in perceiving movement.

Role of the Extrastriate Cortex LO 6.20 Describe the role of the extrastriate cortex in perceiving movement. Research with humans and other animals has helped to reveal the role of the extrastriate cortex in visual perception of movement.

171

Thought Question Imagine that you are asked to consult on a case study of an individual with agnosia. The female patient has been diagnosed with Turner syndrome, a genetic disorder in which people have only one functional copy of the X chromosome. Like many other women with Turner syndrome, the patient has form blindness (cannot perceive geometric shapes) and deficits in spatial perception but has otherwise normal vision. Suggest areas of the brain that may be involved in these visual agnosias.

Figure 6.36

Orientation Sensitivity

An orieintation-sensitive neuron in the striate cortex will become active only when a line of a particular orientation appears within its receptive field. For example, the neuron depicted in this figure responds best to a bar that is vertically oriented. Source: Adapted from Hubel, D. H., and Wiesel, T. N. (1959). Receptive fields of single· neurons in the cat's striate cortex. Journal of Physiology [London], 148, 5741-591.

Stimulus

•0 0 0 0

Neuron firing rate

11

IIll I 111111 11111 111

• STUDIES WITH LABORATORY ANIMALS Area VS of the extrastriate cortex-also known as area MT, for medial tempoi•al-contains neurons that respond to movement. (See Figure 6.14.) Damage to this region severely disrupts a mornkey's ability to perceive moving stimuli (Siegel & Andersen, 1986). Area VS receives input directly from the striate cortex and from several other regions of the extrastriate cortex. It also receives input from the superior colliculus, which is involved in visual reflexes, including reflexive control of eye movements. A·ccurately determining the velocity and direction of movement of an object is an important ability. That moving

172 Chapter 6

object could be a prey animal trying to run away, a predator trying to catch you, or a projectile you are trying to catch (or keep from hitting you). If we are to accurately track moving objects, the information received by VS must be up to date. In fact, the axons that transmit information from the magnocellular system are thick and heavily myelinated, which increases the rate at which they conduct action potentials. Petersen and colleagues (1988) recorded the responses of neurons in areas V4 and VS and found that visual information reached the VS neurons sooner than it reached those in area V4, whose neurons are involved in the analysis of form and color. The input from the superior colliculus contributes in some way to the movement sensitivity of neurons in area VS. Rodman and colleagues (1989, 1990) found that destruction of the striate cortex or the superior colliculus alone does not eliminate the movement sensitivity of VS neurons, but destruction of both areas does. The roles played by these two sources of input are not yet known. Clearly, both inputs provide useful information; Seagraves and colleagues (1987) found that monkeys still could detect movement after lesions of the striate cortex but had difficulty estimating its rate. A region adjacent to area VS, area MST, or medial superior temporal, receives information about movement from VS and performs a further analysis. (See Figure 6.14.) MST neurons respond to complex patterns of movement, including radial, circular, and spiral motion (see Vaina, 1998 for a review). One important function of this region-in particular, the dorsolateral MST, or MSTdappears to be analysis of optic flow. As we move around in our environment or as objects in our environment move in relation to us, the sizes, shapes, and locations of environmental features on our retinas change. Imagine the image seen by a video camera as you walk along a street, pointing the lens of the camera straight in front of you. Suppose you will pass a mailbox to the left. The image of the mailbox will slowly get larger. Finally, as you pass the mailbox, its image will veer to the left and disappear. Points on the sidewalk will move downward, and branches of trees that you pass under will move upward. Analysis of the relative movement of the visual elements of your environment-the optic flow- will tell you where you are going, how fast you are approaching different items in front of you, and whether you will pass to the left or right of (or under or over) these items. The point toward which we are moving does not move, but all other points in the visual scene move away from it. This point is called the center of expansion. If we keep moving in the same d irection, we will eventually bump into an object that lies at the center of expansion. We can also use optic flow to determine whether an object approaching us will hit us or pass us by.

Bradley et al. (1996) recorded from single units in MSTd of monkeys and found that particular neurons responded selectively to tlhe center of expansion located in particular regions of the visual field. These neurons compensated for eye movements, which means that their activity identified the location in the environment toward which an animal was moving. Britten and van Wezel (1998) found that electrical stimulation of MSTd disrupted monkeys' ability to perceive the apparent direction in which they were heading. In this way, these neurons do indeed seem to play an essential role in heading estiimation derived from optic flow. STUDIES WITH HUMANS Research with human participants has been essential in improving understanding of the functions of extrastriate cortex in the perception of motion, optic flow, form from motion, biological motion, and the compensaition of eye movements in motion.

Perception of Motion Functional-imaging studies suggest that motion-sensitive area VS is found within the inferior temporal sulcus of the human brain (Dukelow et al., 2001). However, a more recent study suggests that this region is located in the lateral occipital cortex, between the lateral and inferior occipital sulci (Annese et al., 200S). Annese and his colleagues examined sections of the brains of deceased individuals that had been stained for the presence of myelin. As we just saw, area VS receives a dense projection of thick, heavily myelinated axons, and the location of this region was revealed by the myelin stain. Bilateral damage to the human brain that includes area VS produces an inability to perceive movementakinetopsia. Instead of a smooth progression of movement in their environment, individuals with akinetopsia experience a series of still images that appear to refresh periodically. For example, Zihl and colleagues (1991) reported the case of a woman (L. M.) with bilateral lesions of the lateral occipital cortex and area VS. Patient L. M. had an almost total loss of movement perception. She was unable to cross a street without traffic lights because she could not: judge the speed at which cars were moving. Although she could perceive movements, she found moving objects very unpleasant to look at. For example, while talking with another person, she avoided looking at the person's mouth because she ·found its movements very disturbing. When the investigators asked her to try to detect movements of a visual target in the latboratory, she said, "First the target is completely at rest. Then itt suddenly jumps upwards and downwards" (Zihl et al., 1991, pp. 22-44). She was able to see that the target was constantly changing its position, but she was unaware of any sensation of movement.

Walsh and colleagues (1998) used TMS to temporarily inactivate area VS in a control group of volunteers. The investigators foiund that during the TMS procedure people

Vision

were unable to detect which of several objects displayed on a computer screen was moving. When the current was off, the volunteers had no trouble detecting the motion. The current had no effect on the volunteers' ability to detect stimuli that varied in their form.

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Figure 6.37 Perceiving Form from Motion An example of the stimuli used in research used to study form from motion..

Optic Flow As we saw, neurons in area MSTd of the monkey brain respond to optic flow, an important source of information about the direction in which the animal is heading. A functional-imaging study by Peuskens and colleagues (2001) found that area VS became active when people judged their heading while viewing a display showing optic flow. Vai na and her colleagues (Jornales et al., 1997; Vaina, 1998) found that people with lesions that included this region were able to perceive motion but could not perceive heading from optic flow. Building on these findings, imaging studies of healthy volunteers extended the regions involved in optic flow to include additional areas of the extrastriate cortex, such as V6, an area involved in distinguishing motion of an object from motion of an observer (Pitzalis et al., 2013). Form from Motion Perception of movement can even help us to perceive three-dimensional forms- a phenomenon known as form from motion. Johansson (1973) demonstrated just how much information we derive from movement. He dressed actors in black and attached small lights to several points on their bodies, such as their wrists, elbows, shoulders, hips, knees, and feet. He made movies of the actors in a darkened room while they were performing various behaviors, such as walking, running, jumping, limping, doing push-ups, and dancing with a partner who was also equipped with lights. Even though observers who watched the films could see only a pattern of moving lights against a dark background, they could readily perceive the pattern as belonging to a moving human and could identify the behavior the actor was performing. Subsequent studies (Barclay et al., 1978; Kozlowski & Cutting, 1977) showed that people could even tell, with reasonable accuracy, the sex of the actor wearing the lights. The cues appeared to be supplied by the relative amounts of movement of the shoulders and hips as the person walked. Figure 6.37 shows an example of the points used to convey form from motion in this type of research. McCleod and colleagues (1996) suggest that the ability to perceive form from motion does not involve area VS. They reported that patient L. M. (studied by Zihl et al., 1991) could recognize people depicted solely by moving points of light even though she could not perceive the movements themselves. Vaina and her colleagues (reported by Vaina, 1998) described a patient with a lesion in the medial right occipital lobe who showed just the opposite deficits: Patient R. A. could perceive movement-even complex radial and circular optic flow-but could not perceive form

from motion. This must mean that perception of motion and pierception of form from motion involve different regions of the visual association cortex. A fu nctional-imaging study by Grossman and colleagues (2000) found that when people viewed a video that showe~d form from motion, a small region on the ventral bank of the posterior end of the superior temporal sulcus became active. More activity was seen in the right hemisphere, whether the images were presented to the left or right visual field. Grossman and Blake (2001) found that this region became active even when people imagined that they were watching points of light representing form from motioin. (See Figure 6.38.) Grossman and colleagues (200S) found that inactivation of this area with TMS disrupted perception of form from motion. Perceiving form from motion might not seem like a phenomenon that has any importance outside the laboratory. However, this phenomenon does occur under natural circumstances, and it appears to involve brain mechanisms differe~nt from those involved in normal object perception. For example, as we saw in the prologue to this chapter, people with visual agnosia can often still perceive actions (such as someone pretending to stir something in a bowl) even though they cannot recognize objects by sight. They

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Chapter 6

Figure 6.38 Responses to Viewing Form from Motion This figure shows horizontal and lateral views of neural activity that occurred while the subject was view ing videos of biological motion. Maximum activity is seen in a small region on the ventral bank of the posterior end of the superior temporal sulcus, primarily in the right hemisphere. Source: Based on Grossman, E. D.. and Blake, R. (2001). Brain activity evoked by inverted and imagined biological motion. Vision Research, 41, 1475- 1482.

may be able to recognize friends by the way they walk, even though they cannot recognize the friends' faces. Le and colleagues (2002) reported the case of patient S. B., a 30-year-old man whose ventral stream was damaged bilaterally by an infection when he was 3 years old. As a result, he was unable to recognize objects, faces, textures, or colors. However, he could perceive movement and could even catch a ball that was thrown to him. 'Furthermore, he could recognize other people's arm and hand movements that mimed common activities such as cutting something with a knife or brushing one's teeth, and he could recognize people he knew by their gait. Biological Motion As we saw earlier in this chapter, neurons in the extrastriate body area (EBA) are activated by the sight of human body parts. A functional-imaging study by Pelphrey and colleagues (2005) showed participants a computer-generated image of a person who made hand, eye, and mouth movements. (Note that the participants were perceiving motion made by a human being, not form from the motion of individual points of light as described in the previous subsection.) The investigators found that movements of different body parts activated different locations just anterior to the EBA. Compensation for Eye Movements So far, this discussion has been confined to movement of objects in the visual field. But if a person moves his or her eyes, head, or whole body, the image on the retina will move even if everything within the person's visual field remains stable. Often, of course, both kinds of movements will occur at the same time. The problem for the visual system is to determine

which of these images are produced by movements of objects in the environment and which are produced by the person's own eye, head, and body movements. To illustrate this problem, think about how a paragraph of text looks as you read it. If we could make a recording of o ne of your retinas, we would see that the image of the text projected there is in constant movement as your eyes make several saccad es along a line and then snap back to the beginning of the next line. Yet the text seems perfectly still to you. On the other hand, if you look at a single point (say, a period at the end of a sentence) and then move the image around while following the period w ith your eyes, you perceive the text as moving, even though tthe image on your retina remains relatively stable. (Try it.) Then think about the images on your retina while you are driving in busy traffic, constantly moving your eyes around to keep track of your own location and that of other cars moving in different directions at different speeds. You are perceiving not only the simple movement of objects but optic flow as well, which helps you keep track of the trajectories of the objects relative to each other and to yourself. Haarmeier and colleagues (1997) reported the case of a patient with bilateral damage to the extrastriate cortex who could not compensate for image movement caused by head and eye movements. When the patient moved his eyes, it looked to him as if the world was moving in the opposite direction. Without the ability to compensate for head and eye movements, any movement of a retii nal image was perceived as movement of the environment. On the basis of evidence from EEG and MEG (magnetoencephalography) studies in human participants and single-unit recordings in monkeys, Their and colleagues (2001) suggest that this compensation involves extrastriate cortex located at the junction of the temporal and parietal lobes near a region involved in the analysis of signals from the vestibular system. Inde•ed, the investigators note that when patients with damage to this region move their eyes, the lack of comptmsation for these movements makes them feel very dizz:y. This chapter explored the structures and functions of the visual system related to perceiving color, form, spatial location, orientation, and movement. Although these sections included a lot of information, you may have noticed themes. For example, each type of per-

ception involved areas of the striate cortex, extrastriate cortex, and the dorsal and ventral processing streams. Much of this information has been summarized in Table 6.3 to help you organize and review your new knowledge of vision.

Vision

Table 6.3

175

Regions of the Human Visual Cortex and Their Functions

V1

Striate cortex

Small modules that analyze orientation, movement, spatial frequency, retinal disparity, and color Further analysis of information from V1

V2

Ventral Stream V3+VP

Further analysis of information from V2

V3A

Processing of visual information across entire visual field of contralateral eye

V4dN4v

V4 dorsaVventral

Anailysis of form; processing of color constancy; V4d visu 1al field, V4v upper visual field

=

=lower

Color perception

V8 LO

lateral occipital complex

Obj•ect recognition

FFA

Fusiform face area

Faoe recognition, object recognition by experts ("flexible fusi1form area")

PPA

Parahippocampal place area

Recognition of particular places

EBA

Extrastriate body area

Perception of body parts other than face

MT/MST

Medial temporaVmedial superior temporal (named for locations in monkey brain)

Perception of motion; perception of biological motion and optic flow in specific subregions

LIP

Lateral intraparietal area

Visual attention; control of saccadic eye movements

VIP

Ventral intraparietal area

Control of visual attention to particular locations; control of eye movements; visual control of pointing

AIP

Anterior intraparietal area

Visual control of hand movements: grasping, manipulation

MIP

Middle intraparietal area; parietal reach region (monkeys)

Visual control of reaching

GIP

Caudal intraparietal area; caudal parietal disparity region

Perception of depth from stereopsis

Dorsal Stream Visual attention; control of eye movements

V7

Module Review: Perceiving Orientation and Movement Role of the Striate Cortex LO 6.19 Explain the role of the striate cortex in p erceiving orientation. Most neurons in the striate cortex are sensitive to orientation and respond by increasing their rate of firing action potentials when a line is in a particular position in their receptive field.

Role of the Extrastriate Cortex LO 6.20 Describe the role of the extrastriate cortex in perceiving movement.

Area VS of the extrastriate cortex (area MT) contains neurons that respond to movement. Bilateral damage to the

humam brain that includes area VS produces akinetopsia. MST neurons receive information from VS and respond to complex patterns of movement, including radial, circular, and spiral motion. More specifically, MSTd neurons ainalyze optic flow. Movements of different body parts activate cells in the extrastriate body.

Thought Question Describe how neurons in the dorsal stream respond to movement and location, and discuss the effects of brain damage on p erception of these features.

176 Chapter 6

Chapter Review Questions 1. Describe the characteristics of light and color, out-

line the anatomy of the eye and its connections with the brain, and describe the transduction of visual information. 2. Describe the coding of visual information by photoreceptors and ganglion cells in the retina. 3. Discuss the striate cortex and how its neurons respond to orientation and movement and spatial frequency. 4. Discuss how neurons in the striate cortex respond to retinal disparity and color, and describe the modular organization of striate cortex.

5. Describe the anatomy of the extrastriate cortex and discuss the location and functions of the two streams of visual analysis that take place there. 6. Discuss the perception of color by neurons in the ventral sbream. 7. Describe the role of the ventral stream in the perception of faces, bodies, objects, and scenes of places. 8. Describe how neurons in the dorsal stream respond to movement and location, and discuss the effects of brain damage on perception of these features.

Chapter 7

Audition, the Body Senses, and the Chemical Senses 1

Confocal microscope image of neurons (green) and glia (red) in the vestibular pathway.

Chapter Outline Audition The Stimulus: Sound Anatomy of the Ear Auditory Hair Cells Transduce Auditory Information The Auditory Pathway

Perceiving Pitch Perceiving Loudness Perceiving Timbre Perceiving Spatial Location Perceiving Complex Sounds Perceiving Music

Vestibular System Anatomy of the Vestibular Apparatus The Vestibular Pathway Somatosenses The Stimuli Anatomy of the Skin and Its Receptive Or;gans Pe1rceiving Cutaneous Stimulation The Somatosensory Pathways Pe1rceiving Pain

177

178 Chapter 7

Gustation

Olfaction

The Stimuli Anatomy of the Taste Buds and Gustatory Cells

The Stimulus and Anatomy of the Olfactory Apparatus

Perceiving Gustatory Information The Gustatory Pathway

Transduciing Olfactory Information Perceiving Specific Odors

m

Learning Objectives

LO 7.1

L07.2

L07.3

L07.4

L07.5

Describe three perceptual dimensions of sound.

LO 7.14 Describe the anatomy and somatosensory

Organize the structures and functions of the ear involved in auditory processing.

LO 7.15 Describe the perception of touch,

Contrast the location and function of hair cells in auditory transduction.

LO 7.16 Describe the components of the

Describe the components of the auditory pathway.

LO 7.17 Describe why pain is experienced, the

Contrast place and rate coding in pitch perception.

receptors of the skin. temperature, pain, and itch. sornatosensory pathways. components of pain, and how pain periception can be modified. LO 7.18 List the six qualities of taste stimuli.

Contrast how loudness in high- and low-frequency sounds is represented.

LO 7.19 Identify the location and structure of

L07.7

Identify the characteristics of timbre.

LO 7.20 Summarize the process of gustatory

L07.8

Compare the processes used to perceive spatial location.

L07.6

L07.9

Compare the anterior and posterior auditory processing streams.

LO 7.10 Summarize the biological basis for

perceiving music. LO 7.11 Summarize the structures and functions

of the vestibular apparatus. LO 7.12 Outline the vestibular pathway. LO 7.13 Provide examples of stimuli that activate

receptors for the somatosenses.

taste receptor cells. transduction. LO 7.21 Describe the components of the gustatory

patlhway. LO 7.22 Org;anize the structures and functions

of the olfactory apparatus involved in olfactory processing. LO 7.23 Summarize the process of olfactory

transduction. LO 7.24 Explain how receptors can detect specific

odors.

179

Audition, the Body Senses, and the Chemical Senses

Thirteen-year-old Ashlyn was in the kitchen, stirring ramen noodles when she dropped the spoon into the pot of boiling water. Without thinking, she reached her right hand in to retrieve the spoon, then took her hand out of the water and stood looking at it, emotionless. She walked to the sink and ran cold water over her hands and the many faded white scars from previous accidents. She then called to her mother, who rushed to her daughter's side w ith ice and pressed it against her daughter's hand, relieved that the burn wasn't worse. Throughout her childhood, Ashlyn was asked lots of questions from her schoolmates and friends. Was she Superman? Could she feel pain from a punch to the face? Could she walk across burning coals as if she were walking on grass? Would it

Ashlyn and Jo have congenital insensitivity to pain. Due to a gene mutation, Ashlyn's nervous system developed without functional nociceptors. Nociceptors are specialized neurons activated by painful stimuli. You'll read more about nociceptors and pathways in the somatosenses module of this chapter. A genetic mutation in a gene for FAAH (the enzyme that deactivates endocannabinoids; see Chapter 4) produced elevated levels of the endocannabinoids responsible for Jo's lack of pain and anxiety, and possibly her accelerated healing (Habib et al., 2019). Ashlyn and Jo's case studies highlight several important concepts from this chapter, including the role of specialized somatosensory receptors and the importance of the senses in guiding our behavior. People often say that we have five senses: sight, hearing, smell, taste, and touch. Actually, we have more than five, but even experts disagree about how the lines between the various categories should be drawn. For example, we could add the vestibular senses that control movement and balance in space to the list of senses, or consider a sense arising from cells capable of transducing the earth's geomagnetic fields (Wang et al., 2019). Reflecting the areas of greatest sensory research, however, this chapter contains five modules: audition, the vestibular system, the somatosenses, gustation, and olfaction. All are vital to how we perceive and navigate the world around us.

hurt if she were stabbed in the arm? The answers are no, no, yes, no. She can feel pressure and texture. She can feel a hug ancl a handshake. She cannot feel pain (Heckert, 2012). Seventy-one-year-old Jo surprised her doctors when she' declined pain medication following invasive hand surgery ancl rated her postsurgical pain 0/ 10. She felt no pain during dental procedures, when receiving stitches, during the birth of her children, or when her hip was severely degenerated and nee,ded to be replaced. She had trouble recognizing when she had been burned or cut. Jo's case held more surprises for resiearchers: Her injuries seemed to heal faster than anyone exp•ected, and she never experienced anxiety (Habib et al., 2019; Muirphy, 2019).

source~

of a sound is but also where it is located. This module describes the nature of the stimulus, the sensory receptors, the brain mechanisms devoted to audition, and some of the details of the physiology of auditory perception.

The Stimulus: Sound LO 7.11 Describe three perceptual dimensions

of sound. We he.ar sounds, which are produced by objects that vibrate and set molecules of air into motion. When an object vibrates., its movements cause molecules of air surrounding it to alternate between compressing and expanding, producing waves that travel away from the object at approximately 1,200 kilometers (km) per hour. If the vibration ranges between approximately 30 and 20,000 times per second, these waves will stimulate receptor cells in human ears and will be perceived as sounds. (See Figure 7.1.) In Chapter 6 we saw that light has three perceptual dimensions-hue, brightness, and saturation-that correspond to three physical dimensions. Similarly, sounds vary in their pitch, loudness, and timbre. The perceived pitch of an auditory stimulus is determined by the frequency of vibration, which is measured in hertz (Hz ), or cycles per

Figure 7 .1

Audition Hearing, or audition, has three primary functions: to detect sounds, to determine the location of their sources, and to recognize the identity of these sources, which helps us understand their meaning and relevance to us (Heffner & Heffner, 1990; Yost, 1991). The auditory system does a phenomenal job of analyzing the vibrations that reach our ears. For example, we can understand speech, recognize a person's emotion from his or her voice, appreciate music, detect the approach of a vehicle or another person, or recognize an animal's call. We can recognize not only what the

Sound Waves

Changes in air pressure from sound waves move the eardrum in and out. Air molecules are closer together in regions of higher pressure and farlther apart in regions of lower pressure. Compressed

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180

Chapter 7

Figure 7 .2

Physical and Perceptual Dimensions of Sound Waves Sound has three perceptual dimensions: Pitch, loudness, and timbre. Physical Dimension

Perceptual Dimension

Frequency

Pitch

Loudness

Complexity

Timbre

~

high

vvw

J\M

soft

..f\..../\.../"

simple

complex

'\IV' 'V\f\

second. Loudness is a function of intensity-the degree to which the compressions and expansions of air differ from each other. More vigorous vibrations of an object produce more intense sound waves and hence louder ones. Timbre provides information about the nature of the particular sound-for example, the sound of an oboe or a train whistle. Most natural acoustic stimuli are complex, consisting of several different frequencies of vibration. The particular mixture determines the sound's timbre. (See Figure 7.2.)

Anatomy of the Ear LO 7.2

Sound is funneled via the pinna (external ear) through tlhe ear canal to the tympanic membrane (eardrum), which vibrates with the sound. When the tympanic membrane is damaged by trauma, infection, or autoimmune attack, hearing is impaired, particularly for sounds with low frequencies (Mehta et al., 2006). Demonstrating the role of the pinna in sound localization, researchers created inserts that altered the shape of the pinna and asked volunteers to wear the inserts in one ear for up to ~;ix weeks. The volunteers' ability to localize the source of various sounds was significantly disrupted at first. After several days, however, auditory adaptation occurred, and the volunteers were able to accurately determine the location of sounds (Hofman et al., 1998). OUTER EAR

loud Amplitude (intensity)

shows the outer anatomy of the ear and auditory canal and illustrate~; many of the structures of the middle and inner ear.

Organize the structures and functions of the ear involved in auditory processin g.

The anatomy of the ear helps to direct sound waves to the auditory receptors. Structures of the ear can be organized by their location in the outer, middle, and inner ear. Figure 7.3

Figure 7 .3

M IDDLE EAlll The middle ear consists of a small hollow region behind the tympanic membrane. It contains the bones of tlhe middle ear, called the ossicles, which are set into vibration by the tympanic membrane. The malleus (hammer) connects with the tympanic membrane and transmits. vibrations via the incus (anvil) and stapes (stirrup) to the cochlea, the structure that contains the receptors. The bottom of the stapes presses against the membrane behind the oval window, the opening in the bone surrounding the cochlea. (Look again at Figure 7.3.)

The cochlea is part of the inner ear. It is filled with fluid, and sounds transmitted through the air must be transferred into its liquid medium. This process

I NNER EAR

Anatomy of the Ear Malle1us } . . lncus Ossie/es (middle Sta1Pes ear bones) Oval

Vestibule

I

Pinna

Ear canal Outer Ear

Tympanic membrane

Round window

Middle Ear

Eustachian tube (connects with throat) Inner Ear

Audition, the Body Senses, and the Chemical Senses

Figure 7 .4

181

The Cochlea and Organ of Corti

This cross-section through the cochlea shows the organ of Corti.

Cilia of hair cell

Inner hair cell

Scala media

Axons of auditory nerve

membrane

~.1:z

Scala tympani

\

Organ of Corti

A"dfo'Y '"""

Spiral ganglio'n Bone

\

Membrane surroundin!g cochlea

Slice Through Cochlea

normally is very inefficient-99.9 percent of the energy of airborne sound would be reflected away if the air impinged directly against the oval window of the cochlea. The chain of ossicles, however, serves as an efficient means of energy transmission. The bones provide a mechanical advantage, with the baseplate of the stapes making smaller but more forceful excursions against the oval window than the tympanic membrane makes against the malleus. The name cochlea comes from the Greek word kokhlos, or "land snail." It is indeed snail-shaped, consisting of two and three-quarters turns of a gradually tapering cylinder, 35 mm long. The cochlea is divided longitudinally into three sections, the scala vestibuli ("entrance stairway"), the scala media ("middle stairway"), and the sea/a tympani ("tympanic stairway"), as shown in Figure 7.4. The receptive organ, known as the organ of Corti, consists of the basilar membrane, the hair cells, and the tectorial membrane. The auditory receptor cells are called hair cells, and they are anchored, via rodlike Deiters's cells, to the basilar membrane. The cilia of the hair cells pass through the reticular membrane, and the ends of some of the hair cells attach to the fairly rigid

tectorial membrane, which is located overhead like a shellf. Sound waves cause the basilar membrane to move relative to the tectorial membrane, which bends the cilia of the hair cells. This bending produces receptor potentials. The vibratory energy exerted on the oval window causes the basilar membrane to bend. The portion of the basila1r membrane that bends the most is determined by the frequency of the sound: High-frequency sounds cause the base of the membrane-the end nearest the oval window-to bend. A flexible membrane-covered opening, the round window, allows the fluid inside the cochlea to move back and forth. The base of the stapes vibrat·es against the membrane behind the oval window and introduces sound waves of high or low frequency into the cochlea. The vibrations cause part of the basilar membrane to flex back and forth. Pressure changes in the fluid iunderneath the basilar membrane are transmitted to the membrane of the round window. When the base of the stapes pushes in, the membrane behind the round window bulges out. As we will see in a later submodule, different frequencies of sound vibrations cause different portions of the basilar membrane to flex. (See Figure 7.5.)

182 Chapter 7

Figure 7 .5

Responses to Sound Waves

Inc us

Stapes vibrates against membrane behind oval window Oval Basilar memlbrane window

Malleus

Eardrum

Round window

Auditory Hair Cells Transduce Auditory Information LO 7 .3

Contrast the location and function of hair cells in auditory transduction.

Two types of auditory receptors, inner and outer auditory hair cells, are located on the basilar membrane. Hair cells contain cilia, fine hairlike projections, arranged in rows according to height. The human cochlea contains approximately 3,500 inner hair cells and 12,000 outer hair cells. The hair cells form synapses with dendrites of bipolar neurons whose axons bring auditory information to the brain. The inner hair cells are necessary for normal hearing. In fact, mutant mice whose cochleas contain only outer hair cells apparently cannot hear at all (Deol & GluecksohnWaelsch, 1979). The outer hair cells are effector cells, involved in altering the mechanical characteristics of the basilar membrane and influencing the effects of sound vibrations on the inner hair cells. We will discuss the role of outer hair cells in the section on place coding of pitch. The bases of the cilia are attached to the basilar membrane, while the tips of the cilia of outer hair cells are attached to the tectorial membrane above. Sound waves cause both the basilar membrane and the tectorial membrane to flex up and down. These movements bend the cilia of the hair cells in one direction or the other. The cilia of the inner hair cells do not touch the overlying tectorial membrane, but the relative movement of the two membranes causes the fluid within the cochlea to flow past them, making them bend back and forth, too. Cilia contain a core of actin filaments surrounded by myosin filaments, and these proteins make the cilia rigid (Flock, 1977). Adjacent cilia are linked to each other by

A particular region of the basilar membrane flexes back and forth in response to sound of a particular frequency

elastic filaments known as tip links. Each tip link is attached to the •end of one cilium and to the side of an adjacent cilium. The points of attachment, known as insertional plaques, look dark under an electron microscope. Receptor potentials are ttriggered at the insertional plaques. Normally, tip links are slightly stretched, which means that they are under a small. amount of tension. Moving the bundle toward the tallest cilium stretches these linking fibers, generating a high rate of action potentials. Moving the bundle in the opposite direction (toward the shortest cilium) relaxes the linking fibers, resulting in a low rate of action potentials. (See Figure 7.6.) Unlike the fluid that surrounds most neurons, the fluid that surrnunds the auditory hair cells is rich in potassium. Each insertional plaque contains a single cation channel, identified as TRPAl, a member of the transient receptor potential cation channel, subfamily A, type 1 (Corey et al., 2004). (We mention the TRP family of receptors because this ifamily includes receptors involved in perceiving touch, temperature, and taste, and you will encounter them again later in the chapter.) When the bundle of cilia is straight, the probability of an individual ion channel b1eing open is approximately 10 percent. This means that a s mall amount of the cations K+ and Ca2+ diffuses into the cilium. When the bundle moves toward the tallest cilium, the increased tension on the tip links opens all the ion channels, the flow of cations into the cilia increases, and the membrane depolarizes. As a result, the release of neurotransmitter by the hair cell increases. When the bundle moves in the opposite direction, toward the shortest cilium, the relaxation of the tip links allows the opened ion channels to close. The influx of cations ceases, the membrane hyperpolarizes, and the release of neurotransmitter decreases.

Audition, the Body Senses, and t he Chemical Senses

Figure 7 .6

183

Transduct ion in Hair Cells of th e lnneir Ear

(a) The figure shows the appearance of the cilia of an auditory hair cell. (b) Moving the bundle of cilia toward the tallest one increases the firing rate of the coichlear nerve axon attached to the hair cell while moving the bundle away from the tallest one decmases it. (c) Moving toward the tallest cilium increases tension on the tip links, which opens the ion channels and increase the influx of K+ and Ca2+ ions. Moving toward the shortest cilium removes t ension from the tip links, which permits the ion channels to close, stopping the influx of cations. 1

Cilia

\

(a)

I

Low rate

I

I

I

I

11

Medium rate

1111111111111 111111

High rate

Action Potentials in Cochlear Nerve Axon (b)

Small amounts of K+ and ca2+ enter ion channel ~

Larger amounts of K+ and ca2 + enter ion channel ~

Tip link - - --1

Open probability= 0 percent

Open probability = 10 percent

Open probability = 100 percent

(c)

The Auditory Pathway LO 7.4

Describe the components of the auditory pathway.

The auditory pathway consists of the structures of the ear, as well as the cochlear nerve, subcortical structures, and the auditory cortex. AFFERENT CO NNECTION S WIT H THE CO CHLEAR N ERVE The organ of Corti sends auditory information to the brain by means of the cochlear nerve. The cochlear

nerve is a bundle of axons of bipolar neurons that send auditory information to the brain. The cell bodies of these bipolar neurons reside in the cochlear nerve ganglion. These unique neurons have axonal processes that protrude from both ends of the soma and convey an action potential. One end of the axonal process acts like a dendrite, responding with excitatory postsynaptic potentials when neurotransmitter is released by the auditory hair cells. The excitatory postsynaptic potentials trigger action potentials in the auditory nerve axons, which form synapses with neurons in the medulla. (Refer back to Figure 7.4.)

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Chapter 7

well as afferent ones. The source of the efferent axons is the superior olivary complex, a group of nuclei in the medulla. The efferent fibers constitute the olivocochlear bundle . The fibers form synapses directly on outer hair cells and on the dendrites that serve the inner hair cells. While the excitatory neurotransmitter at the afferent synapses is glutamate, the efferent terminal buttons secrete acetylcholine, which has an inhibitory effect on the hair cells. Why would neurons in the brain need to send messages to the cochlea? Several functions of this inhibitory pathway have been proposed, including a protective mechanism to prevent noise-induced damage to the cochlea (Ciuman, 2010; 2013).

Note that axons enter the cochlear nucleus of the medulla and synapse there. Most of the neurons in the cochlear nucleus send axons to the superior olivary complex, also located in the medulla. Axons of neurons in these nuclei pass through a large fiber bundle called the lateral lemniscus to the inferior colliculus, located in the dorsal rniclbrain. Neurons there send their axons to the medial geniculate nucleus of the thalamus, which sends its axons to the auditory cortex of the temporal lobe. Each hemisphere of the brain receives information from both ears but primarily from the contralateral one. Some auditory information also makes its way to the cerebellum and reticular formation. Altogether, subcortical auditory processing requires many neurons and synapses in complex networks that span multiple regions of the brain.

SUBCORTICAL STRUCTURES The anatomy of the sub-

AUDITORY CORTEX Let's take a closer look at the final

cortical components of the auditory system is more complicated than that of the visual system. Rather than giving a detailed verbal description of the pathways here, we will refer you to Figure 7.7.

destination of the auditory pathway: the auditory cortex. The auditory cortex has a unique relationship with the basilar membrane in the cochlea. The frequency map of the basilar membrane is preserved through processing in

EFFERENT CONNECTIONS WITH THE COCHLEAR NERVE The cochlear nerve contains efferent axons as

Figure 7.7

Pathways of the Aud itory System

The major pathways are indicated by heavy arrows.

Medial geniculate nucleus

Inferior colliculus Midbrain

Ventral cochlear nucleus

Audition, the Body Senses, and the Chemical Senses

185

Figure 7 .8 Tonotopic Mapping in the Cochlea and Auditory Cortex The frequency map of the basilar membrane is preserved through processi1ng in the subcortical structures and mapped in the primary auditory cortex.

1600 Hz 800 Hz 400 Hz 200 Hz 100 Hz 50 Hz

25 Hz

· ......:;~... ...-..~ --.:;.....Joi 1-.....:;.....1 . _.:;....... .......:;__.

l"rnl~IJ~~ Scala vestibuli Scala tympani

Primary auditory cortex

Secondary auditory cortex

the subcortical structures and mapped in the primary auditory cortex. (See Figure 7.8.) The basal end of the basilar membrane (the end toward the oval window, which responds to the highest frequencies) is represented most medially in the auditory cortex, and the apical end (the end farther from the oval window, which responds to the lowest frequencies) is represented most laterally there. Because, as we will see, different parts of the basilar membrane respond best to different frequencies of sound, this relationship between cortex and basilar membrane is referred to as tonotopic representation (tonos means "tone," and topos means "place"). Hierarchical Organization in the Auditory Cortex As we saw in Chapter 6, the visual cortex is arranged in a hierarchy. Modules in the striate cortex (primary visual cortex) analyze features of visual information and pass the results of this analysis to regions of the extrastriate cortex (visual association areas) that surround the striate cortex, which perform further analyses and pass information on to other regions, culminating in the most complex levels of visual processing in the parietal and inferior temporal lobes. The auditory cortex seems to be similarly arranged. The primary auditory cortex lies hidden on the upper bank of the lateral fissure. The core region, which contains the

I

"Uncoiled" cochlea

Corresponds to base of cochlea

I

Cochlear apex

Corresponds to apex of cochlea

primary auditory cortex, actually consists of three regions, each of which receives a separate tonotopic map of auditory information from the ventral division from the medial geniculate nucleus. The first level of auditory association cortex., the belt region, surrounds the primary auditory cortex, much as the extrastriate cortex surrounds the primary visual (striate) cortex. The belt region, which consists of at least seven divisions, receives information both from the primary auditory cortex and from the dorsal and medial divisions of the medial geniculate nucleus (subcortical auditory processing regions). The highest level of auditory association cortex, the parabelt region, located ventral to the lateral parabelt, receives information from the belt region and from the divisions of the medial geniculate nucleus that also piroject to the belt region. (See Figure 7.9.) Two Streams in the Auditory Cortex As we saw in Chapter 6, proces;sing in the extrastriate cortex is arranged in two streams-dorsal and ventral. The dorsal stream, which ends in the parietal cortex, is involved in perceiving location ("where"), while the ventral stream, which ends in the inferior temporal cortex, is involved in perceiving form ("what"). Processing in the auditory association cortex is similarly arranged in two streams. The anterior stream, which begins in the anterior parabelt region, is involved

186 Chapter 7

highest frequencies are the first to be lost, and the lowest are the last. High-frequency hearing loss can also be caused by exposure to loud sounds.

Figure 7 .9 The Auditory Cortex Premotor cortex

Anterior stream (analysis of complex sound)

Parietal lobe

Superior temporal sulcus

with analyzing complex sounds. The posterior stream, which begins in the posterior parabelt region, is involved with sound localization (Rauschecker & Scott, 2009; Rauschecker & Tian, 2000). (Look again at Figure 7.9.)

Perceiving Pitch LO 7.5

Contrast place and rate coding in pitch perception.

As you saw in the previous section, the perceptual dimension of pitch corresponds to the physical dimension of frequency. The cochlea detects frequency by two means: Moderate to high frequencies are detected by place coding, and low frequencies are detected by rate coding. These two types of coding are described next. Due to the mechanical construction of the cochlea and basilar membrane, acoustic stimuli of different frequencies cause different parts of the basilar membrane to flex back and forth. This suggests that at least some frequencies of sound waves are detected by means of a place code. For example, if neurons at one end of the basilar membrane are excited by higher frequencies and those at the other end are excited by lower frequencies, we can say that the frequency of the sound is coded by the particular neurons that are active. In turn, the firing of particular axons in the cochlear nerve tells the brain about the presence of specific frequencies of sound. Evidence for place coding of pitch comes from several sources. High doses of antibiotic drugs produce degeneration of the auditory hair cells. The damage begins at the basal end of the cochlea and progresses toward the apical end. The progressive death of hair cells induced by an antibiotic closely parallels a progressive hearing loss: The PLACE CODING

Cochlear Implants Evidence for place coding of pitch in the human cochlea comes from the effectiveness of cochlear implants. Cochlear implants are devices that are used to restone hearing in people with deafness caused by damage to the hair cells. The external part of a cochlear implant consiists of a microphone and a miniaturized electronic signal processor. The internal part contains a very thin, flexible array of electrodes, which the surgeon carefully inserts into the cochlea in such a way that it follows the snail-like curl and ends up resting along the entire length o•f the basilar membrane. Each electrode in the array stimulates a different part of the basilar membrane. Information from the signal processor is passed to the electrodes by means of flat coils of wire, implanted under the skin. (See lFigure 7.10.) Cochlear implants are most useful for two groups of people with hearing loss: individuals who became deaf in adulthood and very young children (Moore & Shannon, 2009). The primary purpose of a cochlear implant is to restore a person's ability to understand speech. Because most of the important acoustical information in speech is contained in frequencies that are too high to be accurately represented by a rate code, the multichannel electrode was developed in an attempt to duplicate the place coding of pitch on the basilar membrane (Copeland & Pillsbury, 2004). When different regions of the basilar membrane are stimulated, the person perceives sounds with different pitches. The si,gnal processor in the external device analyzes the sounds d etected by the microphone and sends separate signals to the appropriate portions of the basilar membrane. Like othe1r people who closely identify with their cultures, many members of the Deaf community are proud of their shared e:xperience and language. Some deaf people say that if they were given the opportunity to hear, for example through a cochlear implant, they might refuse it. You can find more information about brain processing of non-spoken language (such as American Sign Language) in Chapter 14. The previous section described how the frequency of a sound can be detected by place coding. However, the lowest frequency sounds do not appear to be accounted for in this manner. Lower-frequency sounds are detected by neurons that fire in synchron y with the movements of the apical end of the basilar membrane. Lowerfrequency sounds are detected by means of rate coding. The most convincing evidence of rate coding of pitch also comes from studies of people with cochlear implants. Pijl and Schwairz (199Sa, 199Sb) found that stimulating a single electrode with pulses of electricity produced sensations RATE CODING

Audition, the Body Senses, and the Chemical Senses

Figure 7 .10

187

Cochlear Implant

A microphone and processor are worn over the ear, an•d the headpiece contains a coil that transmits signals to the implant.

Electrode array

of pitch that were proportional to the frequency of the stimulation. In fact, the participants could even recognize familiar tunes produced by modulating the pulse frequency. (The participants had become deaf later in life, after they had already learned to recognize the tunes.) As we would expect, the participants' perceptions were best when the tip of the basilar membrane was stimulated, and only low frequencies could be distinguished by this method.

Perceiving Loudness LO 7.6

Contrast how loudness in high- and low-frequency sounds is represented.

The cochlea is an extremely sensitive organ. In very quiet environments, a healthy ear is limited in its ability to detect sounds in the air by the masking noise of blood rushing through the cranial blood vessels rather than by the sensitivity of the auditory system itself.

Table 7 .1

The axons of the cochlear nerve appear to inform the brain of the loudness of a stimulus by altering their rate of firing action potentials. Louder sounds produce more intense vibrations of the eardrum and ossicles, which produce a more intense shearing force on the cilia of the auditory hair cells. As a result, these cells release more neurotransmitter, producing a higher rate of firing by the cochlear nerve axons. This explanation seems simpl•? for the axons involved in place coding of pitch. In this case, pitch is signaled by which neurons fire, and loudness is signaled by their rate of firing. However, the neurons in the apex of the basilar membrane that signal the lowest frequencies do so by their rate of firing. If they fire more frequently, they signal a higher pitch. Therefore, most investigators believe that the loudness of low-frequency sounds is signaled by the number of axons arising from these neurons that are active at a given time . (See Table 7.1.)

Perception of Pitch and Loudness for High- , Moderate-, anid Low-Frequency Sounds

This table summarizes how pitch and loudness are represented by the activity of hair cells in the cochlea.

High-frequency sounds

Place coding; firing by hair cells at location of basilar membrane that is active

Determined by rate of action potentials from hair cells

Moderate-frequency sounds

Place coding; firing by hair cells at location of basilar membrane that is active

Determined by rate of action potentials from hair cells

Rate coding; hair cells at apical end of basilar membrane fire in synchrony with

Determined by number of active hair cells

Low-frequency sounds

frequency of sound wave

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Chapter 7

Perceiving Timbre LO 7.7

Identify the characteristics of timbre.

Although laboratory investigations of the auditory system often use single-frequency sound stimuli, these sounds are seldom encountered outside the laboratory. Instead, we hear sounds with a rich mixture of frequencies-sounds of complex timbre. For example, consider the sound of a flute playing a particular note. If we hear it, we can identify it as a flute and not a piano or a violin. The reason we can do so is that these three instruments produce sounds of different timbre, which our auditory system can distinguish. The flute note possesses a fundamental frequency, which corresponds to the perceived pitch of the note. The note also has many overtones, frequencies of complex tones that occur at multiples of the fundamental frequency. Different instruments produce overtones with different intensities. Electronic synthesizers simulate the sounds of real instruments by producing a series of overtones of the

Figure 7 .11

Fundamental Frequency and

Overtones

proper intensities, mixing them, and passing them through a speaker. Figure 7.11 illustrates the fundamental frequency and overtones. of a clarinet. When th1e basilar membrane is stimulated by the sound of an instrument, different portions respond to each of the overtones. This response produces a unique anatomically coded pattern of activity in the cochlear nerve, which is subsequently identified by circuits in the auditory association cortex. Actually, the recognition of complex sounds is not quite that simple. The earlier explanation only applies to the analysis o:f the sustained sound of a flute. Most sounds are dynamic; lthat is, their beginning, middle, and end are different from each other. The beginning of a note played on a flute (the attack) contains frequencies that appear and disappear in a few milliseconds. At th e end of th e note (the decay), some frequencies disappear before others. If we are to recognize different sounds, the auditory cortex must analyze a complex sequence of multiple frequencies that appear, chang;e in amplitude, and disappear. And when you consider t:he fact that we can listen to an orchestra and identify several instruments that are playing simultaneously, you ccui appreciate the complexity of the analysis performed by the auditory system.

Perceiving Spatial Location LO 7.8

So far, we have discussed coding of pitch, loudness, and timbre (the la:st of which is actually a complex frequency analysis). The auditory system also responds to other qualities of acoustic stimuli. For example, our ears are very good at determining whether the source of a sound is to the right or left of us. Three physiological mechanisms detect the location of sotmd sources: We use phase differences for low frequencies (less than approximately 3,000 Hz) and intensity differences for high frequencies; in addition, we use an analysis of timbre to determine the height of the source of a sound and recognize whether it is in front of us or behind us.

2 3 4 5 6 7

Compare the processes used to perceive s pati.al location.

Simple waves that make up sound of clarinet

LOCALIZATI ON BY M EANS OF ARRIVAL TIME AN D PHASE DIFFERENCES Even without visual information,

8

we can still determine with a rather good accuracy the location of a stimulus that emits a click. We are most accurate at judging the azi11111th- that is, the horizontal (left or right)

9

angle of the source of the sound relative to the midline of

10

our body. Neurons in our auditory system respond selectively to different arrival times of the sound waves at the left and right ears. If the source of the dick is to the right or left of the midline, the sound pressure wave will reach one ear sooner and initiate action potentials th ere first. Only if the stimulus is straight ahead will the ears be stimulated simultaneously. Many neurons in the auditory system

11 12 13 14 15 16 17 18 19 20

Audition, the Body Senses, and t he Chemical Senses

Figure 7 .12

189

Sound Localization

This method localizes the source of low-frequency and medium-frequency sounds through phase differences. (a) Source of a 1,000 Hz tone to the right. The pres.sure waves on each eardrum are out of phase; one eard rum is pushed in while th e other is pushed out . (b) Source of a sound directly in front. The vibrations of the eard rums are synchronized (in phase).

Left eardrum

Right eardrum pushed in

pulled out

(a)

respond to sounds presented to either ear. Some of these neurons, especially those in the superior olivary complex of the medulla, respond according to the difference in arrival times of sound waves prod uced by clicks presented binaurally (that is, to both ears). Their response rates reflect

differences as small as a fraction of a millisecond. Of course, we can hear continuous sounds as well as clicks, and we can also perceive the location of their source. We detect the source of continuous low-pitched sounds by means of phase differences. Phase differences refer to the simultaneous arrival, at each ear, of different portions (phases) of the oscillating sound wave. For example, if we assume that sound travels at approximately 1,200 km per hour through the air, adjacent cycles of a 1,000 Hz tone are approximately 30 centimeters (cm) apart. This means that if the source of the sound is located to one side of the head, one eardrum is pulled out while the other is pushed in. The movement of the eardrums will reverse, or be 180° out of phase. If the source were located directly in front of the head, the movemen ts would be perfectly in phase (0° out of phase). (See Figure 7.12.) Because some auditory neurons respond only when the eardrums (and the bending of the basilar membrane) are at least somewhat ou t of phase, neurons in the superior olivary complex in the brain are able to use the information they provide to detect the source of a continuous sound. Neurons receive information from two sets of axons coming from th e two ears. Each neu ron serves as a coincidence detector; it responds only if it received signals simultaneously from synapses belonging to both sets of axons. If a signal reaches the two ears simultaneously, neurons in the middle of the array w ill fire. However, if the signal reaches one ear before the other, then neurons

Both eardrums pushed in

(b)

farther away from the "early" ear will be stimulated Geffress, 1948). (See Figure 7.13.) Coincidence detectors can be stud ied in the barn owl, a nocturnal bird that can detect very accurately the source of a sound (such as that made by an unfortunate mouse). (See Figur€~ 7.14.) The branches of two axons, one from each ear, project to the nucleus laminaris, the barn owl analog of the mamnnalian medial superior olivary complex. Axons from the ipsilateral and contralateral ears enter the nucleus from opposite d irections. This means that dorsally located neurons within the nucleus are stimulated by sounds that first reach the contralateral ear. Carr and Konishi (1989, 1990) recorded from single units within the nucleus and found that the response characteristics of the neurons located there were consistent with the coincidence-detector model. LOCALIZATION BY MEANS OF INTENSITY DIFFERENCES The auditory system cannot readily detect binaural phase differences of high-frequency stimuli; the differences in phases of such rapid sine waves are just too short to be measu red by the neurons. However, highfreq uency stimuli that occur to the right or left of the midline stimulate the ears unequally. The head absorbs high frequencies, producing a "sonic shadow," so the ear closest to the source of the sound receives the most intense stimulation. Some neurons in the auditory system respond differentially to binaural stimuli of different in tensity in each ear, which means tha t they provide information that can be used to detect the source of tones of higlh frequency. The neurons that detect binaural differences in loudness are located in the superior olivary complex. But whereas neurons that detect binaural differences in phase

190 Chapter 7

Figure 7 .13

Model of a Coincidence Detector

This model detector can determine differences in arrival times at each ear of an auditory stimulus. Dendrite From left ear

-.

Incoming axon

Cell body

Axons of

Right ear leads

From right ear

Left ear leads This neuron is stimulated when click reaches two ears simultaneously

or arrival time are located in the medial superior olivary complex, these neurons are located in the lateral superior olivary complex. Information from both sets of neurons is sent to other levels of the auditory system. LOCALIZATION BY MEANS OF TIMBRE We just saw

that left-right localization of the source of high- and lowfrequency sounds is accomplished by two different mechanisms: differences in phase and intensity. But how can we determine the elevation of the source of a sound and perceive whether it is in front of us or behind us? One answer is that we can turn and tilt our heads, to transform the discrimination into a left-right decision. But we have another means by which we can determine elevation and distinguish front from back: analysis of timbre. This method involves a part of the auditory system that we have not said much about: the external ear (pinna). People's external ears contain several folds and ridges. Most of the sound waves that we hear bounce off the folds and ridges of the pinna before they enter the ear canal. Depending on the angle at which the sound waves strike these folds and ridges, different frequencies will be enhanced or attenuated. In other words, the pattern of reflections will change with the location of the source of the sound, which will alter the timbre of the sound that is perceived. Sounds coming from behind the head will sound different from those coming from above the head or in front of it, and sounds coming from above will sound different from those coming from the level of our ears. The timbre of sounds that reaches an ear changes along with the elevation of the source of the sound. Figure 7.15 shows the effects of elevation on the intensity of sounds of various frequencies received at

Figure 7 .14,

Coincidence Detectors in the Barn Owl

Coincidence-detecting neurons in the owl's nucleus laminaris compare the arrival of sound in the right and left ears to determine the location of the mouse. Auditory stimuli reaching the left ear first indicate that the source of the sound is on the left side of the head. Source: From Knuclsen, E. I. (2002). Instructed learning in the auditory localization pathwa1y of the barn owl. Nature, 417(6886), 322-328.

Auditory stimulus

i[ ~() Q)

I

~ [ i ~(D

VI

I I

an ear (Oertel & Young, 2004). The experimenters placed a small microjphone in a cat's ear and recorded the sound produced by an auditory stimulus presented at various elevations relative to the cat's head. They used a computer to plot the ear's transfer functions-a graph that compares

Audition, the Body Senses, and t he Chemical Senses

Figure 7 .15

Changes in T imbre of Sounds w ith Changes in Elevation The graphs are transfer functions, which compare the intensity of various frequencies of sound received by the ear to the intensity of these frequencies received by a microphone in open air. The 0° transfer function (blue) is reprinted with the transfer functions obtained at 60°, 30°, and -30°. The differences in the transfer functions at various elevations provide cues that aid in perceiving the location of a sound source. Source: Adapted from Oertel, D., and Young, E. D. (2004). What's a cerebellar circuit doing in the auditory system? Trends in Neuroscience, 27, 104-110.

r~,

Elevation

r~\ Ill(

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co 30 ~ f-30· o ~ ~"\

//1,

i

- 3Q

I

11 11111

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10 Frequency (kHz)

the intensity of various frequencies of sound received by the ear to the intensity of these frequencies received by a microphone in open air. The important point in Figure 7.15 is that the transfer functions varied with the elevation of the source of the sound. The timbre of sounds that reaches the cat's ear changed along with the elevation of the source of the sound. People's ears differ in shape. This means that the changes in the timbre of a sound coming from different locations will also differ from person to person. In addition, as children grow, the size of their ears changes. Each individual must learn to recognize the subtle changes in the timbre of sounds that originate in locations in front of the head, behind it, above it, or below it. The neural circuits that accomplish this task are not genetically programmed; they must be gained through experience. An experiment by Zwiers and colleagues (2001) found evidence for the role of experience in calibrating the sensitivity of the auditory system to changes in elevation. They found that individuals who were blind had more difficulty judging the elevation of sounds than people with sight did, especially if some noise was present. Presumably, the increased accuracy of sighted people reflected the fact that they had had the opportunity to calibrate the changes in

191

the timbre of sounds caused by changes in the height of their sources, which they could see. In contrast, the ability of individuals who were blind to perceive the horizontal location of the sources of sounds was equal to that of sighted people. Blind individuals have much experience navigating to and around the sources of sounds located at ground level (and objects that reflect sounds, such as that of a tapping cane). These perceptions can be calibrated by physical contact with these objects. Kumpik and colleagues (2010) obtained further evidence for the role of learning in the ability to recognize the location of the source of sounds. They found that when one ear was partially plugged, people had difficulty localizing sounds. However, if they practiced several days for a period of time with the plug in, they learned to accurately localize sounds.

Perceiving Complex Sounds LO 7.0

Compare the anterior and posterior auditory p rocessing streams.

As we: said at the outset of this module, hearing has three primary functions: to detect sounds, to determine the location olf their sources, and to recognize the identity of these sources. We will now consider the third function: recognizing thee identity of a sound source. Riight now perhaps you can hear the sound of people talking, a television in the background, the muffled din of music playing in another room, or perhaps you're in a very quiet, remote place and hear only the sound of the breeze in the tre·es. How can you recognize these sound sources? The axons in your cochlear nerve contain a constantly changing pattem of activity corresponding to the constantly changing mixtures of frequencies that strike your eardrums. Somehow, the auditory system of your brain recognizes partic1Ular patterns that belong to particular sources, and you perceive each of them as an independent entity. PERCJEIVING ENVIRONMENTAL SOUNDS AND THEIR LOCATION The auditory system is constantly involved

in pattern recognition. The auditory system must recognize that particular patterns of constantly changing activity belong to different sound sources. And as we saw, few pattenns are simple mixtures of fixed frequencies. For example, notes of different pitches produce different patterns of activity in our cochlear nerve, yet we recognize each of the notes :as belonging to a flute. In addition, the notes played on a flute have a characteristic attack and decay. And consider the complexity of sounds that occur in the environment: cars honking, birds chirping, people coughing, doors slamming, and so on. (We will discuss speech recognitionan even more complicated task- in Chapter 14.) Perhaps unsuriprisingly, we are far from understanding how pattern recognition of such complex sounds works.

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Chapter 7

Perceiving complex sounds appears to be accomplished by circuits of neurons in the auditory cortex. Recognizing complex sounds requires that the timing of changes in the components of the sounds be preserved all the way to the auditory cortex. In fact, the neurons that convey information to the auditory cortex contain special features that permit them to conduct this information rapidly and accurately (Trussell, 1999). Their axons contain special low-threshold voltagegated potassium channels that produce very short action potentials. Their terminal buttons are large and release large amounts of glutamate, and the postsynaptic membrane contains neurotransmitter-dependent ion channels that act unusually rapidly to produce very strong EPSPs. The terminal buttons form synapses with the somatic membrane of the postsynaptic neurons, whkh minimizes the distance between the synapses and the axon-and the delay in conducting information to the axon of the postsynaptic neuron. As we mentioned earlier in this chapter, the auditory cortex, like the visual cortex, is organized into two streams: an anterior stream, involved in perceiving complex sounds (the "what" system); and a posterior stream, involved in perceiving location (the "where" system). In a single-unit recording study with monkeys, Rauschecker and Tian (2000) found that neurons in the "what" system discriminated between different monkey calls, while neurons in the "where" system discriminated between different locations of loudspeakers presenting these calls. Figure 7.16 compares the regions of the monkey brain that are devoted to processing visual and auditory information. As you can see, the visual and auditory "where" streams overlap in the parietal lobe. This overlap is undoubtedly related to the fact that monkeys (and humans, too) can use the convergence of sight and sound to recognize which of several objects in the environment is making a noise. In addition, we can learn the association between the sight of an object and the sounds it makes. Information

Figure 7 .16 Processing Visual and Auditory Information Regions of monkey brain devoted to processing visual and auditory information. vlPFC = ventrolateral prefrontal cortex, dlPFC = dorsolateral prefrontal cortex. Dorsal

Anterior stream "what"

~

Inferior temporal cortex

stream "where"

from both the visual and auditory systems is also projected to specific regions of the frontal lobes-again, with a region where both systems overlap. The role of the frontal lobes in learning and memory is discussed in Chapter 13. AUDITORY CORTEX D AM AGE IMPAIRS COMPLEX SOUND PERCEPTION As we saw in Chapter 6, lesions

of the visual association cortex can selectively impair various aspects of visual perception. Damage to the ventral stream can produce visual agnosias-the inability to recognize objects even though the visual acuity may be good ("what"' system)-and lesions of the dorsal stream disrupt performance on a variety of tasks that require perceiving aind remembering the locations of objects ("where" syst·em). Lesions of the auditory association cortex can produce deficits analogous to these-impairment of various as1pects of auditory perception, even though the individualls are not deaf. A review of 38 functional-imaging studies with human participants (Arnott et al., 2004) reported a consistent result: Perceiving the identity of sounds activated the "what" stream of the auditory cortex, and perceiving the location of sounds activated the "where" stream. A functional MRI (fMRI) study by Alain and colleagues (2008) supports this conclusion. The investigators presented people with sounds of animals, humans, and musical instruments (for example, the bark of a dog, a cough, and the sound of a flute) in one of three locations: 90° to the left, straight ahead, or 90° to the right. On some blocks of trials the participants were asked to press a button when they heard two sounds of any kind from the same location. On other blocks of trials they were asked to indicate when they heard the same kind of sound twice in a row, regardless of its location. As Figure 7.17 shows, judgments of location activated dorsal

Figure 7.17' "Where" vs. "What" Auditory Processing The figure show~> regional brain activity in response to judgments of the category {blu1e) and location (red) of sounds. IFG = inferior frontal gyrus, IPL = infell'ior parietal lobule, MFG = middle frontal gyrus, SFG =superior frontal gyrus, SPL = superior parietal lobule, STG = superior temporal gyrus. Source: From Alain, C., He, Y., and Grady, C. (2008). The contribution of t~e inferior parietal lobe to auditory spatial working memory. Journal of Cognitive Neuroscience, 20, 285-295. Reprinted with permission.

Audition, the Body Senses, and the Chemical Senses

regions ("where" system), and judgments of the nature of a sound activated ventral regions ("what" system). Inhibiting structures in these pathways results in specific deficits in perceiving "what" and "where" for auditory stimuli. Lomber and Malhotra (2008) implanted coiled tubes that circulated a chilled liquid in the cerebral cortex of cats. Circulating the liquid temporarily deactivated the cortical area under the coil. Deactivating a region of the "what" pathway disrupted the cats' ability to recognize an auditory stimulus, and deactivating a region of the "where" pathway disrupted their ability to recognize its location. Although damage can impair the perception of complex sounds, there is also plasticity in the auditory processing pathways. For example, the superior auditory abilities of blind individuals have long been recognized: Loss of vision appears to increase the sensitivity of the auditory system. A functional-imaging study by Klinge and colleagues (2010) found that input to the auditory cortex was identical in individuals who were blind and sighted, but that neural connections between the auditory cortex and the visual cortex were stronger in people who were blind. In addition, the visual cortex showed enhanced responsiveness to auditory stimuli. These findings suggest that the analysis of auditory stimuli can be extended to the visual cortex in people who are blind. Clarke and colleagues (2000) reported the cases of three pa-

tients with brain damage that affected different portions of the auditory cortex. The investigators tested the patients' ability to recognize environmental sounds, to identify the locations from which the sounds were coming, and to detect when the source of a sound was moving. Patient F. D. had difficulty recogniz ing environmental sounds but could identify sound location or movement. Patient C. Z. could recognize environmental sounds but could not identify sound location or movement. Finally, although patient M. A. was not deaf, she showed deficits in all three tasks: recognition, localization, and perception of movement. Although the lesions in these patients were too large to determine the exact locations of the brain regions responsible for the perception of environmental sounds and the location of their sources, we can certainly conclude that different regions of the auditory cortex are involved in perceiving what and where.

Perceiving Music LO 7 .10 Summarize the biological basis for perceiving

music. Perception of music is a special form of auditory perception. Music consists of sounds of various pitches and timbres played in a particular sequence with an underlying rhythm. Particular combinations of musical notes played simultaneously are perceived as consonant or dissonant, pleasant or unpleasant. The intervals between notes of musical scales follow specific rules, which may vary in the music of different cultures. In Western music, melodies played using notes that follow one set of rules (the major mode) usually sound

193

happy; while those played using another set of rules (the minor mode) generally sound sad. In addition, a melody is recognized by the relative intervals between its notes, not by their absolute value. A melody is perceived as unchanging even when it is played in different keys- that is, when the pitches of all the notes are raised or lowered without changing the relative intervals between them. This means that musical perception requires recognition of sequences of not·es, their adherence to rules that govern permissible pitches, harmonic combinations of notes, and rhythmical struch.l!e. Because the duration of musical pieces is several seconds to many minutes, musical perception involves a substantial memory capacity. The neural mechanisms required[ for musical perception are complex. Studies with monkeys and humans have found that the primary auditory cortex responds to pure tones of different frequencies but that recognition of the pitch of complex sounds is accomplished only by the auditory association cortex (Bendor & Wang, 2006). Functional-imaging studies with humans indicate that pitch d iscrimination takes ]place in a region of the superior temporal gyrus rostral and lateral to the primary auditory cortex, in a region of the "what" stream. (See Figure 7.18.) Different regions of the brain are involved in different aspects of musical perception (Peretz & Zatorre, 2005). For example, the inferior frontal cortex appears to be involved in reo::ignition of harmony, the right auditory cortex appears to be involved in the perception of the underlying beat in music, and the left auditory cortex appears to be involved in perception of rhythmic patterns that are superimposed on the rhythmic beat. (Think of a drummer indicating the regular, underlying beat by operating the foot pedal of the bass drum and superimposing a more complex pattern of beats on smaller drums with the drumsticks.) In additioon, the cerebellum and basal ganglia are involved in the timing of musical rhythms, as they are in the timing of movements. Everyone learns language, but only some people become musicians. Musical training obviously makes chang•es in the brain-changes in motor systems involved in singing or playing an instrument, and changes in the auditory system involved in recognizing subtle complexities of harmony, rhythm, and other characteristics of musical structure. Here, we will consider aspects of musical expertise related to audition. Some of the effects of musical training can be seen in chang es in the structure or activity of portions of the auditory system of the brain. For example, a study by Schneider and colleagues (2002) found that the volume of the primary .auditory cortex of musicians was 130 percent larger than that of non-musicians, and the neural response in this area to musical tones was 102 percent greater in musicians. Moreover, both of these measures were positively related to a person's musical aptitude. 1

194 Chapter 7

Figure 7 .18

Figure 7 .19 Consonance vs. Dissonance in Newborn Infants

Regions of the Brain Involved in Musical Perception

The underlying beat of the bass a drummer controls with the foot pedal is detected by our right auditory cortex, while the various beats a drummer plays over the bass with the drumsticks is detected by our left auditory cortex.

Primary auditory cortex

cortex Patient I. R., a right-handed woman in her early forties, sustained

Auditory association cortex

bilateral dama9e during surgical treatment of aneurysms located on her middle cerebral arteries. Aneurysms (discussed in more detail in Chapter 16) are balloon-like swellings on blood vessels that can sometimes rupture, having fatal consequences. The surgery successfully clipped off the aneurysms but resulted in damage to most of the left superior temporal gyrus, and some of the inferior frontal and parietal lobes bordering the lateral fissure. Damage to th1:i right hemisphere was less severe but included the anterior th1ird of the superior temporal gyrus and the right

Left auditory cortex

Right auditory cortex

inferior and mi1jdle frontal gyri. Ten years after the surgery I. R. had normal hearing, could understand speech and converse, and could recognize environmental sounds, but she showed a nearly complete amusia-loss of the ability to percei~e or produce melodic or rhythmic aspects of music. She had been raised in a musical environment; both her grandmother and brother were professional musicians. After her surgery, she lost the ability to recognize melodies that she had been familiar with previously, including simple pieces such as "Happy Birthday." She was no longer able to sing (Peretz et al., 1998). Remarkal)ly, I. R. insisted that she still enjoyed listening to music, and she was still able to recognize emotional aspects of music. Although she could not recognize specific pieces of music, she recognized whether the music sounded happy or sad. She could also recognize happiness, sadness, fear, anger, surprise, and 1jisgust in a person's tone of voice. The ability to recognize emotion in music contrasts with her inability to recognize dissonance in music-a quality that listeners typically find intensely unpleasant. Peretz and her colleagues (2001) discovered that I. R. was totally insensitive to changes in music that irritate most listeners. Even four-month-old babies prefer conso-

Evidence suggests that neural circuits used to process music are already present in newborn infants. A functionalimaging study by Perani and colleagues (2010) found that one- to three-day-old infants showed changes in brain activity (primarily in the right hemisphere) when music they were hearing changed key. (See Figure 7.19.) Brain activity also altered when babies heard dissonant music, which adults find unpleasant.

nant music to dissonant music, which shows that recogn ition of dissonance develops very early in life (Zentner & Kagan, 1998).

Approximately 4 percent of the population exhibits congenital amusia that becomes apparent early in life. People with amusia cannot recognize or differentiate between tunes, and they even try to avoid social situations that involve music.

Audition, the Body Senses, and the Chemical Senses

Musical ability in general and congenital amusia, in particular, appear to have a genetic basis. Drayna and colleagues (2001) had pairs of twins listen to simple popular melodies and determine which ones contained some wrong-and discordant- notes. They found that the correlation between the scores of the twin pairs was .67 for monozygotic twins but only .44 for dizygotic twins. These

195

results indicate a heritability index in this kind of musical ability of approximately .75 (on a scale of 0-1.0). Peretz and her colleagues (2007) found that 39 percent of first-degree relatives (siblings, parents, or children) of people with amusia also had amusia, compared with an incidence of only 3 percent in the first-degree relatives of people in control families.

Module Review: Audition The Stimulus: Sound LO 7.1 Describe three perceptual dimensions of sound.

The perceived pitch of an auditory stimulus is determined by the frequency of vibration, which is measured in hertz (Hz). Loudness is a function of intensity-the degree to which the compressions and expansions of air differ from each other. Timbre provides information about the nature of the particular sound-for example, the sound of an oboe or a train whistle.

Anatomy of the Ear

from tlh.e cochlear nerve to the superior olivary nucleus, and on to the inferior colliculus, the medial geniculate nucleus, and finally to the auditory cortex. The auditory cortex has a tono·topic representation for auditory stimuli and is divided into primary and association areas. Processing in the auditory cortex progresses from the core region (primary cortex), to the belt region and then the parabelt region (association cortex). Cortical auditory processing consists of two streams. The anterior stream, which begins in the anterior 1parabelt region, is involved with analysis of complex sounds. The posterior stream, which begins in the posterior parabelt region, is involved with sound localization.

LO 7 .2 Organize the structures and functions of the

ear involved in auditory processing. The outer ear contains the pinna, ear canal, and tympanic membrane. The middle ear contains the ossicles (malleus, incus, and stapes). The inner ear contains the cochlea, organ of Corti (including the basilar membrane, hair cells, tectorial membrane, and reticular membrane), and the round window.

Auditory H air Cells Transduce Auditory Information LO 7.3 Contrast the location and function of hair cells

in auditory transduction.

Perceiving Pitch LO 7.!5 Contrast place and rate coding in pitch

perception. The cochlea detects frequency by two means: Moderate to high frequencies are detected by place coding, and low frequencies are detected by rate coding. Place coding occurs because acoustic stimuli of different frequencies ca1use different parts of the basilar membrane to flex back aind forth, triggering the neurons in those locations to fire:. Rate coding occurs because lower frequencies are detected by neurons that fire in synchrony with the movements of the apical end of the basilar membrane.

Inner and outer auditory hair cells are located on the basilar membrane. Hair cells contain rows of cilia and synapse with dendrites of bipolar neurons whose axons bring auditory information to the brain. Movement of the basilar membrane causes the cilia to move, bending back and forth. Cilia are arranged in bundles, and bending the bundle of cilia causes receptor potentials. The inner hair cells are necessary for normal hearing. The outer hair cells are involved in altering the mechanical characteristics of the basilar membrane and influencing the effects of sound vibrations on the inner hair cells.

Loudness in high-frequency sounds is represented by an increased rate of action potentials from the auditory hair cells. ]Loudness in low-frequency sounds is represented by the number of axons arising from the low-frequencydetecting neurons at the apical end of the basilar membrane that are active at a given time.

The Auditory Pathway

Perceiving Timbre

LO 7.4 Describe the components of the auditory

LO 7.'7 Identify the characteristics of timbre.

pathway. The organ of Corti sends auditory information to the brain through the cochlear nerve. Auditory information travels

Perceiving Loudness LO 7.16 Contrast how loudness in high- and

low-frequency sounds is represented.

Timbre includes identifying a fundamental frequency and overtones as well as identifying the beginning, middle, and end of a sound.

196 Chapter 7

Perceiving Spatial Location LO 7.8 Compare the processes used to perceive spatial location.

Neurons in our auditory system respond selectively to different arrival times of the sound waves at the left and right ears to determine the horizontal location of an intermittent sound. Phase differences include the simultaneous arrival, at each ear, of differen t portions (phases) of the sound wave to detect the horizontal location of a continuous sound. Coincidence-detecting cells compare binaural input and help determine location. Some neurons in the auditory system respond differentially to binaural stimuli of different intensity in each ear, which means that they provide information that can be used to detect the source of tones of high frequency. Difference in timbre is used to determine the vertical location of a sound.

stru ctures in these pathways results in specific deficits in perceiving "what" and "where" for auditory stimuli.

Perceiving :Music LO 7.10 Summarize the biological basis for perceiving music.

Different regions of the brain are involved in different aspects of musical perception. The primary auditory cortex responds to pure tones of different frequencies, and recognition of th1e pitch of complex sounds is accomplished by the auditory association cortex. The inferior frontal cortex is invollved in recognizing harmony, the right auditory cortex is involved in perceiving the underlying beat in music, and the left auditory cortex is involved in perceiving rhythmic patterns that are superimposed on the rhythmic beat. Damage to the auditory cortex can result in amusia . Musical ability and the occurrence of congenital amusia appear to have a genetic basis.

Perceiving Complex Sounds LO 7.9 Compare the anterior and posterior auditory processing streams.

The anterior stream is involved in perceiving complex sounds ("what"), and the posterior stream is involved in perceiving location ("where"). Damage to these streams can lead to impairment of various aspects of auditory perception, even though the individuals are not deaf. Inhibiting

Vestibular System The functions of the vestibular system include balance, maintaining the head in an upright position, and adjusting eye movement to compensate for head movements. Vestibular stimulation does not produce any readily definable sensation; however, certain low-frequency stimulation of the vestibular sacs can produce nausea, and stimulating the semicircular canals can produce dizziness and rhythmic eye movements (nystagmus). Typically, we are not directly aware of the information received from these organs. This module describes the vestibular apparatus and the vestibular pathway in the brain.

Anatomy of the Vestibular Apparatus LO 7 .11 Summarize the s tructures and functions of the

ves tibular apparatus. The vestibular system has two components: the vestibular sacs and the semicircular canals. They represent the

Thought Question As a student in a laboratory studying auditory processing, you have been asked to propose a new line of research to enhance hearing. For your proposal, select one area of the auditory processing pathway and describe a possible intervention to enhance auditory perception by targeting this area.

second and third components of the labyrinths of the inner ear. (We just sltudied the first component, the cochlea.) The vestibular sac:s respond to the force of gravity and inform the brain about the head's orientation. The semicircular canals respond to angular acceleration-changes in the rotation of the h ead-but not to steady rotation. They also respond (but rather weakly) to changes in position or to linear accelerntion. Figure 7.20 shows the labyrinths of the inner ear, which include: the cochlea, the semicircular canals, and the two vestibular sacs: the utricle ("little pouch") and the saccule ("little sack"). The semicircular canals approximate the three major planes of the head: sagittal, transverse, and horizontal. Re·ceptors in each canal respond maximally to angular acceleration in one plane. The semicircular canal consists of a membranous canal floating within a bony one; the membranous canal con tains a flu id called endolymph. An enlargement called the ampulla contains the organ in which the sensory receptors reside. The sensory receptors are hair cells similar to those found in th e cochlea. Their cilia are embedded in a gelatinous mass called the cupula, which blocks ]part of the ampulla.

Audition, the Body Senses, and the Chemical Senses

Figure 7 .20

197

Receptive Organ of the Semicircular Canals Semicircular canals

Semicircular canals

Cochlea

Section of ampulla

To explain the effects of angular acceleration on the semicircular canals, we will first describe an "experiment." If we place a glass of water on the exact center of a turntable and then start the turntable spinning, the water in the glass wiU, at first, remain stationary (the glass will move with respect to the water it contains). Eventually, however, the water will begin rotating with the container. If we then stop the turntable, the water will continue spinning for a while because of its inertia. The semicircular canals operate on the same principle. The endolyrnph within these canals, like the water in the glass, resists movement when the head begins to rotate. This inertial resistance pushes the endolyrnph against the cupula, causing it to bend until the fluid begins to move at the same speed as the head. If the head rotation is then stopped, the endolymph, still circulating through the canal, pushes the cupula the other way. Angular acceleration is translated into bending of the cupula, which exerts a shearing force on the cilia of the hair cells. (Of course, unlike the glass of water in the example, we do not normally spin around in circles; the semicircular canals measure very

Cupula

slight and very brief rotations of the head.) With this explanation in mind, what might be responsible for the perception of movement after a person stops spinning? The vestibular sacs (the utricle and saccule) work very differe:ntly. These organs are roughly circular, and each contains a patch of receptive tissue. The receptive tissue is located on the "floor" of the utricle and on the "wall" of the saccule when the head is in an upright position. The receptive tissue, like that of the semicircular canals and cochlea, contains hair cells. The cilia of these receptors are embedded in an overlying gelatinous mass, which contains sometlhing rather unusual: otoconia, which are small crystals of calcium carbonate. (See Figure 7.21.) The weight of the crystalls causes the gelatinous mass to shift in position as the orientation of the head changes. In this way, movement produces a shearing force on the cilia of the receptive hair cells. The hair cells of the semicircular canal and vestibular sacs are similar in appearance. Each hair cell contains several cilia, graduated in length from short to long. These hair cells resemble the auditory hair cells found in the cochlea, and their transduction mechanism is also

198 Chapter 7

Figure 7.21

Receptive Tissue of the Vestibular Sacs: The Utricle and thB Saccule

Efferent axon

Vestibular

Saccule

Otolithic membrane

similar: A shearing force of the cilia opens ion channels, and the entry of potassium ions depolarizes the ciliary membrane. All three forms of hair cells employ the same receptor molecules: TRPAI, which we described earlier in this chapter. Figure 7.22 shows two views of a hair cell of a bullfrog saccule made by a scanning electron microscope.

Figure 7 .22

Saccular Hair Cells

These scanning electron microscope views of hair cells of a bullfrog saccule show (a) an oblique view of a normal bundle of vestibular hair cells and (b) a top view of a bundle of hair cells from which the longest has been detached. Source: From Hudspeth, A. J., and Jacobs, R. (1979). Stereocilia mediate transduction in vertebrate hair cells. Proceedings of the National Academy of Sciences, USA, 76, 1506-1509. Reprinted with permission.

(a)

(b)

Cilia

The Vestibular Pathway LO 7.12 Outline the vestibular pathway. As seen in Fig;ure 7.23, the vestibular and cochlear nerves constitute the two branches of the eighth cranial nerve (auditory nerve). The bipolar cell bodies that give rise to the afferemt axons of the vestibular nerve (a branch of the eighth cranial nerve) are located in the vestibular ganglion, which appears as a nodule on the vestibular nerve. Most of the axons of the vestibular nerve synapse within the vestibular nuclei in the medulla, but some axons travel directly to the cerebellum. Neurons of the vestibular nuclei send their axons to the cerebellum, spinal cord, medulla, and pons. There also appear to be vestibular projections to 1the temporal cortex, but the precise pathways have not been determined. Most investigators believe that the cortical projections are responsible for feelings of dizziness; the activity of projections to the lower brain stem can produce nausea and vomiting that accompany motion sickness. Projections to brain stem nuclei controlling neck muscles are dearly involved in maintaining an upright position of the head. Perhaps t:he most interesting connections are those to the cranial nerve nuclei (third, fourth, and sixth) that control the eye muscles. As we walk or (especially) run, the head is jarred. The vestibular system exerts direct control on eyoe movement to compensate for the sudden head movements. This process, called the vestibulo-ocular

Audition, the Body Senses, and the Chemical Senses

Figure 7 .23

199

Vestibular Pathway

Ventral posterior nucleus in thalamus

Vestibular area in cerebral cortex

Vestibular branch of vestibulocochlear nerve

Vestibular

IVth Cranial nerve

Vestibular nuclei

reflex, maintains a fairly steady retinal image. Test this reflex yourself: Look at a distant object and hit yourself (gently) on the side of the head. Note that your image of the world jumps a bit but not too much. People who

1'7---

Vestibulospinal tract Spinal cord

have suffered vestibular damage and who lack the vestibulo-ocular reflex have difficulty seeing anything while walking or running. Everything becomes a blur of movement.

Module Review: Vestibular System Anatomy of the Vestibular Apparatus LO 7 .11 Summarize the structures and functions of the

vestibular apparatus. The vestibular apparatus contains the vestibular sacs (the utricle and saccule) and the semicircular canals of the ear. The vestibular sacs respond to the force of gravity and inform the brain about the head's orientation. The semicircular canals respond to angular acceleration and changes in position or linear acceleration.

The Vestibular Pathway LO 7.12 Outline the vestibular pathway.

From the hair cells, vestibular information is relayed to the brain via the vestibular and cochlear nerves. The vestibular nerve projects to the medulla, which sends

infornnation to the cerebellum, spinal cord, pons, and other 1regions of the medulla. The cranial nerve relays information to the eye muscles to compensate for sudden head movements. There also appear to be vestibular projections to the temporal cortex, but the precise pathways have not been determined.

Thought Question Persistent dizziness has a lifetime prevalence of approximately 25 percent and represents a significant risk factor for fallls among older adults. Select one structure involved in ves1tibular perception and explain how damage or dysfunction in this structure could contribute to the experience of dizziness (even if the exact cortical pathways are not yet identified).

200 Chapter 7

Somatosenses This chapter began with the cases of Ashlyn and Jo. Their cases highlight the important role of somatosenses in influencing our behavior. The somatosenses provide information about what is happening on the surface of our body

and inside it. The cutaneous senses (skin senses) are the most studied of the somatosenses and include several submodalities commonly referred to as touch. Proprioception and kinesthesia provide information about body position and movement. We will describe the contribution of sensory receptors in the skin to these perceptual systems in this module. The muscle receptors and their role in feedback from limb position and movement are also discussed in this module and in Chapter 8. The organic senses arise from receptors in and around the internal organs. (See Table 7.2.)

control movement. These receptors will be discussed separately in Chapter 8. We are aware of some of the information received through the organic senses, which can provide us with unpleasant sensations such as stomachaches or gallbladder attacks, or pleasurable ones such as those provided by a warm drink on a cold winter day. We are unaware of some information, s uch as that provided from receptors in the digestive system, kidneys, liver, heart, and blood vessels that are sensitive to nutrients and minerals. This information, which pllays a role in the control of metabolism and water and mineral balance, is described in Chapter 12.

Anatomy of the Skin and Its Receptive Organs LO 7.14 Describe the anatomy and somatosensory

receptors of the skin.

The Stimuli LO 7.13 Prov ide examples of s timuli that activate

receptors for the somatosenses. The cutaneous senses respond to several different types of stimuli: pressure, vibration, heating, cooling, and events that cause tissue damage (and hence pain). Feelings of pressure are caused by mechanical deformation of the skin. Vibration occurs when we move our fingers across a rough surface. We use vibration sensitivity to judge an object's roughness. Sensations of warmth and coolness are produced by objects that raise or lower skin temperature. Sensations of pain can be caused by many different types of stimuli, but it appears that most cause at least some tissue damage. One source of kinesthesia is the stretch receptors found in skeletal muscles that report changes in muscle length to the central nervous system. Receptors within joints between adjacent bones respond to the magnitude and direction of limb movement. However, the most important source of kinesthetic feedback appears to come from receptors that respond to changes in the stretching of the skin during movements of the joints or of the muscles themselves, such as those in the face Gohansson & Flanagan, 2009). Muscle length d etectors, located within the muscles, do not give rise to conscious sensations; their information is used to

The skin is a complex and vital organ of the body-one that we often tend to take for granted. We cannot survive without it; extensive skin burns are fatal. Our cells, which must be bathed by a warm fluid, are protected from the hostile environment loy the skin's outer layers. The skin participates in therrnoregulation by producing sweat to cool the body, or by restricting its circulation of blood to conserve heat. Skin's appearance varies widely across the body, from mucous memlbranes to hairy skin to the smooth, hairless skin of the palms and the soles of the feet, which is known as glabrou s sk in . The skin consists of subcutaneous tissue, dermis, and epidermis, and it contains various receptors scattered throughout these layers. Glabrous skin contains a dense, complex mixture of receptors, which reflects the fact that we use the palms of our hands and the inside surfaces of our fingers to actively explore the environment: We use our hands and fingers to hold and touch objects. In contrast, the rest of owr body most often contacts the environment passively; that is, other things come into contact with it. Figure 7.24 shows the appearance of free nerve endings and the four types of encapsulated somatosensory receptors (M erkel's disk s, Ruffini corpuscles, M eissner's corpuscles, and Pacinian corpuscles). The locations and functions of these receptors are lis ted in Table 7.3.

Perceiving Cutaneous Stimulation Table 7 .2 Somatosenses

LO 7.15 Describe the perception of tou ch, temperature,

p ai n,, and itch . Cutaneous Senses

Provide information from the surface of the body

Proprioception

Provide information about location of the body in space

Kinesthesia

Provide information about movement of the body through space

Organic Senses

Provide information from, in, and around internal organs

The three most important qualities of cutaneous stimulation are touch, temperature, and pain. These qualities, along with itch and some new directions in cutaneous perception resear·ch, are described in the sections that follow. TOUCH Stimuli that cause vibration in the skin or changes in pn~ssure against it (tactile s timuli) are d etected

Audition, the Body Senses, and the Chemical Senses

Figure 7 .24

Patient G. L., a 54-year-old woman, experienced a permanent loss of afferent neurons involved in somatosensation. G. L. lost

Cutaneous Receptors Hairy Skin

201

Glabrous Skin

the albility to perceive tickle but retained the ability to perceive temp13rature, pain, and itch (Olausson et al., 2002, pp. 902-903). When the hairy skin on her forearm or the back of her hand was stroked with a soft brush, she reported a faint, pleasant sens~ttion.

However, she could not determine the direction of the

stroking or its precise location. An fMRI analysis showed that this stimulation activated the insular cortex, a region that is known to be associated with emotional responses and sensations from intemal organs. The somatosensory cortex was not activated. When regions of hairy skin of control participants were stimulated this way, fMRI showed activation of the primary and secondary somatosensory cortex as well as the insular cortex because the stimulation activated both large and small axons. The glabrous skin on the palm of the hand is served only by large-diameter myeli1nated axons. When this region was stroked with a brush, G. L. reported no sensation at all, presumably because of the Artery

absence of small, unmyelinated axons. The investigators con-

Vein

cluded that, besides conveying information about noxious and

mechanoreceptors- the encapsulated receptors shown

thermal stimuli, small-diameter unmyelinated axons constitute a "systom for limbic touch that may underlie emotional, hormonal

in Figure 7.24-and some types of free nerve endings. Most

and aiffiliative responses to caress-like, skin-to-skin contact be-

by

investigators believe that the encapsulated nerve endings

tween individuals" (Olausson et al., 2002, p . 900). And, as we

serve only to modify the physical stimulus transduced

saw, G. L. could no longer perceive tickle. Tickling sensations,

by the dendrites that reside within them. But what i s the

which were previously believed to be transmitted by these small axons, are apparently transmitted by the large myelinated axons

mechanism of transduction? How does movement of the dendrites of mechanoreceptors produce changes in membrane potentials? It appears that the movem ent causes ion

that were destroyed in patient G. L. Olausson and his colleagues (Loken et al., 2009) note that

channels to open, and the flow of i ons into or out of the

the s13nsory endings that detect pleasurable stroking are found only in hairy skin, and that stroking of glabrous skin does not

dendrite causes a change in the membrane potential. You

provide these sensations. However, we can think of pleasur-

TRPAl, a member of the TRP (transient re-

able tactile stimuli that can be experienced through the glabrous

will recall that

ceptor potential) family of receptor proteins, is responsible

skin of the palms and fingers-for example, those provided by

for the transduction of mechanical information in auditory

stroking a warm, furry animal or touching a loved one. When our hairy skin contacts the skin of another person, it is more likely

and vestibular hair cells. Most information about tactile stimulation is precisely localized-that is, we can perceive the location on our skin where we are being touched. However, a case study by Olausson and colleagues (2002) discovered a new category of tactile sen sation. Read the following case study to learn more about a unique case of cutaneous stimulation.

Table 7.3

that that person is touching us. In contrast, when our glabrous skin contacts the skin of another person, it is more likely that we are touching them. Based on this information, we might expect receptors in hairy skin to provide pleasurable sensations when someone caresses us but expect receptors in glabrous skin to provicje pleasurable sensations when we caress someone else.

Categories of Cutaneous Receptors

Small. sharp borders

Merkel's disks

Hairy and glabrous skin

Detectiorn of form and roughness, especially by fingertips

Large, diffuse borders

Ruffini corpuscles

Hairy and glabrous skin

Detectiorn of static force against skin; skin stretching; proprioception

Small, sharp borders

Meissner's corpuscles

Glabrous skin

Detectiorn of edge contours; Braille-like stimuli, especially by fingertips

Large, diffuse borders

Pacinian corpuscles

Hairy and glabrous skin

Detectioni of vibration; information from end of elongated object being held, such as tool

Hair follicle ending

Base of hair follicle

Detectioni of movement of hair

Free nerve ending

Hairy and glabrous skin

Detection1 of thermal stimuli (coolness or warmth), noxious stimuli (pain), tickle

Free nerve ending

Hairy skin

Detectiorn of pleasurable touch from gentle stroking with a soft object

202

Chapter 7

Our cutaneous senses are often used to analyze the shapes and textures of stimulus objects that are moving with respect to the surface of the skin. Sometimes, the object itself moves, but more often, we do the moving ourselves. If an object is placed in your palm and you are asked to keep your hand still, you will have a great deal of difficulty recognizing the object by touch alone. If you are then allowed to move your hand, you will manipulate the object, letting its surface slide across your palm and the pads of your fingers. You will be able to describe the object's threedimensional shape, hardness, texture, slipperiness, and so on. In order to describe it, your motor system must cooperate, and you need kinesthetic sensation from your muscles and joints, in addition to the cutaneous information. If you squeeze the object and feel a lot of well-localized pressure in return, it is hard. If you feel a less intense, more diffuse pressure in return, it is soft. If it produces vibrations as it moves over the ridges on your fingers, it is rough. If very little effort is needed to move the object while pressing it against your skin, it is slippery. If it does not produce vibrations as it moves across your skin but moves in a jerky fashion, and if it takes effort to remove your fingers from its surface, it is sticky. Our somatosenses work dynamically with the motor system to provide useful information about the nature of objects that come into contact with our skin. Studies of people who make especially precise use of their fingertips show changes in the regions of somatosensory cortex that receive information from this part of the body. For example, violinists must make very precise movements of the four fingers of the left hand, which are used to play notes by pressing the strings against the fingerboard. Tactile feedback and proprioceptive feedback are very important in accurately moving and positioning these fingers so that sounds of the proper pitch are produced. In contrast, placement of the thumb, which slides along the bottom of the neck of the violin, is less critical. In a study of violin players, Elbert and colleagues (1995) found that the portions of their right somatosensory cortex that receive information from the four fingers of their left hand were enlarged relative to the corresponding parts of the left somatosensory cortex. The amount of somatosensory cortex that receives information from the thumb was not enlarged. (The right hand holds the bow, and the violinist makes precise movements with the arm and wrist, but tactile information from the fingers of this hand is much less important.) Schwenkrels and colleagues (2007) stimulated the median and ulnar nerves of non-musicians and professional violinists and recorded the subsequent activity of their somatosensory cortex. The median and ulnar nerves convey sensory information from the hands. The researchers found that stimulating the nerves of the left hand of the violinists produced greater activity in the right compared to the left somatosensory cortex of the musicians. Stimulating the hands of the non-musicians produced similar activity in the right and left somatosensory cortex. Figure 7.25 shows

a representation of the results of the study. The violinist (panel A) had a larger area of the right somatosensory cortex devoted to processing sensory information from the left hand (the red and blue dots represent that area corresponding to the stimulation of the median and ulnar nerves). Feelings of warmth and coolness are relative, not absolute, except at the extremes. There is a temperature l1evel that, for a particular region of skin, will produce a sensation of temperature neutrality-neither

TEMPERATU RE

Figure 7 .2S Asymmetry in Somatosensory Cortex Mapping in Mtusicians Brain activity mapping after stimulating the median nerve (red) and the ulnar nerve (blue) in (a) right-handed violin players and (b) nonmusician volunte?ers. Notice the greater distance between the points in the right hemi::;phere (left hand stimulation) compared to the left hemisphere (right hand stimulation) in the violinists.

)

(a)

)

(b)

Audition, the Body Senses, and the Chemical Senses warmth nor coolness. This neutral point is not an absolute value but depends on the prior history of thermal stimulation of that area. If the temperature of a region of skin is raised by a few degrees, the initial feeling of warmth is replaced by one of neutrality. If the skin temperature is lowered to its initial value, it now feels cool. Increases in temperature lower the sensitivity of warmth receptors and raise the sensitivity of cold receptors. The converse holds for decreases in skin temperature. This adaptation to temperature can be demonstrated easily by placing one hand in a bucket of warm water and the other in a bucket of cool water until some adaptation has taken place. If you then simultaneously immerse both hands in water at room temperature, it will feel warm to one hand and cool to the other. There are two categories of free nerve-ending thermal receptors: those that respond to warmth and those that respond to coolness. Cold sensors in the skin are located just beneath the epidermis, and warmth sensors are located more deeply in the skin. We can detect thermal stimuli over a very wide range of temperatures, from less than 8° C (noxious cold) to over 52° C (noxious heat). Investigators have long believed that no single receptor could detect such a range of temperatures, and recent research indicates that this belief was correct. At present we know of six mammalian thermoreceptors-all members of the TRP family (Bandell et al., 2007; Romanovsky, 2007). The thermoreceptors are listed in Table 7.4. Some of the thermal receptors respond to particular chemicals as well as to changes in temperature. For example, the M in TRPM8 stands for menthol, a compound found in the leaves of many members of the mint family. Peppermint tastes cool in the mouth, and menthol is added to some cigarettes to make the smoke feel cooler and perhaps less harsh and damaging to the lungs. Menthol provides a cooling sensation because it binds with and stimulates the TRPM8 receptor and produces neural activity that the brain interprets as coolness. Chemicals can produce the sensation of heat also. Later in this chapter, you'll learn more about the perception of "heat" from capsaicin, the chemical responsible for the burning sensation you experience when eating chile peppers. This experience of heat is due to the activation of pain receptors.

Table 7.4

Categories of Mammalian Thermal Receptors

TRPV1 , capsaicin

Heat

Above43° C

TRPV2

Noxious heat

Above52° C

TRPV3

Warmth

Above31 ° C

TRPV4

Warmth

Above25° C

TRPM8, menthol

Coolness

Below28°

c

203

The story of pain is quite different from that of temperature and pressure; pain is a much more complicated sensation. Our awareness of pain and our emotional reaction to it are controlled by mechanisms within the brain. Stimuli that produce pain also tend to trigger species-typical escape and withdrawal responses. Subjectively, these stimuli hurt, and we try hard to avoid or escape from them. However, sometimes we are better off ignoring pain and getting on with important tasks. In fact, our brains possess mechanisms that can reduce pain, partly through the action of the endogenous opioids. These mechanisms are descrilbed in more detail in a later module of this chapter. Pain perception, like thermoreception, is accomplished by the networks of free nerve endings in the skin. There appear to be at least three types of pain receptors (usually referred to as nociceptors, or "detectors of noxious stimuli"). High-lthreshold mechanoreceptors are free nerve endings that respond to intense pressure, which might be caused by something striking, stretching, or pinching the skin. The second type of free nerve ending appears to respond to extremes of heat, to acids, and to the presence of capsaicin, the active ingredient in chile peppers. (Note that we say that chile peppers make food taste "hot.") This type of fiber contains TRPVl receptors (Kress & Zeilhofer, 1999). The V stands for vanilloid-a group of chemicals of which capsaicin is a member. Caterina and colleagues (2000) found that mice with a knockout of the gene for the TRPVl receptor showed less sensitivity to painful hightemperature stimuli and would drink water to which capsaicin had been added. The mice responded normally to noxious mechanical stimuli. Presumably, the TRPVl receptor is responsible for pain produced by burning of the skin and to changes in the acid/base balance within the skin. These receptors are responsible for the irritating effect of chemicals such as ammonia on the mucous membranes of the nose (Dhaka et al., 2009). TRPVl receptors also appear to play a role in regulation of body temperature. In addition, Ghilardi and colleagues (2005) found that a drug that blocks TRPVl receptors reduced pain in patients with bone cancer, which is apparently caused by the productio•n of acid by the tumors. Another type of nociceptive fiber contains TRPAl receptors, which, as we saw earlier in this chapter, are found in the cilia of auditory and vestibular hair cells. TRPAl receptors are sensitive to pungent irritants found in mustard oil, wintergreen oil, horseradish, and garlic and to a variety of environmental irritants, including those found in vehicle exhaust and tear gas (Bautista et al., 2006; Nilius et al., :2007). The primary function of this receptor appears to be t:o provide information about the presence of chemicals that produce inflammation. PAIN

ITCH Another noxious sensation, itch (or, more formally, pruritus) is caused by skin irritation. Itch was defined by a seventeenth-century German physician as an "unpleasant

204 Chapter 7 sensation that elicits the desire or reflex to scratch" (Ikoma et al., 2006, p. 535). If an adult sees a child scratching at an insect bite or another form of skin irritation, the adult is likely to say, "Stop that-it will only make it worse!" The scratching may indeed make the irritation worse, but the immediate effect of scratching is to reduce the itching. Davidson and colleagues (2009) found that scratching inhibited the activity of neurons in the spinothalarnic tract of monkeys that transmit itch sensations to the brain. Presumably, the scratch response to stimuli that produce itching helps rid skin of irritating debris or parasites (Davidson & Giesler, 2010). Scratching reduces itching because pain suppresses itching (and, ironically, itching reduces pain). Histamine and other chemicals released by skin irritation and allergic reactions are important sources of itching. Experiments have shown that painful stimuli such as heat and electrical shock can reduce sensations of itch produced by an injection of histamine into the skin, even when the painful stimuli are applied up to 10 cm from the site of irritation (Nilsson et al., 1997; Ward et al., 1996). On the other hand, administering an opiate into the epidural space around the spinal cord diminishes pain but often produces itching as an unwelcome side effect (Chaney, 1995). Naloxone, a drug that blocks opiate receptors, has been used to reduce cholestatic pruritus, a condition of itching that sometimes accompanies pregnancy (Bergasa, 2005). Little is known about the receptors that are responsible for the sensation of itch, but at least two different types of neurons transmit itch-related information to the CNS. Johanek and colleagues (2007) produced itch in volunteers with intradermal injections of histamine and applications of cowhage spicules- tiny, needlelike plant fibers that contain an enzyme that breaks down proteins in the skin. Both treatments produce intense itch, but only histamine produces an area of vasodilation. Pretreating a patch of skin with a topical antihistamine prevented histamine from producing an itch at that spot but had no effect on the itch produced by cowhage. In contrast, pretreating a patch of skin with capsaicin prevented cowhage-induced itch but not histamine-induced itch.

The Somatosensory Pathways LO 7.16 Describe the components of the somatosensory

pathways. The somatosensory pathways relay information about somatosensation from the receptors, through subcortical structures to the primary and secondary somatosensory cortex, enabling somatosensory perception. NERVES AND SUBCORTICAL PROCESSIN G Somatosensory axons from the skin, mu scles, or internal organs enter the central nervous system via spinal

nerves. Those located in the face and head primarily enter through the trigeminal nerve (fifth cranial nerve). The cell bodies of the unipolar neurons are located in the dorsal root ganglia and cranial nerve ganglia. Axons that convey precisely localized information, such as fine touch, ascend through the dorsal columns in the white matter of the spinal cord to nuclei in the lower medulla. From there, axons cross the brain and ascend through the medial lemniscus to the ventral posterior nuclei of the thalamus, the relay nuclei for somatosensation. Axons from the thallamus project to the primary somatosensory cortex, which in turn sends axons to the secondary somatosensory cortex. In contrast, axons that convey poorly localized information, such as pain or temperature, form sy1napses with other neurons as soon as they en ter the spinal cord. The axons of these neurons cross to the other s ide of the spinal cord and ascend through the spinothalamic tract to the ventral posterior nuclei of the thalamus. (See Figure 7.26.) THE SOMATOSENSORY CORTEX The primary and secondary regions of the somatosensory cortex are arranged in columns and divided into multiple maps of the body surface. Column Organization Recall from Chapter 6 that the primary visual cortex contains columns of cells, each of which responds to particular features, s uch as orientation, ocular dominance, or spatial frequency. Within these columns are blobs that contain cells that respond to particular colors. The somatosensory cortex also has a columnar arrangement; in fact, cortical columns were discovered in the somatosensory cortex before they were found in the visual and auditory cortex (Mountcastle, 1957). Within a column, neurons respond to a particular type of stimulus (for example, temperature or pressure) applied to a particular part of the body. Map Organization Dykes (1983) has reviewed research indicating that the primary and secondary somatosensory cortical areas are divided into at least five (and perhaps as many as 10) different maps of the body surface. Within each map, cellls respond to a particular submodality of somatosensory receptors. Separate areas have been identified that respond to cutaneous receptors, receptors that detect changes in muscle length, receptors located in the joints, and Pacinian corpuscles. As we saw in Chapter 6, damage to th•e visual association cortex can cause visual agnosia, and as we saw earlier in this chapter, damage to the auditory association cortex can cause auditory agnosia. You may not be surprised, then, to learn that damage to the somatosensory association cortex can cause tactile agnosia.

Audition, the Body Senses, and the Chemical Senses

Figure 7 .26

205

Somatosensory Pathways

The figure shows the somatosensory pathways from the spinal cord to the somatosensory cortex. Note that precisely localized information (such as fine touch) and imp•recisely localized information (such as pain and temperature) are transmitted by different pathways.

Spinal Cord

Patient E. C., a woman with left parietal lobe damage, was unable to recognize common objects by touch. For example, she identified a pine cone as a brush, a ribbon as a rubber band, and a snail shell as a bottle cap. The deficit was not due to a simple loss of tactile sensitivity; the patient was still sensitive to light touch and to warm and cold objects, and she could easily discriminate objects by their size, weight, and roughness (Reed et al., 1996). Nakamura and colleagues (1998) described patient M. T. , who had a different type of tactile agnosia. M. T. had bilateral lesions of the angular gyrus, a region of the parietal

Dorsal root ganglion

lobe surrounding the caudal end of the lateral fissu re. This patient, like E. C., had normal tactile sensitivity, but he could not iclentify objects by touch. However, unlike E. C., he could draw objects that he touched even though he could not reco9nize what they were. (See Figure 7.27.) The fact that he could draw the objects means that his ability to perceive three -dimensional objects by touch must have been intact. However, the brain damage prevented the information analyzed by the somatosensory association cortex from being transmitted to parts of the brain responsible for the control of language-and for consciousness.

206

Chapter 7

Figure 7 .27

Tactile Agnosia

(a) Drawings of wrenches felt but not seen by M. T. Although the patient did not recogn ize the objects as wrenches, he was able to draw them accurately. (b) Drawings of objects felt but not seen by E. C. The patient could neither recognize the objects by touch nor draw them accurately. Source: Based on Nakamura, J., Endo, K. , Sumida, T., and Hasegawa, T. (1998). Bilateral tactile agnosia: A case report. Cortex, 34, 375-388; and Reed, C. L. , Caselli, R. J., and Farah, M. J. (1996). Tactile agnosia. Underlying impairment and implications for normal tactile object recognition. Brain, 119, 875-888. Reprinted with permission.

Cox and colleagues (2006) studied three families from northern Pakistan whose members included several people with a complete absence of pain and discovered the location of the gene responsible for this disorder. The gene, an autosomal recessive allele located on chromosome 2, encodes for a voltage-dependent sodium channel. The case that brought the families to the researchers'

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electric shocks to their wrists and rated the intensity of the pain that the shocks produced. As Figure 7.33 shows, participants who believed that they had received an expensive pill showed a stronger reduction in pain perception than those who believed they had received an inexpensive one. A functional-imaging study by Wager and colleagues (2004) supports the suggestion that the prefrontal cortex plays a role in placebo analgesia. They administered painful stimuli (heat or electrical shocks) to the skin with or without the application of an "analgesic" skin cream that was actually an unmedicated placebo. They observed a placebo effect-reports of less intense pain and decreased

activity in the primary pain-reactive regions of the brain, including the thalamus, ACC, and insular cortex. They also observed increased activity in the prefrontal cortex and the periaqueductal gray matter of the midbrain. Presumably, the expectation of decreased sensitivity to pain caused the increased activity of the prefrontal cortex, and connections of this region with the periaqueductal gray matter activated endogenous mechanisms of analgesia. (See Figure 7.34.) It appears that a considerable amount of neural circuitry is devoted to reducing the intensity of pain. What functions do these circuits perform? When an animal encounters a noxious stimulus, the animal usually stops

Figure 7 .33 Effect of Perceived Price of a Drug on Placebo Analgesia

Functional MRI s:cans show increased activity in the dorsolateral prefrontal cortex and the periaqueductal gray matter of the midbrain of participants who showed decreased sensitivity to pain in response to administrationi of a placebo.

Figure 7 .34, The Placebo

The graph shows that participants reported less pain reduction from a placebo when they thought it was priced at a discount.

c

35

Effect

Source: Based on Wager, T. 0 ., Rilling, J. K., Smith, E. E., Sokolik, A., Casey, K. L., Davidson, R. J ., Kosslyn, S. M., Rose, R. M., and Cohen, J. 0. (2004). Placebo-induced changes in fMRI in the anticipation and experience of pain, Science, 303, 116~~-1166.

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70

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Dorsolateral

Audition, the Body Senses, and the Chemical Senses what it is doing and engages in withdrawal or escape behaviors. Obviously, these responses are quite appropriate. However, they are sometimes counterproductive. For example, males fighting for access to females during mating season will fail to pass on their genes if pain elicits withdrawal responses that interfere with fighting. In fact, fighting and sexual activity both stimulate brain mechanisms of analgesia. Komisaruk and Larsson (1971) found that tactile stimulation of a rat's vagina produced analgesia. Such stimulation also increases the activity of neurons in the

211

periaqueductal gray matter and decreases the responsiveness of neurons in the ventrobasal thalamus to painful stimulation (Komisaruk & Steinman, 1987). The phenomenon also occurs in humans; Whipple and Komisaruk (1988) found that self-administered vaginal stimulation reduces sensitivity to painful stimuli but not to neutral tactile stimuli. Pr1esumably, copulation triggers analgesic mechanisms. The adaptive significance of this phenomenon is clear: Painful! stimuli encountered during the course of copulation are less likely to cause the behavior to be interrupted, and the chances of pregnancy are increased.

Module Review: Somatosenses The Stimuli

The Somatosensory Pathw ays

LO 7 .13 Provide examples of stimuli that activate

LO 7:16 Describe the components of the somatosensory

receptors for the somatosenses. Mechan ical deformation of the skin activates pressure receptors. Changes in temperatu re activate temperature receptors. Sensations of pain can be caused by many different types of stimuli, but most cause tissue damage and activate nociceptors. Skeletal muscle stretch and limb movement activate k inesthetic receptors.

Anatomy of the Skin and Its Receptive Organs LO 7.14 Describe the anatomy and somatosensory

receptors of the skin. Skin consists of subcutaneous tissue, dermis, and epidermis. Skin contains free nerve endings and encapsulated receptors. The encapsulated receptors are found in hairy and glabrous skin and are responsible for a variety of functions.

Perceiving Cutaneous Stimulation LO 7 .15 Describe the perception of touch,

temperature, pain, and itch. Mec han orecep tors are act ivated by vibration . Vibratory movement causes ion channels to open and change membrane potential to transduce the signal. Thermal receptors are free nerve endings that are activated by a relative change in temperature. Pain receptors are free nerve endings that are stimulated by intense pressure, heat, and chemical irritants. Little is known about the receptors that are responsible for the sensation of itch.

pathways. Somatosensory axons enter the central nervous system via spilnal and cranial nerves. Information from the nerves passes through the medulla, the medial lemniscus of the m idbrain, the ventral posterior nucleus of the thalamus, the p rimary somatosensory cortex, and finally the secondary (association) somatosensory cortex. The sensory cortex includes column organization by stimulus type and multiple maps of the body surface, each corresponding to different types of somatosensory information.

Perceiving Pain LO 7 :17 Describe why pain is experienced, the

components of pain, and how pain perception can be modified. Pain S•erves a constructive role: to reduce the likelihood of further injury. It consists of three perceptual and behavioral effects: perceptions of the intensity of a painful stimulus, immediate emotional consequences, and long-term emotional implications of chronic pain. Pain perception can be modified by activating analgesia circuits, through the rellease of endogenous opioids, or by administering exogemous opioids.

Thought Question Do alll placebos have the same effects on pain reduction? Design an experiment to test the effects of various characteristics of a placebo on pain relief. Consider what aspects of a placebo may make it more effective (for example, price was described in the previous module) and how itt may be administered or for what kinds of pain it may be most effective.

212 Chapter 7

Gustation A 75-year-old woman experienced a sudden stroke while cooking in her kitchen. Six months following the stroke, the woman had recovered many of her impaired functions (which included weakness on her right side); however, she had lost 6.35 kg (approximately 14 lb.) and found her favorite foods unappealing. She reported that everything she ate tasted unappetizing to her and although she could distinguish among different tastes, she perceived foods to have unusual, non-food-like flavors. This experience resulted in the patient eating less food, losing weight, and experiencing feelings of isolation because she did not enjoy sharing meals or eating in restaurants with friends or family. CT scans of the patient's brain immediately following the stroke revealed that the lesion was localized to the left insular cortex (Dutta et al., 2013).

The stimuli that we have encountered so far produce receptor potentials by imparting physical energy: thermal, photic (involving light), or kinetic. However, the stimuli received by the last two senses to be studied-gustation and olfaction-interact with their receptors chemically. This module discusses the first of them: gustation. As demonstrated in the case study you just read, gustation is important in maintaining both adequate nutrition and quality of life. As with the other senses, regions of the cortex are devoted to perceiving taste, and damage to these regions can result in loss of sensory perception.

The Stimuli LO 7 .18 List the six qualities of taste s timuli.

Gustation is clearly related to eating; this sense modality helps us to determine the nature of things we put in our mouths. For a substance to be tasted, molecules of it must dissolve in the saliva and stimulate the taste receptors on the tongue. Tastes of different substances vary, though much less than we generally realize. There are only six qualities of taste: bitterness, sourness, sweetness, saltiness, umami, and fat. Flavor, as opposed to taste, is a composite of olfaction and gustation. Much of the flavor of food depends on its odor; people with anosmia (who lack the sense of smell) or people whose nostrils are blocked have difficulty distinguishing between different foods by taste alone. Most vertebrates possess gustatory systems that respond to all six taste qualities. (An exception is the cat family; lions, tigers, leopards, and domestic cats do not detect sweetness.) Sweetness receptors are food detectors. Most sweet-tasting foods, such as fruits and some vegetables, are safe to eat (Ramirez, 1990). Saltiness receptors detect the presence of sodium chloride. In some environments, it is difficult to obtain adequate amounts of this mineral from

the usual sour•ces of food, so sodium chloride detectors help the animal to detect its presence. Injuries that cause bleeding deplete an organism of its supply of sodium rapidly, so the ability to find salt quickly can be critical. In recent years, researchers have recognized the existence of a fifth taste quality: umami. Umami, a Japanese word that means "good taste," refers to the taste of monosodium glutamate (MSG), a substance that is often used as a flavor enhancer in Asian cuisine 1(Kurihara, 1987; Scott & Plata-Salaman, 1991). The umami receptor detects the presence of glutamate, an amino acid found in proteins. Presumably, the umami receptor proviides the ability to taste types of protein, an important nutrient. Most species of animals will readily ingest substances that taste sweet or somewhat salty. Similarly, they are attracted to foods that are rich in amino acids, which explains the use of MSG as a flavor enhancer. However, they will tend to avoid substances that taste sour or bitter. Because of bacterial activity, many foods become acidic when they spoil. In addition, most unripe fruits are acidic. Acidity tastes sour and causes an avoidance reaction. (However, we have learned to make highly preferred mixtures of sweet and sour, such as lemonade.) Bitterness is almost universaIJy avoided and cannot easily be improved by adding some sweetness. Many plants produce poisonous alkaloids, which protect them from being eaten by animals. Alkaloids tasbe bitter. The bitterness receptor undoubtedly serves to warn animals away from these chemicals. For many years, researchers have known that many species of anilmals (including our own) show a d istinct preference for high-fat foods. Because there is not a distinct taste that is associated with the presence of fat, most investigators concluded that we detected fat by its odor and texture ("mouth feel"). However, Fukuwatari and colleagues (2003) found that rats whose olfactory sense was destroyed continued to show a preference for a liquid diet containing a long-chain fatty acid, one of the breakdown products of fat. V\lhen fats reach the tongue, some of these molecules are broken down into fatty acids by an enzyme called lingual .lipase, which is found in the vicinity of taste buds. The actiivity of lingual lipase ensures that fatty acid detectors are stimulated when food containing fat enters the mouth. Cartoni and colleagues (2010) identified two G protein-coupled receptors that appear to be responsible for detecting t:he presence of fatty acids in the mouth. The investigators found that mice with a targeted mutation against the gE!nes responsible for the production of these receptors showed a decreased preference for fatty acids, and that responses of the taste nerves to fatty acids were also d iminished. Recent research has begun to explore the role of fat taste sensitivity in obesity and changes in this taste sensitivity in response to high- and low-fat diets (Liu et al., 2016).

Audition, the Body Senses, and the Chemical Senses

Anatomy of the Taste Buds and Gustatory Cells

Perceiving Gustatory Information LO 7.~m Summarize the process of gustatory

LO 7.19 Identify the location and structure of taste

receptor cells. The tongue, palate, pharynx, and larynx contain approximately 10,000 taste buds. Most of these receptive organs are arranged around papillae, small protuberances of the tongue. Fungiform papillae, located on the anterior two-thirds of the tongue, contain up to eight taste buds, along with receptors for pressure, touch, and temperature. Foliate papillae consist of up to eight parallel folds along each edge of the back of the tongue. Approximately 1,300 taste buds are located in these folds. Circumvallate papillae, arranged in an inverted V on the posterior third of the tongue, contain approximately 250 taste buds. They are shaped like little plateaus surrounded by moatlike trenches. Taste buds consist of groups of 20 to 50 receptor cells, specialized neurons arranged somewhat like the segments of an orange. Cilia are located at the end of each cell and project through the opening of the taste bud (the pore) into the saliva that coats the tongue. Tight junctions between adjacent taste cells prevent substances in the saliva from diffusing freely into the taste bud itself. Figure 7.35 shows the appearance of a circumvallate papilla; a cross section through the surrounding trench contains a taste bud. Taste receptor cells form synapses with dendrites of bipolar neurons whose axons convey gustatory information to the brain through the seventh, ninth, and tenth cranial nerves. The neurotransmitter released by the receptor cells is adenosine triphosphate (ATP), the molecule produced by mitochondria that stores energy within cells (Finger et al., 2005). The receptor cells have a life span of only 10 days. They quickly wear out, being d irectly exposed to a rather hostile environment. As they degenerate, they are replaced by newly developed cells; the dendrite of the bipolar neuron is passed on to the new cell (Beidler, 1970).

Figure 7 .35

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femal1~ mammals other than higher primates is controlled by the~ ovarian hormones estradiol and progesterone. (In some species, such as cats and rabbits, only estradiol is necessary.) As Wallen (1990) points out, the ovarian hormones control not only the interest of an estrous fema le in malting but also her ability to mate. Female rodents do not emgage in lordosis outside of estrus, making copulation impossible outside of estrus. The evolutionary process in rats: seems to have selected animals that mate only at a time when the female is able to become pregnant. In higher primates (including our own species) the ability to engage in sexiual behavior is not controlled by ovarian hormones. There are no physical barriers to sexual intercourse during any part of the menstrual cycle. Although ovarian hormones do not solely control women's sexual activity, they may influence women's sexual interest, behavior, and physiology. For example, women report increased sexual behavior during the fertile phase of the menstrual cycle (Wilcox et al., 2004). Whether women experience obvious physical changes during the fertile period of their menstrual cycle is currently being investigated. Roberts and colleagues (2004) took photos of women's faces during fertile and nonfertile phases of their menstrual cycle and found that both men and women judged the photos taken during the fertile period to be more attractive than those taken during a nonfertile period. (:See Figure 10.9.) Other studies have found greater attractiveness ratings for women's face shape (Oberzaucher et al., 2012), voices (Pipitone & Gallup, 2008), body odors (Kuukasjarvi et al., 2004), and gait (Provost et al., 2008) during fertile phases. In addition, women's attraction to male featunes appears to vary across the menstrual cycle, as do other ]physiological measures, odors, voice, and behaviors. Resea1cch has begun to investigate the interactions between behaviors and physiology of pair-bonded couples, which also seem to vary across fertile and nonfertile phases of the menstrual cycle (for review, see Gangestad & Haselton, 2015). Other research has found increased flirting behavior by women in the fertile phase, but this behavior is directed toward potential partners the women preferred for shortterm, rather than long-term, relationships (for a clever reseanch design, see Canru et al., 2014). A study of lesbian couples (whose menstrual cycles and fliuctuations in ovarian hormones are likely to be synchronized) found a significant increase in sexual interest and ac:tivity during the middle portions of the women's cycles (Matteo & Rissman, 1984), which suggests that ovarian hormones can influence women's sexual interest. A study of heterosexual partners by Van Goozen and colleagues (1997) supports this suggestion. The investigato1cs found that the sexual activity initiated by men and women showed very different relationships to the

300 Chapter 10

woman's menstrual cycle (and hence to her level of ovarian hormones). Men initiated sexual activity at about the same rate throughout a woman's cycle, whereas sexual activity initiated by women showed a peak around the time of ovulation, when estradiol levels are highest. (See Figure 10.11.) Similarly, Bullivant and colleagues (2004) found that women were more likely to initiate sexual activity and were more likely to engage in sexual fantasies just before and during the surge in luteinizing hormone that stimulates ovulation. Wallen (2001) points out that although ovarian hormones may affect a woman's sexual interest, her behavior is influenced by other factors as well. For example, if a woman does not want to become pregnant and does not have absolute confidence in her method of birth control, she may avoid sexual intercourse at midcycle, around the time of ovulation-even if her potential sexual interest is at a peak. In fact, Harvey (1987) found that women were more likely to engage in autosexual activity at this time. On the other hand, women who want to become pregnant are more likely to initiate sexual intercourse during the time when they are most likely to conceive. A review by Gangestad and Thornhill (2008) suggests that women's interest in sexual partners changes across the menstrual cycle in a particular way. Women do not become indiscriminately more interested in sexual contact during their fertile period, which occurs around the time of ovulation. Instead, because they are more likely to become pregnant if they engage in unprotected sex at that time, they become more selective in mate choice. In particular, they become more attracted to characteristics that might indicate high genetic quality (or did so in the evolution of our species). For example, Gangestad and Thornhm note that

Figure 10.11

Sexual Activity of Heterosexual Couples

This graph shows the distribution of sexual activity initiated by men and women during the phases of the woman's menstrual cycle. Source: Based on data from Wallen, K. (2001). Sex and context: Hormones and primate sexual motivation. Hormones and Behavior, 40, 339-357.

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studies have shown that at midcycle, women's preference increases for the sight of facial and bodily masculinity, for masculine behavioral displays, for masculine vocal qualities, for androgen-related scents, and for body symmetry, which correlates with genetic fitness. These changes may be irrelevant for women in monogamous relationships who have already chosen their partners, or for women using hormone-based contraceptives such as birth control pills, which stabilize levels of circulating hormones. Changes in interest in sexual partners across fertile and nonfertile periods is pronounced in female chimpanzees (Stumpf & Boesch, 2005). During their nonfertile periods, female chimpanzees initiate sexual activity with many males in their group. However, during their period of peak fertility, they become much more selective and tend to mate with the same few males-presumably, those that showed the most promise of being able to supply good genes for their offspring. Several studies suggest that women's sexual interest can be stimulated by androgens. There are two primary sources of androgens in the female body: the ovaries and the adrenal glands. The primary ovarian sex steroids are estra.diol and progesterone, but these glands also produce testosterone. The adrenal glands produce another androgen, anclrostenedione, along with other adrenocortical steroids. However, the available evidence indicates that androgens by themselves (in the absence of estradiol) do not directly stimulate women's sexual interest but appear to amplify the effects of estradiol. For example, Shifren and colleagues (2000) studied women aged 31-56 who had their ovaries removed and were receiving estrogen-replacement therapy. The women were given either a placebo or testosterone, delivered through transdermal patches. Although the estrogen replacement plus placebo produced a positive effect, the addition of testosterone produced an even greater increase in sexual activity and rate of orgasm: The percentage of women who had sex fantasies, masturbated, and had intercourse increased two to three times over baseline levels, and these women reported higher levels of well-being. ACTIVATIONAL EFFECTS OF SEX HORMONES IN MEN Although women and mammals with estrous cycles differ in ltheir behavioral responsiveness to sex hormones, men more closely resemble other mammals in their behavioral responsiveness to testosterone. Without testosterone, sperm production and sexual interest cease. In a double-blind study, Bagatell and colleagues (1994) gave a placebo or a gonadotropin-releasing hormone (GnRH) antagonist to male volunteers to suppress secretion of testicular androgens. Within 2 weeks, the participants who received the GnRH antagonist reported a decrease in sexual interest, sexual fantasy, and intercourse. Men who received replacement closes of testosterone along with the antagonist did not show these changes.

Reproductive and Parental Behavior

Declining sexual activity after castration is variable however. As reported by Money and Ehrhardt (1972), some men decrease sexual activity immediately, whereas others show a slow, gradual decline over several years. Wallen and his colleagues (Wallen et al., 1991; Wallen, 2001) injected a GnRH antagonist in seven adult male rhesus monkeys that were part of a larger group. The injection suppressed testosterone secretion, and sexual behavior declined after 1 week. However, the decline was related to the animal's social rank and sexual experience: More sexually experienced, high-ranking males continued to copulate. In fact, the highest-ranking male continued to copulate and ejaculate at the same rate as before receiving the antagonist, even though his testosterone secretion was suppressed for almost 8 weeks. The mounting behavior of the lowest-ranking monkey completely ceased and did not resume until testosterone secretion recovered from the anti-GnRH treatment. Testosterone not only affects sexual activity but also is affected by it-or even by thinking about it. This effect occurs in both men and women. Among men, anecdotal accounts of changes related to increased testosterone in anticipation of seeing a partner after a separation suggests this pattern; however, testosterone changes in response to viewing sexual content are mixed (reviewed in Goldey & van Anders, 2015). In rodents, LH and testosterone release can be classically conditioned in anticipation of sexual activity (Graham & Desjardins, 1980). Women can experience increased testosterone level in anticipation of sexual activity. Researchers have reported increases in women's testosterone levels before sexual activities (compared to control activities; van Anders et al., 2007). Hamilton and Meston (2010) studied women in long-distance relationships who saw their romantic partners only intermittently. The investigators found that the women's testosterone levels in saliva increased the day before they rejoined their partners-presumably in anticipation of their reunion. These findings support the conclusions from previous research that testosterone, as well as estradiol, plays a role in women's sexual interest and activity. In another study, Goldey and van Anders (2011) found that imagining a positive sexual encounter with an attractive person increased testosterone levels among women, but only those not taking hormone contraceptives. (See Figure 10.12.)

Figure 10.12 Long-Distance Relationships and Testosterone Levels in Women Testosterone levels increased in women anticipating sexual activity with a partner. Source· Data from Hamilton, L. 0., and Meston, C. M. (2010). The effects of part~Br togetherness on salivary testosterone in women in long-distance relationships. Hormones and Behavior, 57(2), 198-202.

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of another. In mammalian species most pheromone communication occurs via specialized receptors that detect the pr1esence of pheromone molecules, similar to olfaction. Some of these chemicals, like hormones, affect reproductive behavior. As you learned in Chapter 7, detecting odors is accomplished by the olfactory bulbs, which constitute the primary olfactory system. However, many of the effects that pheromones have on reproductive cycles are mediated by another sensory organ-the vomeronasal organ (VNO)which consists of a small group of sensory receptors arranged around a pouch connected by a duct to the nasal passage. The VNO, which is present in all orders of mammals except for cetaceans (whales and dolphins), projects to the accessory olfactory bulb, located immediately behind the olfactory bulb (Wysocki, 1979). (See Figure 10.13.) The VNO contains over 200 G-protein-linked receptor molecules that detect many of the chemicals that serve as

Figure 10.13

The Rodent Accessory Olfactory Bulb

Source: Adapted from Wysocki, C. J. (19879). Neurobehavioral evidence for the involvement of the vomeronasal system in mammalian reproduction. Neuroscience & Biobehavioral Reviews, 3, 301-341.

Brain

Effects of Pheromones LO 10.8

Describe the roles of pheromones in reproductive behavior.

Hormones transmit messages from one part of the body (the secreting gland) to another (the target tissue). Another class of chemicals, called pheromones, carries messages from one animal to another. Pheromones are released by one animal and directly affect the physiology or behavior

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Chapter 10

pheromones (Dulac & Axel, 1995; Ryba & Tirindelli, 1997; Stowers & Marton, 2005). These receptor molecules are only distantly related to the ones present in the olfactory epithelium. The accessory olfactory bulb sends axons to the medial nucleus of the amygdala, which in turn projects to the preoptic area and anterior hypothalamus and to the ventromedial nucleus of the hypothalamus. (As you learned in Chapter 7, so does the main olfactory bulb.) The neural circuit responsible for the effects of pheromones appears to involve these regions. As we will see, the preoptic area, the medial amygdala, the ventromedial nucleus of the hypothalamus, and the medial preoptic area all play important roles in reproductive behavior. (See Figure 10.14.) ANIMAL EXAMPLES Although the VNO can respond to some airborne molecules, it is primarily sensitive to nonvolatile compounds found in urine or other substances (Brennan & Keverne, 2004). Luo and colleagues (2003) found that neurons of the vomeronasal system responded only when mice were actively investigating another animal's face or anogenital region. The neurons selectively responded to different strains of mice and between male and female mice.

Figure 10.14 The Amygdala of a Rat This schematic of a cross section through a rat brain shows the location of the amygdala. Source: Adapted from Swanson, L. W. (1992). Brain Maps: Structure of the Rat Brain. New York: Elsevier.

Lateral ventricle

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Fornix Central nucleus of amygdala

Hippocampus Fimbria Thalamus

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Basomedial nucleus of amygdala

In related research, He and colleagues (2008) investigated cells of the mouse VNO and reported that although many neurons were activated by mouse urine, only two or three resp•onded uniquely to urine from males, and approximately eight responded uniquely to urine from females. It seems, then, that a small number of receptors are tuned specifically to chemicals secreted by males or females. Urine from different individuals produced different patterns of activity of large numbers of neurons, undoubtedly reflecting the existence of different concentrations of large numbers of chemicals in the animals' urine. The VNO is essential for the ability of a rodent to identify the sex of another individual. Normally, when a male mouse smells another mouse, he approaches and sniffs the other mouse's face and anogenital region. In mammals, pheromones acre found in urine, vaginal secretions, saliva, and tears. This investigatory behavior permits the animal to detect nonvolatile chemicals secreted by the other animal. If the other animal is a female in estrus, the male courts and mates with her. If it is an unfamiliar male, he attacks it. If it is a familiar male (say, one of its littermates), he will usually tolerate its presence. The main olfactory system stimulates investigatory behavior when the presence of another mouse is detected, and information provided by the vomeronasal system determines the gender, estrous condition, and identity of the other animal. Without the information from the VNO, the animal indiscriminately displays sexual behavior. In contrast, if a male mouse is made anosmic (incapable of detecting odors) by removing the olfactory bulbs, by a genetic knockout that prevents transducing olfactory information in the main olfactory epithelium, or by applying a chemical that damages olfactory receptors, he will not approach and sniff another mouse and, consequently, will not attack or attempt to mate with it (Mandiyan et al., 2005; Wang et al., 2006). If transduction of chemical information in the VNO is prevented by a knockout olf a gene required for this process (TRPC2), mice can no longer distinguish between males and females (Stowers et al., 2002). The male~s of some species produce sex-attractant pheromones that affect the behavior of females. For example, a pheromone present in the saliva of boars (male pigs) elicits sexual behavior in sows. This response persists even after the sow's VNO is destroyed, which suggests that the main olfactory system can detect the pheromone a111d elicit the behavior (Dorries et al., 1997). Other male plheromones that attract females are also detected by the main olfactory system. For example, Mak and colleagues (2007) found that the odor of soiled bedding taken from the cage of a male mouse activated neurons in the main olfactory system and hippocampus of female mice. The odor even stimulated neurogenesis (production of new neurons). The researchers found new neurons in the olfactory bulb and hippocampus.

Reproductive and Parental Behavior

Moreover, bedding from cages of dominant males stimulated neurogenesis more effectively than did bedding from subordinate males. Pheromones can affect reproductive physiology or behavior in several ways. When groups of female mice are housed together, their estrous cycles slow down and eventually stop. This phenomenon is known as the LeeBoot effect (van der Lee & Boot, 1955). If groups of females are exposed to the pheromones of a male (or of his urine), they begin cycling again, and their cycles tend to be synchronized. This phenomenon is known as the Whitten effect (Whitten, 1959). The Vandenbergh effect (Vandenbergh et al., 1975) is the acceleration of the onset of puberty in a female rodent caused by the pheromone of a male. Both the Whitten effect and the Vandenbergh effect are caused by a group of compounds that are present only in the urine of intact adult males (Ma et al., 1999; Novotny et al., 1999). The urine of a juvenile or castrated male will not produce these effects. The production of the pheromone by a male requires the presence of testosterone. The Bruce effect (Bruce, 1960) occurs when a recently impregnated female mouse encounters a male mouse other than the one with which she mated, and the pregnancy is aborted. This effect, too, is caused by a substance secreted in the urine of intact males-but not of males that have been castrated. In this way, a male mouse that encounters a pregnant female is able to prevent the birth of offspring carrying another male's genes and subsequently mate with the female himself. This phenomenon may be advantageous from the female's (and new male's) point of view. The fact that the new male has managed to take over the old male's territory indicates that he is likely to be healthier. Therefore, his genes will contribute to offspring that are more likely to survive. (See Table 10.3.) HUMAN EXAMPLES The topic of human pheromones has generated a great d eal of debate and critique of the available evidence. After reading about the examples summarized here, what will you conclude about the strength of the evidence for active human pheromones?

Table 10.3

Pheromones and Behavior

Lee-Boot Effect

Estrous cycles stop in groups of female rodents living together

Whitten Effect

Groups of female rodents who are not cycling are exposed to male urine and begin cycling synchronously

Vandenbergh Effect

Acceleration of onset of puberty in female rodents exposed to odor of male

Bruce Effect

Exposure to urine of novel male results in failure of pregnancy in newly pregnant female

303

It appears that at least some pheromone-related

pheno•mena can occur in humans. Early research in this area revealed that women who spend a large amount of time together tend to have menstrual cycles that are synchronized by pheromones (McClintock, 1971; Russell et al., 1980). These results were confirmed by Stern and McClintock (1998), who found that compounds from the armpits of women that were collected around the time of ovulation lengthened other women's menstrual cycles, and compounds collected late in the cycle shortened them. Preti and colleagues (2003) performed a similar exjperiment but exposed women to extracts of sweat collec1ted from men. They found that the extract (but not a placebo) advanced the onset of the next pulse of the women's LH secretion, reduced tension, and increased relaxation. SE!veral studies have found that compounds present in human sweat have different effects in men and women. Singh and Bronstad (2001) had men smell T-shirts that had been worn by women for several days. The men reported that shirts worn by women during the fertile phase of their menstrual cycle smelled more pleasant and more attractive than those worn during the nonfertile phase. Jacob and McCiintock (2000) found that the androgenic chemical androstadienone (AND), found in men's sweat, increases alertrn~ss and positive mood in women but decreases positive mood in men. Wyart and colleagues (2007) found that women who smelled AND showed higher levels of cortisol (an adrenal hormone involved in a variety of emotional behaviors) and reported a more positive mood and an increase in sexual arousal. Saxton and colleagues (2008) applied a solution containing AND or a placebo to women's upper lips and then had them participate in a "speeddating;" event organized by a private agency at a local bar. During the event, the women met and talked with several men, one at a time, for 3 minutes each. Afterward, the women were asked to rate the men's attractiveness. Most of the women exposed to AND found the men they met to be more attractive. In another line of human pheromone research, men show a brain response to a chemical found in women's urine. A functional-imaging study by Savic and colleagues (2001) found that the estrogenic chemical estratetraene (EST) activated the paraventricular nucleus and dorsomedial h ypothalamus in men but not in women. Sweat and urine might not be the only vehicles for pheromone communication in humans. Research has investigated hand shaking and the potential for pheromonemedia ted communication via this behavior (Frumin et al., 2015). Some research has even sought to address the presence and effects of pheromones found in tears derived from emotion (but not an irritant, or saline control condition). So far, results of these investigations have yielded potentially conflicting results, and additional research and replication

304 Chapter 10

will be needed to clarify the extent of pheromone production in various secretions of the human body (Gelstein et al., 2011; Gracanin et al., 2016; Sobel, 2017). What sensory organ detects the presence of human pheromones? Although humans have a small VNO located along the nasal septum (bridge of tissue between the nostrils) approximately 2 cm from the opening of the nostril (GarciaVelasco & Mondragon, 1991), the human VNO is generally thought to be a vestigial, nonfunctional organ. The density of neurons in the VNO is very sparse, and investigators have not found any neural connections from this organ to the brain (Doty, 2001). Evidence suggests that human reproductive physiology is affected by pheromones, but these chemical signals may be detected by the "standard" olfactory systemthe receptor cells in the olfactory epithelium-and not by cells in the VNO. In support of this conclusion, Savic and colleagues (2009) found that EST activated the brains of men with intact olfactory systems, but not those of men whose olfactory epithelium had been destroyed by nasal polyps but whose VNOs were intact. Other researchers have suggested that a different class of receptors, the trace amine-associated receptors (TAARs) may be responsible for pheromone detection in some species. TAARs in the epithelium of the mouse olfactory system are sensitive to amines in mouse urine that may function as pheromones (Liberles & Buck, 2006). (See Figure 10.15.) Some TAARs are exceptionally sensitive to stimuli, making them an interesting target for future research in this area (Zhang et al., 2013). TAARs have been identified in human epithelium (Carnicelli et al., 2010); however, more research is needed to fully understand their functions.

Figure 10.1.5

TAAR Expression in the Olfactory System

(a) Anatomy of the mouse nose in a sagittal view. (b) A section of VNO tissue shows the epithelium (top of image) and round bundles of nerve cells (middle of image). VNO = vomeron:asal organ MOE = main olfaictory epithelium

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Module Review: Control of Sexual Beh8lvior by Hormones and Pheromones Hormonal Control of Female Reproductive Cycles

Hormonal Control of Sexual Behavior of Laboratory Animals

LO 10.4

LO 10.5

Summ arize the roles of hormones in phases of the menstrual cycle. The menstrual cycle begins with the maturation of one or more ovarian follicles, which occurs in response to the secretion of FSH by the anterior pituitary gland. As the ovarian follicle matures, it secretes estradiol, which causes the lining of the uterus to develop. When estradiol reaches a critical level, it causes the pituitary gland to secrete a surge of LH, triggering ovulation. The empty ovarian follicle becomes a corpus luteum, under the continued influence of LH, and secretes estradiol and progesterone. If pregnancy does not occur, the corpus luteum stops producing hormones, and menstruation begins.

Compare the roles of hormones in sexual behavior of male and femal e rodents. Sexual behavior of male rodents depends on testosterone. Sexual behavior of female rodents depends on estradiol and progesterone. In rats, after being primed with estradiol, progesterone levels increase just before the onset of the receptive period. Both estradiol and progesterone are low in the estrus phase, and then increase moderately in the metestrus phase before decreasing again in diestrus. Both of these hormones increase more in the proestrus phase, which ends with ovulatiom. Levels of both hormones decline after ovulation and return to estrus levels. Oxytocin is released at the time of orgasm in both males and females and appears to contribute to the contractions of the smooth muscle in the male ejaculato1ry system and of the vagina and uterus.

Reproductive and Parental Behavior

305

Organizational Effects of Androgens on Behavior: Masculinization and Defeminization

Effects of Pheromones

LO 10.6

Pheromones are chemicals that signal information among members of the same species. They are detected by receptors in the vomeronasal organ of some species and convey information about an animal's sex, estrous condition, and identity. Odorants present in the urine of female mice affect their estrous cycles, lengthening and evenhially stopping them (the Lee-Boot effect). Odorants present in the urine of male mice abolish these effects and cause the females' cycles to become synchronized (the Whittcen effect). (Phenomena similar to the Lee-Boot effect and the Whitten effect also occur in women.) Odorants can also accelerate the onset of puberty in females (the Vandenbergh effect). In addition, the odor of the urine from a male other than the one that impregnated a female mouse will cause her to abort (the Bruce effect). Pheromones appear to play a role in human behavior, and may influence menstrual cycles, mood, changes in attractiveness ratings, and brain activity.

Contrast behavioral masculinization and defeminization in rodents.

In response to prenatal androgen exposure, behavioral defeminization occurs and inhibits female sexual behavior in adulthood. Behavioral masculinization enables individuals to engage in male sexual behavior in adulthood.

Human Sexual Behavior LO 10.7

Compare the activational effects of hormones on sexual behavior in men and women.

Testosterone has an activational effect on the sexual behavior of men. Women do not require estradiol or progesterone to experience sexual interest or to engage in sexual behavior. Some research suggests proceptivity may be related to ovarian hormones, even in higher primates. Studies with women suggest that variations in levels of ovarian hormones across the menstrual cycle affect sexual interest but that other factors (such as initiation of sexual activity by partners or a desire to avoid or attain pregnancy) can also affect sexual behavior. The presence of androgens may facilitate the effect of estradiol on women's sexual interest.

Neural Control of Sexual Behavior The control of sexual behavior-at least in laboratory animals-involves different neural mechanisms in males and females. This module describes these mechanisms.

Male Sexual Behavior LO 10.9

Identify the role of spinal and brain mechanisms in male sexual behavior.

Both spinal and brain mechanisms are important in the neural control of male sexual behavior. These mechanisms coordinate to control male sexual posturing, erection, and ejaculation. Erection and ejaculation are controlled by circuits of neurons that reside in the lumbar section of the spinal cord in rats (Coolen et al., 2004; Coolen, 2005) and humans (Chehensse et al., 2017). These circuits are called the spinal ejaculation generator. However, brain mechanisms have both excitatory and inhibitory control of these circuits. The medial preoptic area (MPA), located

LO 101.8

Describe the roles of pheromones in reproductive behavior.

Thought Question Imagine that you have accepted a research position working in a lab that studies human pheromones. What research questions would you be most interested in studying, and why?

just rostral to the hypothalamus, is the forebrain region most •Critical for male sexual behavior. (As we will see later in this chapter, it is also critical for other behavior, including maternal behavior.) Electrical stimulation of this region elicits male copulatory behavior (Malsbury, 1971), and sexual activity increases the firing rate of single neurons in the MPA (Mas, 1995; Shimura et al., 1994). In addition, the act of copulation activates neurons in the MPA (Oaknin et al., 1989; Robertson et al., 1991; Wood & Newman, 1993). Dominguez, Gil, and Hull (2006) found that mating increased the release of glutamate in the MPA and that infusion of glutamate into the MPA increased the frequency of ejaculation. Will and colleagues (2017) report increases in glutamate as well as dopamine, in the MPA following sexual activity. Finally, destruction of the MPA abolishes male sexual behavior (Heimer & Larsson, 1966/1967).

The organizational effects of androgens are responsible for changes in brain structure. Gorski and colleagues (1978) discovered a nucleus within the MPA of the rat that is three to seven times larger in males than in females. This area is called the sexually dimorphic nucleus (SON) of the preoptic area.

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(This brain region, which is called the uncinate nucleus in humans, is sexually dimorphic in our species as well and corresponds with gender identity.) The size of this nucleus is controlled by the amount of androgens present during fetal development. According to Rhees and colleagues (1990a, 1990b), the critical period for masculinization of the rat SDN appears to start on the eighteenth day of gestation and end once the animals are 5 days old. (Normally, rats are born on the twentysecond day of gestation.) De Jonge and colleagues (1989) found that lesions of the rat SDN decrease masculine sexual behavior in rats. (See Figure 10.16.) The MPA does not act alone. It receives chemosensory input from the vomeronasal organ through connections with the medial amygdala and the bed nucleus of the stria terminalis (BNST). The MPA also receives somatosensory information from the genitals, the central tegmental field of the midbrain, and the medial amygdala. Androgens also exert their activational effects on neurons in the MPA and associated brain regions. If a male rodent is castrated in adulthood, its sexual behavior will cease. However, the behavior can be reinstated by implanting a small amount of testosterone directly into the MPA or in two regions whose axons project to the MPA: the central tegmental field and the medial amygdala (Coolen & Wood, 1999; Sipos & Nyby, 1996). Both of these regions contain a high concentration of androgen receptors in the male rat brain (Cottingham & Ffaff, 1986).

Figure 10.16

As we saw earlier in this chapter, the primary and accessory olfacbory systems play important roles in rodent reproductive !behavior. Both of these systems send axons to the mediall nucleus of the amygdala, which in turn sends axons 'to the MPA. Several studies (for example, Heeb & Yahr, 2000; Lehman & Winans, 1982) have found that lesions oJf the medial amygdala abolished the sexual behavior of male rodents, presumably because the lesions disrupted the activating effects of pheromones on the MPA. The medial amygdala, like the MPA, is sexually dimorphic: One region within this structure (which contains an especially lhigh concentration of androgen receptors) is 85 percent larger in male rats than in female rats (Hines et al., 1992). The MPA also receives somatosensory information firom the genitals through connections with the central teg;mental field of the midbrain and the medial amygdala. The act of copulation activates neurons in both of these regions (Greco et al., 1998). As we saw previously, the lumbar region of the spinal cord contains a group of neurons that play a critical role in ejaculation (Coolen et al., 2004). Anatomical tracing studies suggest that the most important connections between the MPA and the spinal ejaculation generator are accomplished through the pieriaqueductal gray matter (PAG) of the mjdbrain and the nucleus paragigantocellularis (nPGi) of the medulla 1(Marson & McKenna, 1996; Normandin & Murphy, 2008). The nPGi normally inhibits spinal cord sexual reflexes, so one of the tasks of the pathway originating

Preoptic Area of the Rat Brain

This figure shows the preoptic area of a rat brain in (a) a typical male, (b) a typical female, and (c) an androgenized female, given an injection of testosterone shortly after birth. SDN-POA = sexually dimorphic nucleus of the pre1optic area; OC = optic chiasm; V = third ventricle; SCN = suprachiasmatic nucl~eus; AC =anterior commissure. Source: Based on Gorski , R. A. (1983). In E. E. Muller and R. M. MacL•:!Od (Eds.), Neuroendocrine perspectives, Vol. 2. Amsterdam: Elsevier-North Holla1nd.

Preoptic ;area of the brain -AC Medial preoptic area (POA)

--~..,

SDN-POA

(a) Male

SDN-POA

(b) Female

Hypothalam"'

--oc

SDN-POA SCN

U--

v SDN-POA

(c) Female

+ testosterone

Reproductive and Parental Behavior in the MPA is to suppress this inhibition. The MPA suppresses the nPGi directly through an inhibitory pathway and does so indirectly by inhibiting the activity of the PAG, which normally excites the nPGi. The inhibitory connections between neurons of the nPGi and those of the spinal ejaculation generator are serotonergic. As Marson and McKenna (1992) showed, application of serotonin (5-HT) to the spinal cord suppresses ejaculation. This connection may explain a side effect of selective serotonin reuptake inhibitors (SSRis). Men who take SSRis as a treatment for depression often report that they have no trouble attaining an erection but have difficulty achjeving an ejaculation. Presumably, the action of the drug as an agonist at theserotonergic synapses in the spinal cord increases the inhibitory influence of nPGi on the spinal ejaculation generator. Ejaculation is accomparued by neural activity in many brain regions, including the junction between the midbrain and the diencephalon, which includes the ventral tegmental area (probably involved in the pleasurable, reinforcing effects of orgasm), other midbrain regions, several thalamic nuclei, the lateral putamen (part of the basal ganglia), and the cerebellum. Decreased activity is seen in the amygdala and nearby entorhinal cortex (Holstege et al., 2003b). The amygdala is involved in defensive behavior, fear, and anxiety-emotions that interfere with erection and ejaculation. Decreased amygdala activation is also seen when people who are deeply in love see pictures of their loved one (Bartels & Zeki, 2000, 2004). Figure 10.17 summarizes several lines of research evidence for the neural basis for male sexual behavior.

Figure 10.17

Ferrtale Sexual Behavior LO 10.10 Identify the role of brain mechanisms in female sexual behavior. Similar to males, the spinal areas involved in female sexual behavior also span the lumbar region (Alexander et al., 2016), and another region in the ventral forebrain plays a role in female sexual behavior: the ventromedial nucleu s of the hypothalamus (VMH) . A female rat with bilateral lesions of the ventromedial nuclei will not display lordosis, even if she is treated with estradiol and progesterone. Conversely, electrical stimulation of the ventromedial nucleus facilitates female sexual behavior (Pfaff & Sakuma, 1979). The medial amygdala of males receives chemosensory information from the vomeronasal system and somatosensory information from the genitals, and it sends efferent axons to the medial preoptic area. These connections are found in females as well. In addition, neurons in the medial amygdala send efferent axons to the VMH. In fact, copulation or stimulation of the genitals or flanks of a female 1rat increases the activation of neurons in both the medial amygdala and the VMH (Pfaus et al., 1993; Tetel et al., 1993). A:s we saw earlier, sexual behavior of female rats is activated by a priming dose of estradiol, followed by progesterone. The estrogen primes the behavior and the progesterone stimulates the sexual behavior. Injections of these hormones directly into the VMH will stimulate sexual behavior even in females whose ovaries have been removed (Pleim & Barfield, 1988; Rubin & Barfield, 1980).

Male Sexual Behavior

This schematic shows a possible explanation of the interacting excitatory effects of pheromones, genital stimulation, and testosterone on male rodent sexual behavior. Black arrows repreisent excitatory pathways. Red arrows represent inhibitory pathways. Periaqueductal Gray Matter • Normally excites the nPGi • Inhibited by the MPA

-

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Input from olfactory bulb and vomeronasal organ

)

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If a chemical that blocks the production of progesterone

receptors is injected into the VMH, the animal's sexual behavior is disrupted (Ogawa et al., 1994). In this way, estradiol and progesterone exert their effects on female rodent sexual behavior by activating neurons in this nucleus. The neurons of the ventromedial nucleus send axons to the periaqueductal gray matter. This region, too, has been implicated in female sexual behavior (Sakuma & Pfaff, 1979a, 1979b, 1980a, 1980b). Rose (1990) recorded from single neurons in the ventromedial hypothalamus of freely moving female hamsters and found that injections of progesterone (following estradiol pretreatment) increased the activity level of these neurons, particularly when the animals were displaying lordosis. Tetel and colleagues (1994) found that neurons in both the VMH and the medial amygdala that showed increased Fos production when the animal's genitals were stimulated also contained estrogen receptors. It appears that the stimulating effects of estradiol and genital stimulation converge on the same neurons. How does estradiol prime a female's sensitivity to progesterone? Estradiol increases the production of progesterone receptors, which greatly increases the effectiveness of progesterone. Blaustein and Feder (1979) administered estradiol to ovariectomized guinea pigs and found a 150 percent increase in the number of progesterone receptors in the hypothalamus. Presumably, the estradiol activates genetic mechanisms in the nucleus that are responsible for the production of progesterone receptors.

Figure 10.18

Daniels and colleagues (1999) injected a transneuronal retrograde tracer, pseudorabies virus, in the muscles responsible for the lordosis response in female rats. They found that the pathway innervating these muscles was as previous studies predicted: VMH ~ PAG ~ nPGi ~motor neurons in the: ventral horn of the lumbar region of the spinal cord. As we saw previously, the brain regions that control male genital :reflexes include the MPA, PAG, and nPGi. Researchers in1terested in anatomical tracing (Marson, 1995; Marson & Mu:rphy, 2006) found retrograde labeling in these three brain structures (and some others as well) after administering the retrograde tracer to the clitorises and vaginas of female 1rats. It seems likely that erections of the penis and clitoris a:re controlled by similar brain mechanisms. This finding is not surprising, because these organs derive from the sami~ embryonic tissue. Holstege and colleagues (2003a) observed activation in the junction between the midbrain and diencephalon, the lateral putamen, and the cerebellum, during orgasm in women, just as was observed in men (Holstege et al., 2003b). They also saw activation in the PAG, a crittical region for copulatory behavior in female laboratory animals. Imaging research in women has replicated this findling and identified a potentially wider range of brain regions involved in female orgasm, including sensory, motor, re:ward, frontal cortical, and brainstem regions (Wise et al., 2017). Figure 10.18 summarizes several lines of research evidence for lbrain regions involved in neural control of female rodent sexual behavior.

Female Sexual Behavior

This schematic shows a possible explanation of the interacting excitatory e,ffects of pheromones, genital stimulation, and estradiol and progesterone on female rodent sexual behavior. All pathways are excitatory.

Input from olfactory bulb and vomeronasal organ

.~_c:;~~VMH A~ 7,.-,

nPGi 01 Mating ~medulla behavior _..----;

PAG of midbrain

~

Medial

---v

~

~ ""'

am;d;la I " " - -/"" Medial Amygdala Periaqueductal Gray Matter • Mating causes production • Destruction abolishes sexual of Fos protein. • Neurons contain behavior. • Estradiol treatment or stimulation estrogen and progesterone receptors. of VMH increases neural activity. • Neurons contain estrogen and progesterone receptors.

Ventromedial Nucleus of Hypothalamus • Destruction abolishes sexual behavior. • Matiing causes production of Fos protein. • Neurons contain estrogen and progesterone receptors. • Injection of estradiol and progesterone enhances sexual behavior of ovariiectomized rats.

Reproductive and Parental Behavior

Formation of Pair Bonds LO 10.11 Compare the roles of oxytocin and vasopressin

in pair bond ing. In approximately 5 percent of mammalian species, individuals form monogamous, long-lasting partnerships. Although there are diverse patterns, there is no doubt that pair bonding occurs in some species, including our own. As naturalists and anthropologists have pointed out, monogamy is not always exclusive: In many species of animals, humans included, individuals sometimes cheat on their partners. In addition, people can display serial monogamy-intense relationships that last for a period of time, that are replaced with similarly intense relationships with new partners. Further reflecting the diverse patterns of pair-bonding that can occur, members of some cultures engage in polygamy. Several laboratories have investigated pair bonding utilizing several closely related species of voles (small rodents that are often mistaken for mice). The different species appear to be almost identical but they display very different patterns of behavior. Prairie voles (Microtus ochrogaster) are monogamous; males and females form pair bonds after mating, and the fathers help to care for the pups. In the wild, most prairie voles whose mates die never find another partner (Getz & Carter, 1996). Meadow voles (Microtus pennsylvanicus) are promiscuous and polygamous; after mating, the male leaves, and the mother cares for the pups by herself. Studies of these vole species revealed a relationship between monogamy and the levels of two peptides in the brain: vasopressin and oxytocin. These compounds are both released as hormones by the posterior pituitary gland and as neurotransmitters by neurons in the brain. In males, vasopressin appears to play the more important role. Monogamous voles have a higher level of Vla vasopressin receptors in the ventral forebrain than do polygamous voles (Insel et al., 1994). This difference appears to be responsible for the presence or absence of monogamy in the voles. Lim and Young (2004) found that mating induced the production of Fos protein in the ventral forebrain of male prairie voles and that an injection of a drug that blocks Vla receptors disrupted the formation of pair bonds. Lim and colleagues (2004) performed an even more convincing experiment. They injected a genetically modified virus that contained the gene for the Vla receptor into the ventral forebrain of normally polygamous male meadow voles. This manipulation increased the synthesis of the Vla receptor in this brain region and transformed the animal's behavior from polygamy to monogamy. Unlike prairie voles, which spend much time in physical contact with their partners after mating, meadow voles normally spend little time with

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them. Lim and colleagues found that male meadow voles with artificially increased levels of Vla receptors spent much more time huddling side by side with their mates. In. female voles, oxytocin appears to play a more significant role in pair bonding. Mating stimulates the release of oxytocin, and peripheral injection of oxytocin or injection into the cerebral ventricles facilitates pair bonding in female prairie voles (Williams et al., 1994). In contrast, a drug that blocks oxytocin receptors disrupts the formation of pair bonds (Cho et al., 1999). Many investigators believe that oxytocin and vasopressin may play a role in pair bonding in humans. For example, after intercourse, at a time when blood levels of oxytocin are increased, people report feelings of calmness and well-being, which are certainly compatible with the fo1rmation of bonds with one's partner. However, it is difficult to envision ways to perform definitive research on this topic. Experimenters can study the effects of these hormones or their antagonists on pair bonding in laboratory animals, but cannot do so with humans. Studies have found, however, that oxytocin affects human social behaviors less momentous than pair bonding. For example·, Rimmele and colleagues (2009) found that people wlho received an intranasal spray of oxytocin before lookinig at photos of faces were more likely to remember these faces later. The hormone had no effect on memory of photos of nonsocial stimuli such as houses, sculptures, or landscapes. Heinrichs and colleagues (2003) found that injections of oxytocin caused relaxation and a reduction of anxiety in human participants. In addition, Kosfeld and colleagues (2005) found that oxytocin increased trust. The investigators had participa nts play a "trust" game, in which they were given money, some or all of which they could give to another player (the trustee) to invest. If the trustee made money with his investment (all participants were male), he could share the winnings with the first player- or he could be selfish and keep everything for himself. Fifty minutes before the start of the game, the participants received a nasal spray containing oxytocin or a placebo. The oxytocin appeared to increase peoplt:~'s trust in other people: The participants who received the oxytocin gave 18 percent more money to the trusteies, and they were twice as likely to give them all of their money to invest. A second study found that oxytocin did not simply make the participants feel more

confidlent. The participants were no more likely to risk their money in an investment game that did not involve other people. As research in this area has progressed, it has become more apparent that the effects of oxytocin are not indiscriminately prosocial. For example, oxytocin administration increases trust, empathy, and altruism, but often

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only among group members or under specific conditions (van Anders, 2013; Van Ijzendoorn, 2012). In some cases, oxytocin has been associated with aggression, possibly as a means to protect in-group members and resources, but at the cost of out-group members (Beery, 2015; De Dreu, 2015). On the other hand, oxytocin administration reduced

outgroup rejedion when that behavior was promoted as a social norm (Marsh et al., 2017). Research with oxytocin has raised many important questions regarding the neural and neuroend.ocrine correlates of social and reproductive behavior. We expect many new avenues for this research in the future.

Module Review: Neural Control of Sexual Behavior Male Sexual Behavior LO 10.9

Identify the role of spinal and brain mechanisms in male sexual behavior.

Sexual reflexes such as sexual posturing, erection, and ejaculation are organized in the spinal cord. Neurons in the lumbar region of the rat spinal cord play a critical role in triggering an ejaculation. Brain mechanisms have excitatory and inhibitory control of the circuits responsible for erection and ejaculation. Stimulating the MPA produces copulatory behavior; destroying it permanently abolishes the behavior. Damaging the SON (part of the MPA) in laboratory animals impairs mating behavior. Ejaculation in men is accompanied by increased behavior in the brain's reinforcement mechanisms, several thalrunic nuclei, the lateral putrunen, and the cerebellum.

Female Sexual Behavior LO 10.10 Identify the role of brain mechanisms in

female sexual behavior. The most important forebrain region for female sexual behavior is the VMH. Destroying the VMH abolishes copulatory behavior in rodents, and stimulating it facilitates this behavior. Both estradiol and progesterone exert their facilitating effects on female rodent sexual behavior in this region, and studies have confirmed the existence of p rogesterone and estrogen receptors there. The priming effect of estradiol is caused by an increase in progesterone receptors in the VMH. The steroid sensitive neurons of the VMH send axons to the PAG of the

Sexual Orientation Sexual orientation encompasses a long-term pattern of emotional, romantic, and/ or sexual attractions to other individuals. Research indicates that sexual orientation is a continuum. Examples of sexual orientation can include gay or lesbian (having emotional, romantic, or sexual attractions to members of one's own gender), bisexual, polysexual or pansexual

midbrain. The:se neurons, through their connections with the medullary reticular formation, control the particular responses that: constitute female sexual behavior. Orgasm in women is accompanied by increased activi ty in regions similar to those activated during ejaculation in men and the periaqueductal gray matter.

Formation of Pair Bonds LO 10.11 Compare the roles of oxytocin and

vasopressin in pair bonding. Vasopressin and oxytocin, peptides that serve as hormones and as neurotransmitters in the brain, appear to facilitate pair bonding. The inser tion of the gene for vasopressin receptors in the basal forebrain of polygamous male voles induces monogamous behavior. Vasopressin plays a key role in males, and oxytocin plays a key role in females for pair bonding. In humans, oxytocin appears to be involved! in a variety of important social behaviors.

Thought Question Using information from this chapter (particularly the details in Figures 10.15 and 10.16), make two recommendations to an organization working on a breeding program for an endangered rodent species. Suggest interventions or strategies that could be used to increase reproductive behavior .in males and females. Imagine that experts working with the organization have access to any possible intervention (such as brain stimulation, hormone exposure, or pheromone exposure).

(having emotional, romantic, or sexual attractions to people with a variety of genders), heterosexual or straight (having emotional, romantic, or sexual attractions to members of another gender), or asexual (does not experience sexual attraction or has little interest in sexual behavior) (American Psychological Association, 2008, 2020). Evidence suggests that about 3.5 ]percent of the U.S. population identifies with a sexual orientation other than heterosexual (Gates, 2011).

Reproductive and Parental Behavior

What contributes to a person's sexual orientation? Researchers once believed that sexual orientation was determined by childhood experiences, especially through interactions between parent and child. Early research failed to find support for this idea (Bell et al., 1981). Since that time, neuroscience research has revealed new biological contributions to the development of sexual orientation, however the factors involved in a complex phenomenon like sexual orientation are myriad. This module will focus on what is currently understood about the biological factors involved in sexual orientation, but it is likely only a sampling of the many yet undiscovered interacting factors involved. Research in this area has identified development of specific brain structures, fraternal birth order, maternal immune sensitivity, and heritability as some of the factors that appear to be involved in sexual orientation. Much of the biological evidence supports a role for organizational hormone effects, and, as you will read in this module, most research suggests that biological factors related to sexual orientation are at play before birth (Bogaert & Skorska, 2011; Breedlove, 2017; Burri et al., 2011; Hines, 2011; Rahman, 2005).

organiizational effects of masculinization of sex organs. At puberty, increased testosterone levels prompt activational effects and the development of secondary sex characteristics. Until puberty, individuals with Scx-reductase deficiency syndrome are often raised as girls, but the majority have a1male gender identity at p uberty and are sexually attracted to women (Bramble et al., 2017; Sobel & ImperatoMcGinley, 2004). This complicated example illustrates the difficuilty in determining the roles of environmental influence, biology, and organizational and activational effects in gender identity and sexual orientation. Another biological contributor to sexual orientation may be a subtle difference in brain structure caused by differences in prenatal exposure to androgens. Prenatal exposure to sex hormones produces permanent, organizational effects (see the "Development of Sex Organs" section for review). The following sections describe evidence from research concerning congenital adrenal hyperplasia, androgen insensitivity, cloaca! exstrophy, heritability, and prenatal factors that sugge~;t prenatal sex hormone exposure permanently influences brain development and structure, resulting in later behavior related to sexual orientation.

Activational and Organizational Effects of Hormones

Role of Steroid Hormones

LO 10.12 Compare activational and organizational

LO 10.13 Describe examples that indicate a role

effects of hormones in sexual orientation. What role might sex hormones play in influencing sexual orientation? Could prenatal organizational effects or later activational effects of sex hormones contribute to sexual orientation? It appears that sexual orientation is not strongly related to variations in the levels of sex hormones during adulthood in the majority of individuals. Many studies have examined the levels of testosterone in gay and heterosexual men and found no differences. Similarly, most studies have found no difference in sex hormones between groups of women who are heterosexual and those who are not. A few studies suggest that some lesbian women have elevated levels of testosterone-but still lower than those found in men (Meyer-Bahlburg, 1984; Hines, 2011). Men who experience reduced testosterone in adulthood do not change their sexual orientation, and men and women who are treated with sex hormones for medical reasons do not change their sexual orientation, further suggesting that exposure to hormones in adulthood is not a factor in the

development of sexual orientation (Hines, 2011). In contrast, studies of individuals with a rare

Scx-reductase deficiency syndrome suggest that the activational effect of hormones (or at least androgens) may play a role in both gender identity and sexual orientation in some cases. In this disorder, individuals with an XY genotype and male sex organs are not exposed to the high levels of androgens prenatally and therefore do not experience

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of prenatal hormone exposure in sexual orientation. Several converging lines of evidence suggest that prenatal hormone exposure is involved in sexual orientation. Studies involving individuals with prenatal exposure to progesterone, elevated levels of androgens, and congenital insensitivity to androgens have yielded some clues to the role of steroid hormones in sexual orientation. PRENfATAL PROGESTERONE EXPOSURE Recent research has investigated the influence of prenatal progesterone exposure on sexual orientation. Reinisch and colleagues (2017) surveyed young adults who were prenatally exposed to synthetic progesterone. Compared to a matched, nonexposed control group, significantly more progesterone-exposed individuals reported a "nonheterosexuall self-labeled identity" and sexual behavior that involved an individual of the same sex. The researchers further reported that self-labeled nonheterosexual identity was associated with increased dosage and duration of prenatal progesterone exposure. The researchers suggest that epigenetic mechanisms involving prenatal hormone exposure may be involved in a complex development of sexual orientation. CON G ENITAL ADRENAL HYPERPLASIA Evidence suggests that prenatal hormone exposure can affect human social !behavior and sexual orientation, as well as anatomy. In a disorder known as congenital adrenal hyperplasia (CAH),

312 Chapter 10 the adrenal glands secrete increased amounts of androgens. The increased androgen secretion begins prenatally, and the syndrome causes prenatal masculinization. Boys (XY chromosomes) born with CAH experience masculinization. Girls (XX chromosomes) with CAH are born with an enlarged clitoris and partially fused labia. CAH suggests that the interaction between androgen exposure and chromosomes is important in sexual orientation, as you'll read in a moment (Bramble et al., 2017). Once diagnosed with CAH, people are typically given a synthetic hormone to suppress excessive androgen secretion. As a group, a larger percentage of women with CAH describe themselves as bisexual, gay, or lesbian, compared to the general population (Bramble et al., 2017; Cohen-Bendahan et al., 2005b). These studies provide insight into the biological factors that may be important in sexual orientation, and contribute to the growing list of relevant social and psychological factors involved Gordan-Young, 2012). Meyer-Bahlberg and colleagues (2008) studied women with a milder form of CAH called nonclassical CAH (NCAH). Girls born with NCAH have female genitalia at birth and do not show signs of increased androgen levels until late childhood or adolescence, when they receive hormones to suppress androgen secretion. Compared to the general population, women with NCAH, like those with CAH, are more likely to self-identify as lesbian or bisexual. Higher androgen exposure is more likely to be associated with identifying as lesbian. Evidence of increased androgen exposure in this population is suggested by features impacted by androgen exposure during development: More masculine patterns of otoacoustic emissions in the inner ear (McFadden & Pasanen, 1999), eyeblink patterns (Rahman et al., 2003) and length of long bones of the arms (Martin & Nguyen, 2004). Research investigating chromosomal disorders suggests a role for chromosomes not only in sexual development, but also in the development of gender identity (Bramble et al., 2017). For example, about 5 percent of genetic females with CAH identify as transgender (compared to about 0.3 percent of individuals in the general population; Bramble et al., 2017; Dessens et al., 2005; Gates, 2011). Studies of CAH (which exposes genetically female fetuses to higher levels of androgens) suggest an interaction between organizational hormone effects and chromosomal sex may play a role in gender identity. CLOACAL EXSTROPHY Studies of genetic males with cloaca/ exstrophy, who are born without a penis, further support the conclusion that prenatal exposure to androgens contributes to a male gender identity and a straight or heterosexual sexual orientation. Individuals with cloacal exstrophy have XY chromosomes and are exposed to androgens prenatally. These individuals fully develop testes but not a penis. In the past, many individuals born

with cloacal exstrophy were raised as girls; however, approximately 50 percent of individuals with cloaca! exstrophy have a male gender identity. Individuals with cloacal exstrophy are often sexually attracted to women (Gooren, 2006; Meyer-Bahlberg, 2005; Reiner, 2005).

ANDROGEN llNSENSITIVITY SYNDROME Studies of individuals with androgen insensitivity syndrome (described in the section on development of internal sex organs), provide a different example of prenatal hormone exposure and its relationship to sexual orientation. It was previously reported that individuals with this syndrome are often, though not always, attracted to male partners (Wisniewski et al., 2000). Recent research has called this conclusion into question, and emphasizes the importance of improved understanding of the interactions between prenatal androgen exposure, chromosomal sex, and sexual orientation (Brunner et al., 2016).

Sexual Orientation and the Brain LO 10.14 Describe research on sexually dimorphic brain

structures and sexual orientation. As you read earlier in this chapter, sexual dimorphism refers to differences between males and females, including differences in brains and behaviors. Anatomical and functional studies suggest dimorphic differences in the corpus callosum, hippocampus, amygdala, hypothalamus, prefrontal cortex, and throughout several neurotransmitter and neuroendocrine systems (Breedlove, 1994; Cahill, 2006; Choleris et al., 2018; Cosgrove et al., 2007; Goldstein et al., 2001; Ruigrok et al., 2014; Swaab et al., 1995).

Figure 10.1.9

Dimorphic Regions of the Brain

This figure illustrates some of the sexually dimorphic structures in the human brain. SDN POA = sexually dimorphic area of the preoptic area SCN = suprachiasmatic nucleus Source: Goldstein, J. M., et al. (2001). Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cerebral Cortex 11, 490-49;r.

Anterior commissure

SCN

Reproductive and Parental Behavior

Most investigators believe that the sexual dimorphism of the human brain is a result of differential exposure to androgens prenatally and during early postnatal life. Additional changes could occur at the time of puberty, when another surge in androgens occurs. Sexual dimorphism in the human brain could also be a result of differences in the social environments of men and women. Because we cannot manipulate hormone exposure in people like we can with laboratory animals, it might be a long time before enough evidence is gathered to support definite conclusions. In addition, some dimorphic features may be better conceptualized along a continuum, rather than as two distinct categories of sex or gender, and some features show overlap in both males and females. McCarthy and colleagues (2012) provide a summary and research recommendations for more inclusive study of sexual dimorphisms in neuroscience. In the future, the field may adopt a continuum-based or polymorphic perspective on sex and gender. For now, the results of most studies focus on dimorphisms. The following section summarizes what is currently known in this area as it relates to sexual orientation. The end of this section also includes the results of preliminary neuroscience research into brain structures associated with another topic: gender identity. Several studies have examined the brains of gay and heterosexual men and women, with an interest in identifying differences in dimorphic structures. So far, these studies have found differences in the size of three different subregions of the brain: the suprachiasmatic nucleus (SCN), a sexually dimorphic nucleus of the hypothalamus, and the anterior commissure (Bao & Swaab, 2011; Allen & Gorski, 1992; LeVay, 1991; Swaab & Hofman, 1990). (See Figure 10.19.) You are already familiar, from Chapter 9, with the SCN. The anterior commissure is a fiber bundle that interconnects parts of the left and right temporal lobes. However, from what we know about brain functions, there is no reason to expect that differences in the SCN or the corpus callosum would play a role in sexual orientation. Also, a follow-up study confirmed the existence of a sexually dimorphic nucleus in the hypothalamus but failed to find a relationship between its size and sexual orientation in men (Byne et al., 2001). Functional-imaging studies have found that the brains of gay men and women reacted differently to the odors of AND and EST, two chemicals that may serve as human pheromones. Savic and colleagues (2005) found that the response of brain regions of gay men to AND and EST was similar to that of the heterosexual women. Berglund and colleagues (2006) found that the response of brain regions of lesbian women to these substances was similar to those of heterosexual men. These studies suggest that a person's sexual orientation affects (or is affected by) their response pattern to these potential pheromones.

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Garcia-Falgueras and Swaab (2008) found another sexuallly dimorphic region of the human brain: the uncinate nucleus of the hypothalamus. They found that this nucleus, which is the human version of the medial preoptic nucleus (a nucleus within the POA) in rodents, is approximately twice as large in men as in women. (See Figure 10.20.) The size of this nucleus is the same in transg;ender and cisgender women. The investigators also provide evidence that the neurons in the uncinate nucleus send atxons to the bed nucleus of the stria terminalis (BNST), the size of which was previously shown to be related to gender identity. The authors suggest that these two structlLlres are part of a neural circuit that is involved in a person's gender identity. Additional research has begun to explore dimorphic brain structures related to gender identity. The size of a p.articular region of the forebrain, the central subdivision o:f BNST, is larger in men than in women (Zhou et al., 1995). In transgender women the size of this nucleus is consistent with cisgender women. The size of this nucleus was the same in men, regardless of their sexual orientation.

Figure 10.20 Anatomical Differences in the Brains of Male and Female Rodents The preoptic area of the brain is essential for sexual behaviors in male mice. An inset of the preoptic area is presented with male anatomical charact,eristics shown on the left side, and female characteristics on the right. TI1e sexually dimorphic nucleus (SND) and principal nucleus of the bed nucleus of the stria terminalis (pBNSl), highlighted in dark green and red respectively, are larger in male mice, while the anteroventral periventricular nucleus (AVPV), highlighted in yellow, is larger in females. Source: Evan Oto/Science Source

D

Male characteristics

Female characteristics

314 Chapter 10

Kruijver and colleagues (2000) replicated these results and found that the size of this region in transgender and cisgender men was the same. The size of the BNST appears to be related to gender identity, not sex assigned at birth or sexual orientation. Other lines of research have begun to employ fMRI, PET single-photon emission computed tomography (SPECT), and diffusion tensor imaging (DTI) techniques to better understand brain structure and function involved in gender identity (Guillamon et al., 2016; Smith et al., 2015). It is difficult to conclude that any of the brain regions mentioned in this section are directly involved in people's sexual orientation or gender identity. It is also possible that differences may lie elsewhere in the brain, in some regions as yet unexplored by researchers. However, the observation that differences in brain structure are related to variation in sexual orientation and gender identity suggests that biological factors, including which combination of chromosomes a person inherits and exposure to prenatal hormones, contribute to important aspects of self-identity.

Role of Prenatal Environment in Sexual Orientation LO 10.15 Summarize the relationsh ips b etween

prenatal en vironmental factors and sexual orientation. Some research has investigated additional factors of the prenatal environment that are related to sexual orientation. One clue arose based on the observation that gay men tend to have a unique pattern of siblings, deemed the fraternal birth order effect (for review see Blanchard, 2018). Blanchard (2001) and Bogaert (2006) found that gay men tend to have more older brothers, but not more older sisters or younger brothers or sisters. In contrast, the numbers of brothers or sisters (younger or older) of women of any sexual orientation did not differ, nor did the age of the mother or father or the interval between births. The presence of older brothers and sisters had no effect on women's sexual orientation. The data obtained by Blanchard suggest that the odds of a man identifying as gay increased by approximately 33 percent for each older brother. This pattern has been replicated across many, but not all, subsequent studies (Blanchard, 2018). What m ight explain this observation? One explanation suggests that when mothers are exposed to several male fetuses, their immune system may become sensitized to proteins that only males possess (such as Y-linked proteins). As a result, the response of the mother's immune system may affect the prenatal brain development of sexually dimorphic structures of later male fetuses. Most men who have several older brothers are not gay, so even if this hypothesis is correct, it appears that only some women become sensitized to a protein produced

by their male: fetuses. In addition, this relationship appears to hold true primarily among right-handed individuals (handedness is also determined prenatally) and has been demonstrated across diverse samples (Bogaert & Skorska, 2011). Antibodies to a Y-linked protein are increased amonig mothers of gay sons, and increased antibody production is associated with a greater number of sons, providing a possible mechanism and support for this hypothesis (Bogaert et al., 2017). Other researchers have critiqued this line of research on several grounds, including its failure to explain all instances of sexual orientation, suggesting instead that epigenetic mechanisms may be responsible (Gavrilets et al., 2018).

Heredity and Sexual Orientation LO 10.16 Summarize what is currently known about the

role of heredity in sexual orientation. Another factor that may play a role in sexual orientation is heredity. A study of nearly 500,000 individuals identified five candidate gene locations involved in hormone regulation and olfaction that were associated with same-sex sexual behavior. However, these gene locations together explained less than 25 percent of the variability in sexual behavior in the sample, meaning that the large majority of variability in human sexual behavior remains unexplained by specific genetic locations. From this result, the researchers concludedl that sexual behavior is influenced by the complex inter·actions of many other locations on the genome, which remain to be identified (Ganna et al., 2019). Prior to w1dertaking studies of specific locations on the genome, early support for the role of heredity in sexual orientation came from twin studies. Twin studies take advantage of the fad that identical twins have identical genes, whereas the g;enetic similarity between fraternal twins is, on the average, 50 percent. Bailey and Pillard (1991) found that the concordance rate for sexual orientation among twin brothers was 52 percent for identical twins and only 22 percent for fraternal twins-a difference of 30 percent. Other studies have shown differences of up to 60 percent (Gooren, 2006), suggesting that a genetic component plays a role in sexual orientation in men. Some studies (Hamer et al., 1993; Sanders et al., 2014) have reported correlations between a region of the X chromosome called Xq28 and sexual orientation in men, while others have found no relationship (Rice et al., 1999). Genetic factors also appear to affect female sexual orientation. Bailey and colleagues (1993) found that the concordance of fema le monozygotic twins for sexual orientation was 48 percent, while that of dizygotic twins was 16 percent. Another study; by Pattatucci and Hamer (1995), found an increased preval·ence of lesbian and bisexual sexual orientation in sisters, daughters, nieces, and female cousins (through a paternal uncle) of women with same-sex partners.

Reproductive and Parental Behavior

Table 10.4

315

Summary of Factors Possibly Contributing to Sexual Orientation

Genetics/Heredity

Twin studies suggest that heredity may play a role in sexual orientation in both men and women.

Honnone exposure

Organizational effects

Evidence from prenatally androgenized gir1s, and androge1n insensitivity suggests a role for prenatal androgen exposure in sexual orientation.

Activational effects

There is limited evidence in support of activational effects of hormones in sexual orientation. One example may come from the interaction between chromosomes and activational effects of hormones in gender identity and sexual orientation of individuals with 5o-reductase deficiency syndrome.

Environment

Prenatal environment

Boys with more older brothers have a higher likelihood of iidentifying as gay. Increased antibodies to a Y·linked protein have been found in mothers of gay sons, supporting the fraternal birth order effect.

Postnatal environment

There is little evidence to suggest that postnatal biological factors play large roles in sexual orientation.

For several decades, investigators have been puzzled by an apparent paradox. On average, gay men have approximately 80 percent fewer children than heterosexual men (Bell & Weinberg, 1978). This reduced fecundity should exert strong selective pressure against any genes involved in gay sexual orientation. Some investigators have suggested that gay men may have an important supportive role in their families, increasing the fecundity of their relatives, who share some of their genes (Wilson, 1975). However, more recent studies (Bobrow & Bailey, 2001; Rahman & Hull, 2005) have found that gay men do not provide more financial or emotional support to their siblings. A study by Camperio-Ciani and colleagues (2004) suggests a possible explanation. They found that the female maternal relatives (for example, maternal aunts and

grandmothers) of gay men had higher fecundity rates. No differences were found in the female paternal relatives. Because men are likely to share an X chromosome with f.emale maternal relatives but not with female paternal re latives, the investigators suggested that a gene or genes on the X chromosome that are involved in men's sexuall orientation also increase a female's fecundity. To summarize, evidence suggests that important biological factors-prenatal environments, hormonal exposurn, and heredity- may affect a p erson's sexual orientation (see also Table 10.4). We can hope that research on the~ biological origins of sexual orientation wiJI reduce prejudlice and misunderstanding and help people to better under:stand the variety of sexual orientations and gender identilties that exist.

Module Review: Sexual Orientation Activational and Organizational Effects of Hormones LO 10.12 Compare activational and organizational effects of hormones in sexual orientation. There is little support for a role of activational effects of hormones in sexual orientation. There is stronger evidence for a role of organizational effects of hormones in sexual orientation.

who aire born without a penis, support the conclusion that prenatal exposure to androgens promotes a male gender identity and heterosexual sexual orientation. If androgens cannot act (as they cannot in cases of androgen insensitivity syndrome), the person's anatomy and behavior are feminized. Recent research has suggested a role for prenatal progesterone exposure in sexual orientation.

Sexual Orientation and the Brain Role of Steroid Hormones LO 10.13 Describe examples that indicate a role of prenatal hormone exposure in sexual orientation. Studies of prenatally androgenized girls suggest that organizational effects of androgens influence the development of sexual orientation; androgenization appears to enhance the likelihood of a lesbian sexual orientation. Studies of genetic males with cloaca} exstrophy,

LO 101.14 Describe research on sexually dimorphic brain structures and sexual orientation. The sizes of some specific regions of the telencephalon and diencephalon are different in males and females, and the sh.ape of the corpus callosum may also be sexually dimorphic. Several postmortem studies have examined the brains. of gay and heterosexual men and women. So far, these :studies have found differences in the size of three differnnt subregions of the brain: the suprachiasmatic

316 Chapter 10

nucleus (SCN), a sexually dimorphic nucleus of the hypothalamus, and the anterior commissure.

Role of Prenatal Environment in Sexual Orientation

Heredity and Sexual Orientation LO 10.16 Summarize what is currently known about the: role of heredity in sexual orientation.

Twin studies suggest that heredity may play a role in sexual orientation in men and women.

LO 10.15 Summarize the relationships between prenatal environmental factors and sexual orientation.

Thought Question

Gay men tend to have more older brothers. When mothers are exposed to several male fetuses, their immune system may become sensitized to proteins that only males possess, which may influence the prenatal environment and subsequent sexual orientation of the child.

Whatever the relative roles played by biological and environmental factors may be, most investigators agree that a person's sexual orientation is not a matter of choice. What brain o:r endocrine-based evidence supports this assertion?

Parental Behavior In most mammalian species, reproductive behavior takes place at the time of conception, as well as after offspring are born. This module examines the role of hormones in the initiation and maintenance of parental behavior, and the role of the neural circuits that are responsible for their expression. Most of the research has involved rodents. Less is known about the neural and endocrine bases of parental behavior in primates. Although most research on the physiology of parental behavior has focused on maternal behavior, some researchers study paternal behavior shown by the males of some species. Parental behavior of human fathers is very important for the offspring of our species, but the physiological basis of this behavior is not yet well understood.

Nest-building provides one important example of maternal behavio1r. During gestation, female rats and mice build nests. The form this structure takes depends on the material available for ilts construction. In the laboratory the animals are usually given strips of paper or lengths of rope or twine. A good brood nest, as it is called, is shown in Figure 10.21. This nest is matde of hemp rope. A piece of the rope is shown below the nest . The mouse laboriously shredded the rope and then wove an enclosed nest, with a small hole for access to the interior. Prolactin and progesterone play important roles in rodent nest-building behavior (Vocci & Carlson, 1973).

Figure 10.2'. 1 A Mouse's Brood Nest Beside the nest is a length of the kind of rope the mouse used to construct it. Source: Carlson, Neil

Maternal Behavior of Rodents LO 10.17 Describe examples of rodent maternal behavior.

The final test of the fitness of an animal's genes is the number of offspring that survive to a reproductive age. Just as the process of natural selection favors reproductively competent animals, it favors those that care adequately for their young, if their young in fact require care. Rat and mouse pups certainly do; they cannot survive without a mother to attend to their needs. At birth, rats and mice resemble fetuses. The infants are blind (their eyes are still shut), and they can only wriggle helplessly. They are poikilothermous ("cold-blooded"); their brain is not yet developed enough to regulate body temperature. They even lack the ability to release their own urine and feces spontaneously and must be helped to do so by their mother. As we will see shortly, this phenomenon actually serves a useful function.

Reproductive and Parental Behavior

At the time of parturition (birth of offspring) the female begins to groom and lick the area around her vagina. As a pup begins to emerge, she assists the uterine contractions by pulling the pup out with her teeth. She then eats the placenta and umbilical cord and cleans off the fetal membranes-a quite delicate operation. (A newborn pup looks as though it is sealed in very thin plastic wrap.) After all the pups have been born and cleaned up, the mother will probably nurse them. Milk is usually present in the mammary glands very near the time of birth. Periodically, the mother licks the pups' anogenital region, stimulating reflexive urination and defecation. Friedman and Bruno (1976) have shown the utility of this mechanism. They noted that a lactating female rat produces approximately 48 grams (g) of milk on the tenth day of lactation. This milk contains approximately 35 milliliters (ml) of water. The experimenters injected some of the pups with tritiated (radioactive) water and later found radioactivity in the mother and in the littermates. They calculated that a lactating rat normally consumes 21 ml of water in the urine of her young, thus recycling approximately twothirds of the water she gives to the pups in the form of milk. The water, traded back and forth between mother and young, serves as a vehicle for the nutrients-fats, protein, and sugar-contained in milk. Because each day the milk production of a lactating rat is approximately 14 percent of her body weight (for a human weighing 120 pounds, that would be around 2 gallons), the recycling is extremely useful, especially when the availability of water is a problem. Besides cleaning, nursing, and helping her offspring urinate and defecate, a female rodent will retrieve pups if they leave or are removed from the nest. The mother will even construct another nest in a new location and move her litter there, should the conditions at the old site become unfavorable (for example, when an inconsiderate experimenter puts a heat lamp over it). The way a female rodent picks up her pup is quite consistent: She gingerly grasps the animal, managing not to injure it with her very sharp teeth. (We can personally attest to the sharpness of a mouse's teeth and the strength of its jaw muscles.) She then carries the pup with a characteristic prancing walk, her head held high. (See Figure 10.22.) The pup is brought back to the nest and is left there. The female then leaves the nest again to search for another pup. She continues to retrieve pups until she finds no more; she does not count her pups and then stop retrieving when she has them all. A mouse or rat will usually accept all the pups she is offered, if they are young enough. One of the authors once observed two lactating female mice with nests in corners of the same cage, diagonally opposite each other. Disturbing their nests triggered a long bout of retrieving, during which each mother stole youngsters from the other's nest. The mothers kept up their exchange for a long time, passing each other in the middle of the cage.

Figure 10.22

317

A Female Mouse Carrying a Pup

Source: Carlson, Neil

Under normal conditions, one of the stimuli that induce a female rat to begin taking care of pups is the act of parturition. Female rodents normally begin taking care of their pups as soon as they are born. Some of this effect is caused by prenatal hormones, but the passage of the pups through the bir·th canal also stimulates maternal behavior: Artificially distending the birth canal in nonpregnant females stimulates maternal behavior, whereas cutting the sensory nerves that innervate the birth canal slows the appearance of maternal belhavior (Graber & Kristal, 1977; Yeo & Keveme, 1986).

Hormonal Control of Maternal Behavior LO 10.18 Explain the role of hormones in maternal behavior. As we saw earlier in this chapter, most sexually dimorphic behaviors are controlled by the organizational and activational effects of sex hormones. Maternal behavior is somewhat different in this respect. First, there is no evidence that organizational effects of hormones play a role in parental behavior. Under the correct conditions, males will take care of infants. Second, although maternal behavior is affocted by hormones, it is not controlled by them. Most virgin female rats will begin to retrieve and care for young pups after having infants placed with them for several days (Wiesner & Sheard, 1933). And once the rats are sensitized, they will thereafter take care of pups as soon as they encounter them; sensitization lasts for a lifetime. Although hormones are not essential for the activation of maternal behavior, many aspects of maternal behavior

318

Chapter 10

Figure 10.23

Hormones in Pregnant Rats

The graph shows blood levels of progesterone, estradiol, :and prolactin in pregnant rats. Source: From Rosenblatt, J. S., Siegel, H. I., and Mayer, A. D. (19T9). Progress in the study of maternal behavior in the rat: Hormonal, nonhormonal, sensory, and developmental aspects. Advances in the Study of Behavior, 10, 2::>5-310. Reprinted with permission.

2

4

6

8

10 12 14 16 18 20 22 Days

are facilitated by hormones. Nest-building behavior is facilitated by progesterone, the principal hormone of pregnancy (Lisk et al., 1969). After parturition, mothers continue to maintain their nests, and they construct new nests if necessary, even though their blood level of progesterone is very low then. Although pregnant female rats will not immediately care for foster pups that are given to them during pregnancy, they will do so as soon as their own pups are born. The hormones that influence a female rodent's responsiveness to her offspring are the ones that are present shortly before parturition. Figure 10.23 shows the levels of the three hormones that have been implicated in maternal behavior: progesterone, estradiol, and prolactin. Note that just before parturition the level of estradiol begins rising, then the level of progesterone falls dramatically, followed by a sharp increase in prolactin, the hormone produced by the anterior pituitary gland that is responsible for milk production. If ovariectomized virgin female rats are given progesterone, estradiol, and prolactin in a pattern that duplicates this sequence, the time it takes to sensitize their maternal behavior is drastically reduced (Bridges et al., 1985). As we saw in the previous module, pair bonding involves vasopressin and oxytocin. In at least some species, oxytocin also appears to be involved in formation of a bond between mother and offspring. In rats the administration of oxytocin facilitates the establishment of maternal behavior (lnsel, 1997). Van Leengoed and colleagues (1987) injected an oxytocin antagonist into the cerebral

Table 10.5

Hormonal Control of Maternal Behavior

Progesterone

Facilitates nest building

Decreased proge1sterone + increased estradiol + prolactin (sequence that e (.)

=

C «I 0

cno

120 80 40 0

No care

0 - 1 hour

1 - 3 hours

3+ hours

The study was conducted in the Philippines, where fathers are frequently involved in paternal care. Fathers with at least l hour of paternal care per day had lower levels of testosterone compared to fathers that reported less paternal care. (See Figure 10.25.) The authors of the study suggest that changes in testosterone are part of an evolved strategy for reproductive success (Gettler et al., 2011).

Module Review: Parental Behavior Maternal Behavior of Rodents

Neural Control of Maternal Behavior

LO 10.17 Describe examples of rodent maternal behavior.

LO 101.19 Identify brain regions and neural pathways involved in maternal behavior.

Rodent maternal behavior includes nest building, delivering pups, cleaning pups, keeping them warm, nursing them, and retrieving them if they are moved out of the nest. The mothers must even induce their pups' urination and defecation, and the mother's ingestion of the urine recycles water, which is often a scarce commodity.

Injections of progesterone, estradiol, and prolactin that duplicate the sequence that occurs during pregnancy facilitate maternal behavior. The hormones appear to act in the medial preoptic area (MPA). Connections between the MPA and the medial amygdala are responsible for the suppression of the aversive effects of the~ odor of pups, and a different circuit starting with the MPA is involved in establishing the reinforcing effect of pups and enhancing motivation to care for them: MPA---+ VTA---+ NAC ---+ ventral pallid um. An flv1RI study with rats showed activation of brain mechanisms of reinforcement when the mothers were presemted with their pups. Women who look at pictures of their infants show increased activity in similar brain regions.

Hormonal Control of Maternal Behavior LO 10.18 Explain the role of hormones in maternal behavior.

Nest-building behavior is facilitated by progesterone, the principal hormone of pregnancy. Injections of progesterone, estradiol, and prolactin that duplicate the sequence that occurs during pregnancy facilitate maternal behavior. Oxytocin facilitates the onset of maternal behavior.

322 Chapter 10

Neural Control of Paternal Behavior LO 10.20 Identify brain regions and neural pathways involved in paternal behavior.

Paternal behavior is relatively rare in mammalian species, but research indicates that sexual dimorphism of the MPA is less pronounced in male voles of monogamous, but not promiscuous, species. Lesions of the MPA abolish paternal behavior of male rats. Some aspects of parental

care may be related to blood levels of prolactin, oxytocin, and testosterone in human fathers.

Thought Question Adults in a variety of species often care for young that they are not biologkally related to. If you could research the biological mechanisms of these care-giving behaviors, what circuits or pathways would you investigate and why?

Chapter Review Questions 1. Describe mammalian sexual development, and

2. 3. 4.

5.

explain the factors that control it. Describe the hormonal control of the female reproductive cycle and of male and female sexual behavior. Describe the role of pheromones in reproductive and sexual behavior. Discuss the activational effects of gonadal hormones on the sexual behavior of women and men. Discuss the neural control of male and female sexual behavior.

6. Discuss the neural control of the formation of pair bonds. 7. Discuss the physiological variables that affect sexual orientation and gender identity in men and women. 8. Describe t:he maternal behavior of rodents, including how it is E~licited and maintained 9. Explain the hormonal and neural mechanisms that control maternal behavior. 10. Explain the neural control of paternal behavior.

Chapter 11

Emotion

Example of pyramidal neurons found in the hippocampus. The hippocampus is important in learning and consolidating memories.

Chapter Outline Fear

Components of Emotional Response Research with Laboratory Animals Research with Humans Aggression

Research with Laboratory Animals Research with Humans Hormonal Control of Aggressive Behavior Impulse Control

Role of the vmPFC Brain Development and Impulse Control

Serotonin and Impulse Control Moral Decision Making Communication of Emotions Facial Expression of Emotions: Innate Responses

Neural Basis of the Communication of Emotions: Recognition Neural Basis of the Communication of Emotions: Expression Feeliing Emotions

The James-Lange Theory Feedback from Emotional Expressions

323

324 Chapter 11

B

Learning Objectives

LO 11.1

Describe the three components of an emotional response.

LO 11.9

Explain the role of serotonin in impulse control regulation.

LO 11.2

Outline evidence for the roles of the amygdala and ventromedial prefrontal cortex in animal models of emotion.

LO 11.10

Describe the brain regions involved in emotional aspects of moral decision making involving impulse control.

LO 11.3

Describe the roles of the amygdala and ventromedial prefrontal cortex in human emotion.

LO 11.11

Describe evidence in support of emotional expressions as innate responses.

LO 11.4

Distinguish the roles of serotonin and neural circuitry in animal models of aggression and predation.

LO 11.12

Summarize the neural basis of emotional recognition, including laterality, diirection of gaze, imitation, and disgust.

LO 11.5

Evaluate the roles of heredity and serotonin in human aggression.

LO 11.13

LO 11.6

Critique the role of hormones in aggression.

Summarize the neural basis of emotional expression, including laterality, laughter, and humor.

LO 11. 7

Describe the role of the ventromedial prefrontal cortex in impulse control.

LO 11.14

Summarize the evidence for and against the James-Lange theory of emotion.

LO 11.8

Provide evidence for a developmental factor in impulse control.

LO 11.15

Critique evidence for the facial fe·edback hypothesis.

Samantha has a rare neurological condition, Urbach-Wiethe disease, which progressively damages neural tissue. UrbachWiethe disease affects about 100 people in the world (van Honk et al., 2016). The disease has affected Samantha's temporal lobes, causing bilateral amygdala destruction. Samantha demonstrates typical measures of attention , cognition, memory, visual ability, language, and executive function such as planning and decision making. She is a single mother of three boys, and has been described by interviewers as "pleasant and friendly, and reflective and thoughtful" (Tranel et al., 2006, p. 224). She exhibits empathy for others, and has experienced considerable adversity in her life, including difficult childhood experiences, the loss of a parent at a young age, and limited financial and social resources.

Samantha's case highlights the role of one brain region

in emotion. From this example, we learn that damage to

The effe:cts of her amygdala damage are not immediately apparent. Samantha has a reduced sense of danger and distrust in others. She both experiences and exhibits a lack of fear and anger in most contexts, and cannot recognize these emotions in others. For example, she did not report experiencing fear when watching movie clips from scary films such as The Shining and The Silence of the Lambs. Other people with amygdala damage due to Urbach-Wiethe disease have described a variety of similarly reduced fear sensitivities (Phelps et al., 1998; Markowitsch et al., 1994); however, at least some individuals demonstrate a very fast initial response to fear-inducing images. Some researchers have speculated t11at other brain regions quickly react to fear-inducing stimuli, while the amygdala then directs and allocates resources to coordinate an emotional response (Pishnamaz.i et al., 2016).

emotion to refer to just the feelings, but not the other components of an emotional

situation. Most of us use the word

the amygdala impairs fear. Fear is an example of an emotion that consists of a feeling (being afraid), physiologi cal

response. Even though they are sometimes easy to over-

changes (for example, increased heart rate), and behaviors

emotion are important for survival. For example, if you

(fighting, freezing, or fleeing). Researchers consider emo-

encounter a hungry predator, feeling afraid may not give

tions to have multiple components that extend beyond just

you a sur viva1l advantage, but your increased heart rate,

the feeling of the emotion to include changes throughout

blood flow to your muscles (physiological changes), and

the body that help prepare us to respond to an emotional

fleeing (behavior) m i ght!

look, physiological changes and behaviors associated with

Emotion 325

Much of the neuroscience research on emotion has focused on the emotions of fear, aggression, and impulse control. The first two modules in this chapter consider the patterns of behavioral and physiological responses that constitute the emotions of fear and aggression. The third section describes the role of emotions in impulse control, moral judgments and social behavior. The fourth section describes the communication of emotions-their expression and recognition. The final section examines the nature of the feelings that accompany emotions. Each of these emotions and emotional behaviors has important implications for our survival.1

Fear Fear is an adaptive emotional response that is coordinated in the brain by the nuclei of the amygdala. An extensive body of research exists investigating the neurological basis for fear in laboratory animals and human volunteers.

Components of Emotional Response LO 11.1

Describe the three components of an em otional response.

An emotional response consists of three types of components: behavioral, autonomic, and hormonal. The behavioral component consists of muscular movements that are appropriate to the situation that elicits them. For example, a dog defending its territory against an intruder first adopts an aggressive posture, growls, and shows its teeth. If the intruder does not leave, the defender runs toward it and attacks. Autonomic responses facilitate the behaviors and provide quick mobilization of energy for vigorous movement. In this example the activity of the sympathetic branch increases while that of the parasympathetic branch decreases. As a consequence, the dog's heart rate increases, and changes in the size of blood vessels shunt the circulation of blood away from the digestive organs toward the muscles. Hormonal responses reinforce the autonomic responses. The hormones secreted by the adrenal medullaepinephrine and norepinephrine-further increase blood flow to the muscles and cause nutrients stored in the musdes to be converted into glucose. In addition, the adrenal cortex secretes steroid hormones, which also help to make glucose available to the muscles. (See Figure 11.1.) 1

As you will see, negative emotions receive much more attention from researchers than positive ones do. Most of the research on the physiology of emotions has been limited to fear and anger-emotions associated with situations in which we may defend ourselves or our loved ones. The physiology of behaviors associated with positive emotions-such as those associated with love, caring for one's offspring, or enjoying delicious food- is described in other chapters.

Figure 11.1 ~havioral

Co ponents

Components of an Emotional Response

Autonomic Components

Hormone Components

Emotional Response

The following modules discuss the control of emotional behav.iors and the autonomic and hormonal responses that accompany them. These components are controlled by separate neural systems. The integration of the components of fear appears to be controlled by the amygdala.

Research with Laboratory Animals LO 11.2

Outline evidence for the roles of the amygdala and ventromedial prefrontal cortex in animal m odels of emotion.

The amygdala plays an important role in responding to emotional situations that have biological significance, such a.s those that warn of pain or other unpleasant consequeneies or signify the presence of food, water, salt, potential mates or rivals, or infants in need of care. For example, neurons in various nuclei of the amygdala become active when emotionally relevant stimuli are presented (Jacobs & McGinty, 1972; Leonard et al., 1985; O'Keefe & Bouma, 1969; :Rolls, 1982). This module describes research on the role of the amygdala in organizing emotional responses produced by aversive stimuli. The amygdala (or, more precisely, the amygdaloid complex) is located within the temporal lobes. It consists of severail groups of nuclei, each with different inputs and outputs-and with different functions (Amaral et al., 1992; Pitkanen et al., 1997; Stefanacci & Amaral, 2000). The amygdala has been subdivided into approximately 12 regions, each containing several subregions. However, we will focus on just three major regions: the lateral nucleus, the basal nucleus, and the central nucleus. The lateral nucleus (LA) receives information from all regions of the neocortex, including the ventromedial prefrontal cortex, the thalamus, and the hippocampal formation. The lateral nucleus sends information to the basal nucleu s (B) and to other parts of the brain, including the ventral striatum (a brain region involved in the effects of reinforciin g stimuli on learning) and the dorsomedial nucleus of the thalamus, whose projection region is the prefrontal cortex. The LA and B nuclei send information to the ventromeodial prefrontal cortex and the central n ucleus (CE),

326 Chapter 11 which projects to regions of the hypothalamus, midbrain, pons, and medulla that are responsible for the expression of the various components of emotional responses. As we will see, activation of the central nucleus elicits a variety of emotional responses: behavioral, autonomic, and hormonal. (See Figure 11.2.) The central nucleus of the amygdala is the most important part of the brain for emotional responses to aversive stimuli. When threatening stimuli are perceived, neurons in the central nucleus become activated (Pascoe & Kapp, 1985; Campeau et al., 1991). Damage to the central nucleus (or to the nuclei that provide it with sensory information) reduces or abolishes a wide range of emotional behaviors and physiological responses. After the central nucleus has been destroyed, animals no longer show signs of fear when confronted with stimuli that have been paired with aversive events. They also act tamer when handled by humans, their blood levels of stress hormones are lower, and they are less likely to develop ulcers or other forms of stress-induced illnesses (Coover et al., 1992; Davis, 1992; LeDoux, 1992). Monkeys typically show signs of fear when they see a snake, but those w ith amygdala lesions do not (Amaral, 2003). In contrast, when the central amygdala is stimulated, animals show physiological and behavioral signs of fear and agitation (Davis, 1992), people report feeling afraid (Gloor et al., 1982; Halgren et al., 1978; White, 1940), and

Figure 11.2

long-term stimulation of the central nucleus produces stress-induced illnesses such as gastric ulcers (Henke, 1982). These observations suggest that the autonomic and endocrine responses controlled by the central nucleus are among those responsible for the harmful effects of longterm stress (s1ee Chapter 18). Figure 11.3 summarizes the regions receiving information from the central amygdala and the respoinses they control. EMOTION A IL CON DITI ON IN G Some stimuli automatically activate the central nucleus of the amygdala and

Figure 11.3: The Outputs of the Central Nucleus of the Amygdala Shown here are :some important brain regions that receive input from the central nucleus of the amygdala and the emotional responses controlled by these regions. Adapted from Davis, M. (1992) The role of the amygdala in fear-potentiated startle: lmplicatiorn> for animal models of anxiety. Trends in Pharmacological Sciences, 13, 35-41.

Behavioral and Physiological Responses

Sympathetic activation: - - - increased heart rate and blood pressure, paleness Parasympathetic activation: .___.,. ulcers, urination, defecation

·: ---., Increased respiration

Amygdala Projections

This figure shows a much-simplified diagram of the major divisions and connections of the amygdala that play a role in emotions.

Behavioral arousal - - - . (dopamine) - - - . Increased vigilance (norepinephrine) Cortical activation - - - . (acetylcholine) ' - - . Augmented startle response

All regions of cerebral cortex thalamus hippocampal formation Ventromedial prefrontal cortex

J

Ventral striatum Dorsomedial nucleus of thalamus (projects>----_ fl to prefrontal cortex)~-,/

Hypothalam"' midbmioA.11 1- Latoml pons medulla nucleus nucleus nucleus

Behavioral arrest - - - (freezing) - - - . Facial expressions of fear ACTH, glucocorticoid - - - . secretion Cortical - - - . activation

Emotion

produce fear reactions-for example, loud unexpected noises, the approach of large animals, heights, or (for some species) specific sounds or odors. Even more important, however, is the ability to learn that a particular stimulus or situation is dangerous or threatening. Once the learning has taken place, that stimulus or situation will evoke fear: heart rate and blood pressure will increase, the muscles will become more tense, the adrenal glands will secrete epinephrine, and the animal will proceed cautiously, alert and ready to respond. The most basic form of emotional learning is a conditioned emotional response, which is produced by a neutral stimulus that has been paired with an emotion-producing stimulus. The word conditioned refers to the process of classical conditioning, which is described in more detail in Chapter 13. Classical conditioning occurs when a neutral stimulus is regularly followed by a stimulus that automatically evokes a response. For example, if a dog regularly hears a bell ring just before it receives some food that makes it salivate, it will begin salivating as soon as it hears the sound of the bell. Several laboratories have investigated the role of the amygdala in the development of classically conditioned emotional responses. For example, these responses can be produced in rats by presenting a stimulus such as a novel floor texture (represented by the color blue in Figure 11.4), followed by a brief electrical shock delivered to the feet through the floor on which the animals are standing. By itself the shock produces an unconditioned emotional response: The animal jumps, its heart rate and blood pressure increase, its breathing becomes more rapid, and its adrenal glands secrete catecholamines and steroid stress hormones. After several pairings of the new texture and the shock, classical conditioning is normally established. The next day, if the conditioned floor texture is presented alone-not followed by a shock-physiological monitoring will show the same

Figure 11.4

327

physiological responses the animals produced when they were shocked during training. In addition, they will show a species-typical defensive response called freezing. In other words, the animals act as if they were expecting to receive a shock. The texture becomes a conditioned stimulus (CS) that elicits freezing: a conditioned response (CR) . i(See Figure 11.4.) The physical changes responsible for a conditioned emotional response take place in the lateral nucleus of the arnygdala (Pare et al., 2004). Neurons in the lateral nucleus communicate with neurons in the central nucleus, which in turn communicate with regions in the hypothalamus, midbrain, pons, and medulla that are responsible for the behavioral, autonomic, and hormonal components of a conditioned emotional response. More recent studies indicate that the neural circuitry responsible for the process of classical conditioning is actually more complex than that (Ciocchi et al., 2010; Duvarci et al., 2011; Haubensak et al., 2010; Karalis et al., 2016; Tovote et al., 2015), but the details of this process can be found in Chapter 13, which discusses the physiology of learning and memory. EXTINCTION The neural mechanisms responsible for classically conditioned emotional responses to fear-related stimuli evolved because they play a role in an animal's survival and increase the likelihood that art animal can avoid dangerous situations. Animals also have a mechamism that can help them learn a different response to a stimulus. For example, if the CS (tone or floor texture) is presented repeatedly by itself, the previously established CR (emotional response) eventually disappears-it becomes extinguished. After all, the value of a conditioned emoti onal response is that it prepares an animal to confront (or, better yet, avoid) an aversive stimulus. If the CS occurs repeatedly but the aversive stimulus does not follow, then it is better for the emotional response-which

An Example of a Conditioned Emotional Response

In this example, a rat experiences a shock in an enclosure with a novel floor texture (shown in blue) (CS). The shock produces a fear response that induces freezing behavior. After pairing the shock with the blue floor, the animal displays freezing behavior in all enclosures with blue floors (CR). The animal displays no fear-related behavior in an unconditioned environment (enclosure with a purple floor).

Pairing shock with blue floor

Conditioned response (fmezing)

No conditioned response (exploration)

328

Chapter 11

Figure 11.5 Extinction In this example, rats experience fear conditioning, pairing a novel floor (represented by the color blue) with a shock. The rats are divided into two groups and experience extinction (exposures to novel floors with no shock) in new enclosure:s with either purple or green floors, as demonstrated by standing up and engaging in exploratory behavior. When the groups of animals are tested after extinction, the animals demonstrate extinction in the same enclosure where they learned not to respond to the floor (extinction). Extinction IHarning is context dependent. In this example, when extinction occurs in one environment, or context (green floor), it does not generalize to a new environment (purple floor) where the rat will experience fear and engage in freezing behavior.

Conditioning

Retrieval test

Extinction

Extinction context

Different context

itself is disruptive and unpleasant-to disappear. And that is exactly what happens. Extinction is not the same as forgetting. Instead, the animal learns that the CS is no longer followed by an aversive stimulus, and, as a result of this learning, the expression of the CR is inhibited. The memory for the association between the CS and the aversive stimulus is not erased. (See Figure 11.5.) Conditioned response inhibition is supplied by the ventromedial prefrontal cortex (vmPFC) (Amano et al., 2010; Sotres-Bayon & Quirk, 2010). Lesioning the vmPFC impairs extinction, and extinction training activates neurons there. Besides playing an essential role in extinction of conditioned emotional responses, the vmPFC can modulate the expression of fear in different circumstances. Depending on the situation, one subregion of the prefrontal cortex can become active and suppress a conditioned fear response, and another subregion can become active and enhance the response. The vmPFC is located just where its name suggests, at the bottom front of the cerebral hemispheres. (See Figure 11.6.) The vmPFC receives direct inputs from the dorsomedial thalamus, temporal cortex, ventral tegmental area, olfactory system, and amygdala. Its

outputs go to several brain regions, including the cingulate cortex, hippocampal formation, temporal cortex, lateral hypothalamus, and amygdala. Finally, it communicates with other regions of the prefrontal cortex. Its inputs provide it wi1th information about what is happening in the environment and what plans are being made by the

Figure 11.6 The Ventromedial Prefrontal Cortex

Ventromeidial prefrontal cortex

Emotion

Table 11.1

Brain Regions Involved in Fear Response

Central Nucleus of the Amygdala

Lateral Nucleus of the Amygdala

Activation produces fear-related behaviors; lesioning prevents production of fear-related behaviors

Involved in producing conditioned emotional response

Ventromedial Prefrontal Cortex (vmPFC)

Involved in extinction of conditioned emotional response

rest of the frontal lobes, and its outputs permit it to affect a variety of behaviors and physiological responses, including emotional responses organized by the amygdala. (See Table 11.1.)

Research with Humans LO 11.3

Describe the roles of the amygdala and ventromedial p refrontal cortex in human emotion.

We humans also acquire conditioned emotional responses. Let's use an example to illustrate this. Suppose you are studying with a friend and decide to have a snack. You put some food in the microwave to heat it up. The microwave makes an unusual noise and you open it to check on your food. Opening the door gives you a painful electrical shock. Your first response would be a defensive reflex: You would let go of the door, which would end the shock. This response is specific because it is aimed at terminating the painful stimulus . In addition, the painful stimulus would elicit nonspecific responses controlled by your autonomic nervous system: For example, your eyes would dilate, your heart rate and blood pressure would increase, and you would breathe faster. The painful stimulus would also trigger the secretion of some stress-related hormones, another nonspecific response. Suppose that a whj]e later you visit your friend again and make popcorn in the microwave. Your friend tells you that the microwave is perfectly safe. It has been fixed. Just seeing the microwave and thinking of using it again makes you a little nervous, but you accept your friend's assurance, open the door, and place the popcorn inside. Just then, it makes the same unusual noise that it did when it shocked you. What would your response be? Almost certainly, you would let go of the door again, even if it did not give you a shock. Your pupils would dilate, your heart rate and blood pressure would increase, and your endocrine glands would secrete some stress-related hormones. The unusual sound would trigger a conditioned emotional response. EMOTIONAL CONDITIONING The amygdala is involved in emotional responses in humans too. One

329

early study observed the reactions of people who were b eing evaluated for s urgical removal of parts of the brain to treat severe seizure disorders. This study found that stimulation of parts of the brain (for example, the h ypotha lamus) produced autonomic responses that a1re often associated w i th fear and anxiety but only when the amygdala was stimulated did people also r eport that they actually felt afraid (Gloor e t al., 1982; Halgren et al., 1978; White, 1940). Inman and colleagUoes (2018) studied the response of patients undergoing intracranial EEG monitoring for seizures as their amygdalae were s timulated with microe lec trodes . The researchers recorded autonomic components of a fear r•esponse and asked patients to report their emotional respon ses. Mos t of the patients experienced the autonomic response without a subjective emotional response, w h ile other patients experienced both an auton1omic and emotional respon se to the s timulation. These resea rchers concluded that s timulating the amygdala may produce changes in autonomic components without necessarily producing a fearful emotional response. Many studies have shown that lesions of the amygdala decrease people's emotional responses. For example, Bechaira and colleagues (1995) and LaBar and colleagues (1995) found that people with amygdala lesions have impaired! acquisition of a conditioned emotional response, just as rats do. Most human fears are probably acquired socially, not through firsthand experience with painful stimuli (Olsson et al., 2007). For example, a child does not have to be .attacked by a dog to develop a fear of dogs: They can develop this fear by watching another person being attacked or (more often) by seeing another person display s igns of fear when encountering a dog. People can also acquire a conditioned fear response through instruction. For example, suppose that someone is told (and believes) that if a warning light goes on, they should leave the room immediately because the light is connected to a sensor that detects dangerous levels of carbon monoxide gas. If the light does go on, the person will leave the room and is also likely to experience a fear response while doing so. EXTINCTION We saw that the vmPFC plays a critical role in extinction of a conditioned emotional response in animal models. The same is true for humans. Phelps and colleagues (2004) d irectly established a conditioned emotional response in volunteers by pairing the appearance of a square visual stimulus with electric shocks to the wrist and then extinguished the response by presenting the squares alone, without any shocks. Increased activity of the m1ed ial prefrontal cortex correlated with extinction of the conditioned response.

330 Chapter 11 Damage to the amygdala interferes with the effects of emotions on memory. Normally, when people encounter events that produce a strong emotional response, they are more likely to remember these events. Cahill and colleagues (1995) studied a patient with bilateral degeneration of the amygdala similar to Samantha's at the beginning of this chapter. The researchers narrated a story about a young boy walking with his mother on his way to visit his father at work. To accompany the story, they showed a series of slides. During one part of the story, the boy was injured in a traffic accident, and gruesome slides illustrated his injuries. When this slide show is presented to healthy volunteers, they remember more details from the emotion-laden part of the story. However, a patient with amygdala damage showed no such increase in memory. In another study, researchers questioned patients with Alzheimer's disease who had witnessed the devastating earthquake that struck Kobe, Japan, in EMOTIONAL MEMORY

1995. They found that memory of this frightening event was inversely correlated with amygdala damage: The more a patient's amygdala was degenerated, the less likely it was that the patient remembered the earthquake (Mori et al., 1'999). As we saw in Chapter 7, Patient I. R., a woman who had sustained damage to the auditory association cortex, was unable to perceive or produce melodic or rhythmic aspects of music (Peretz et al., 2001). She could not tell the d i fference between consonant (pleasant) and dissonant (wlpleasant) music. However, she was still able to recognize the mood conveyed by music. Gosselin and colleagues (2005) found that patients with damage to the amygdala showed the opposite symptoms: They had no trouble w:ith musical perception but were unable to recognize scairy music. They could still recognize happy and sad music. These results suggest that amygdala lesions impair recognition of a musical style that is normally associated with fear.

Module Review: Fear Components of Emotional Response LO 11.1

Describe the three components of an emotional response.

responses results in classically conditioned emotional responses. Learning these responses takes place primarily in the amygdala. Extinction of conditioned emotional

responses involves inhibitory control of amygdala activ-

The behavioral component consists of muscular movements that are appropriate to the situation that elicits them. Autonomic responses facilitate the behaviors and provide quick mobilization of energy for vigorous movement. Hormonal responses reinforce the autonomic responses.

ity by the vmP FC.

Research with Laboratory Animals

Functional-imaging and lesion studies with humans indicate that th•e amygdala is involved in emotional conditioning and emotional memory in our species, too. However, many of our conditioned emotional responses are acquired by observing the responses of other people or even through verbal instruction. The vmPFC plays an important rol1e in extinction of a conditioned emotional response.

LO 11.2

Outline evidence for the roles of the amygdala and ventromedial prefrontal cortex in animal models of emotion.

The amygdala organizes behavioral, autonomic, and hormonal responses to a variety of situations, including those that produce fear, anger, or disgust. It receives inputs from the olfactory system, the association cortex of the temporal lobe, the frontal cortex, and the rest of the limbic system. Its outputs go to the frontal cortex, hypothalamus, hippocampal formation, and brain stem nuclei that control autonomic functions and some

Research with Humans LO 11.3

Describe the roles of the amygdala and ventromedial prefrontal cortex in human emotion.

Thought Question Phobias can be seen as dramatic examples of conditioned emotional responses. These responses can even

species-typical behaviors. Electrical recordings of single

be contagious. We can acquire them without direct

neurons in the amygdala indicate that some of them respond when the animal perceives particular stimuli with emotional significance. Stimulating the amygdala leads to emotional responses, and destroying it disrupts them. Pairing neutral stimuli with those that elicit emotional

experience with an aversive stimulus. For example, a child who see~; a parent show signs of fear in the presence of a dog may also develop a fear reaction to the dog. Do you think that some biases or prejudices might be learned in this way, too?

Emotion

Aggression Almost all species of animals engage in aggressive behaviors, which involve threatening gestures or actual attacks directed toward other animals. Aggressive behaviors are species-typical, which means that the patterns of movements (for example, posturing, biting, striking, or hissing) are organized by neural circuits whose development is largely programmed by an animal's genes. Many aggressive behaviors are related to reproduction. For example, aggressive behaviors that gain access to mates, defend territory needed to attract mates or to provide a site for building a nest, or defend offspring against intruders can all be rega rded as reproductive behaviors. Other aggressive behaviors are related to self-defense, such as that of an animal threatened by a predator or an intruder of the same species. Aggressive behaviors can consist of actual attacks, or they may simply involve threat behaviors, which consist of postures or gestures that warn the adversary to leave or it will become the target of an attack. The threatened animal might show defensive behaviors-threat behaviors or an actual attack against the animal that is threatening it-or it might show submissive behaviors- behaviors that indicate that it accepts defeat and will not challenge the other animal. In the natural environment most animals display far more threats than actual attacks. Threat behaviors are useful in reinforcing social hierarchies in organjzed groups of animals or in warning intruders away from an animal's territory. They have the advantage of not involving actual fighting, which can harm one or both of the combatants. Predation involves a member of one species attacking a member of another species, usually for food. While engaged in attacking a member of the same species or defending itself against the attack, activity of the sympathetic branch of an animal 's autonomic nervous system is high. In contrast, a predatory attack Lacks a high level of sympathetic activation. A predator is not angry with its prey; a ttacking the prey is simply a means to an end.

Research with Laboratory Animals LO 11.4

Distinguish the roles of serotonin and neural circuitry in animal models of aggression and p redation.

The motor behaviors that an animal displays during aggression are programmed by neural circuits in the brain stem. Whether an arumal attacks depends on many factors, including the nature of the eliciting stimuli in the environment and the animal's previous experience. The activity of the brain stem circuits appears to be controlled by the hypothalamus and the amygdala, which also influence many

331

other species-typical behaviors. The activity of the Limbic system is controlled by perceptual systems that detect the status of the en vironment, including the presence of other anima ls. NEURAL CIRCUITRY A series of s tudies by Shaikh, Siegel, and their colleagues (reviewed by Gregg & Siegel, 2001) .investigated the neural circuitry involved in aggressive attack and predation by recording from the brains of cats. They found that aggressive attack and p redation can be elicited by stimulation of different parts of the periaqueductal gray matter (PAG). In addition, the h ypothalamus and amygdala influence attack and predation behaviors throug h excitatory and inhibitory connections with the PAG. Three principal regions of the amygdala and two regions of the hypothalamus affect defensive rage and predatiorn, both of which appear to be organized by the PAG. A pos:sible connection between the lateral hypothalamus and the ventral PAG has not yet been verified. Figure 11.7 summa rizes some of the neural connections involved in predaltion and defensive behavior.

Figure 11.7

Neural Circuitry in Defensive Behavior

and Predation The diagram shows interconnections of parts of the amygdala, hypoth;:ilamus, and periaqueductal gray matter (PAG) and their effects on defensive behaviors and predation in cats, based on the studies by Shaikh, Siegel, and their colleagues. Black arrows indicato excitation; red arrows indicate inhibition.

----Amygdala ~~:~! ~ Basal nucleus

Medial nucleus

~ Dorsal PAG __.... Defensive behaviors Ventral PAG __.... Predation

332 Chapter 11

ROLE OF SEROTONIN The cumulative results of many studies suggest that the activity of serotonergic synapses inhibits aggression (e.g., Audero et al., 2013). In contrast, destruction of serotonergic axons in the forebrain (Vergnes et al., 1988) or targeted mutation to reduce serotonin synthesis (Mosienko et al., 2012) facilitates aggressive attack, presumably by removing an inhibitory effect. Genetic studies with a variety of species confirm that serotonin has an inhibitory role in aggression. For example, selective breeding of rats and silver foxes has yielded animals that display tameness and friendly responses to human contact, and these animals show increased brain levels of serotonin and 5-HIAA (a metabolite of serotonin) (Popova, 2006). Selectively bred tame foxes show genetic alterations that support the conclusion that changes in the serotonin systems are involved in their lack of aggressive behaviors (Wang et al., 2018). A group of researchers has studied the relationship between serotonergic activity and aggressiveness in a free-ranging colony of rhesus monkeys (reviewed by Howell et al., 2007). The researchers assessed serotonergic activity by capturing the monkeys, removing a sample of cerebrospinal fluid, and analyzing it for 5-HIAA. When serotonin 5-HT is released, most of the neurotransrni tter is taken back into the terminal buttons by means of reuptake, but some escapes and is broken down to 5-HIAA, which finds its way into the cerebrospinal fluid. High levels of 5-HIAA in the CSF indicate an elevated level of serotonergic activity. The researchers found that young male monkeys with the lowest levels of 5-HIAA showed a pattern of risk-taking behavior, including high levels of aggression directed toward animals that were older and much larger than themselves. These individuals were much more likely to take dangerous unprovoked long leaps from tree to tree at a height of more than 7 m (27.6 ft). They were also more likely to pick fights that they could not possibly win. Of the preadolescent male monkeys that the investigators followed for 4 years, a large percentage of those with the lowest 5-HIAA levels died, while all of the monkeys with the highest levels survived. (See Figure 11.8.) Most of the monkeys that died were killed by other monkeys. In fact, the first monkey to be killed had the lowest level of 5-HIAA and was seen attacking two mature males the night before his death. Serotonin does not simply inhibit aggression; rather, it exerts a controlling influence on risky behavior, which includes aggression. The monkeys low in 5-HIAA weren't just more inclined to attack other animals, they were also more likely to take bigger risks, such as taking longer leaps between trees.

Research with Humans LO 11.5

Evaluate the roles of heredity and serotonin in human aggression.

Human violence and aggression are complex behaviors that pose serious social problems. Consider the following case:

Figure 11.8

Serotonin and Risk-Taking Behavior

The graph shows the percentage of young male monkeys alive or dead as a funiction of 5-HIAA level in the cerebrospinal fluid, measured 4 years previously. Source: Based on data from Higley, J. D., Mehlman, P. T., Poland, R. E. , Taub, D. M., Vickers, J., Suomi, S. J., & Linnoila, M. (1996). CSF testosterone and

5-HIM correlate with different types of aggressive behaviora. Biological Psychiatry, 40(11 ), 1067-1082. doi:10.1016/s0006-3223(95)00675-3

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Steve was hyperactive, irritable, and disobedient as a toddler .... After dropping out of school at age 14, Steve spent his teein years fighting, stealing, taking drugs, and beating up g;irlfriends .... School counseling, a probation officer, and meetings with child protective services failed to fore:stall disaster: At 19, several weeks after his last interview with researchers, Steve visited a girlfriend who had reoently dumped him, found her with another man, and shot him to death. The same day he tried to kill himself. Now he's serving a life sentence without parole. (Holden, 2000, p. 580) Steve's case illlustrates the emergence of aggressive behaviors early in life. This case also demonstrates a pervasive pattern of agg;ressive behavior. Neuroscience research has begun to reveal some of the factors involved in aggressive behavior in humans. In this section, we will look at two factors associated with human aggression: heredity and serotonin. ROLE OF HEJR.EDITY Early experiences can foster later aggressive behavior, but studies have shown that heredity plays a significant role as well. For example, Viding and colleagues (2005, 2008) studied a group of same-sex twins at the ages of 7 years and 9 years and found a higher correlation between monozygotic twins than dizygotic twins on measures of antisocial behavior and levels of callous, unemotional behavior, which indicates a genetic component in developmelrlt of these traits. Various studies have suggested that the heritability of aggression ranges from about 50 percent to 65 percent; however, additionatl research to better understand the genetic and epigenetic mechanisms is still needed (Waites et al., 2016).

Emotion

Which inherited genes are responsible for aggressive behavior? It is unlikely that one gene (or even a small number of genes) is solely responsible for aggressive behavior. Some researchers have become interested in the heritability of genes involved in serotonin signaling and aggression (you'll read more abou t the role of serotonin in human aggression next). Changes in genes that regulate the production of tryptophan hydroxylase (an enzyme involved in serotonin synthesis), serotonin receptors, serotonin transporters, and monoamine oxidases (MAOs; enzymes that inactivate serotonin) may be involved in the heritability of aggressive behaviors (Waltes et al., 2016). A recent study identified a variety of genes associated with human aggression, including genes involved in serotonin and dopamine signaling (Zhang-James & Faraone, 2016). In a study using a different methodological approach, researchers confirmed the finding of genes associated with serotonin and dopamine signaling, as well as hormonerela ted genes, involved in aggressive behavior (FemandezCastillo & Cormand, 2016). Because aggressive behavior is more common in men than women, the Y chromosome is another candidate of interest. You have already read about the role of serotonin in aggressive behavior, but why did dopamine genes turn up in multiple genetic studies? Aggressive behaviors involve the mesolimbic dopamine system, possibly because it provides the motivation to engage in the behavior. Drugs that block dopamine receptors reduce aggression. However, the role of dopamine in aggression is complicated. Some studies that have used genetic manipulations to alter dopamine signaling have reported conflicting results among measures of aggression (for review, see Nelson & Trainor, 2007). ROLE OF SEROTONIN Some, but not all, stud ies have found that serotonergic neurons play an inhibitory role in

humain aggression (Duke et al., 2013). Reduced serotonin releas•e (indicated by low levels of 5-HIAA in the CSF) is associated with aggression and other forms of antisocial behavior, including assault, arson, murder, and child abuse (Lidberg et al., 1984, 1985; Virkkunen et al., 1989). Amonig men with a history of aggression, those with the lowest serotonergic activity were most likely to have close relatives with a history of similar behavior problems (Cocc.aro et al., 1994). On the other hand, more recent studies have reported a very weak inverse relationship between serotonin and aggression, suggesting that more resear1ch is needed (Duke et al., 2013). If low levels of serotonin release contribute to aggression, drugs that act as serotonin agonists might help to reduce aggressive behavior. Coccaro and coIJeagues found that fl1uoxetine (Prozac), a serotonin agonist, decreased irritability and aggressiveness (1997), and reduced impulsive aggression (Coccaro, Lee, & Kavoussi, 2009). Figure 11.9 depicts some of the neuronal and molecular pathways involved in serotonergic regulation of aggression.

Hormonal Control of Aggressive Behavior LO 11.6

Critique the role of hormones in aggression.

Many instances of aggressive behavior are related to reproduction. For example, males of some species establish territories that attract females during the breeding season. To do so, they must defend the territories against the intrusion oJf other males. Even in species in which breeding does not depend on establishing a territory, males may compete for aocess to females, competition that also involves aggressive behavior. Females, too, often compete with other

Figure 11.9 Serotonergic Pathways Involved in Regulating of Aggression The figure depicts serotonin (5-HT) pathways (a) involved in regulating aggression and (b) highlights the roles of some of the genes involved in aggression. TPH = gene for tryptophan hydroxylase (enzyme in 5-HT synthesis pathway) SLC6A4 = gene for 5-HT transporter MAOA = gene for monoamine oxidase A (enzyme that deactivated 5-HT) HTR1 A/B, 1A/F, 2A, 3, SA, 4/6fi = genes for 5-HT receptors

Rap he nuclei (serotonin cell bodies located here terminate throughout central nervous system)

(a)

333

(b)

334

Chapter 11

females for space in which to build nests or dens in which to rear their offspring, and they will defend their offspring against the intrusion of other animals. As you learned in Chapter 10, most reproductive behaviors are controlled by the organizational and activational effects of hormones; therefore, it makes sense that many forms of aggressive behavior are, like mating, affected by hormones. Two adult female rodents that meet in a neutral territory are less likely than males to fight. But aggression between females, like aggression between males, appears to be facilitated by testosterone. Van de Poll and colleagues (1988) ovariectomized female rats and then gave them daily injections of testosterone, estradiol, or a placebo for 14 days. The animals were then placed in a test cage, and an unfamiliar female was introduced. As Figure 11.10 shows, testosterone increased aggressiveness, whereas estradiol had no effect. Androgens have an organizational effect on the aggressiveness of females, and a certain amount of prenatal androgenization appears to occur naturally. Most rodent fetuses share their mother's uterus with brothers and sisters, arranged in a row like peas in a pod. A female mouse may have zero, one, or two brothers adjacent to her. Researchers refer to these females as OM, lM, or 2M, respectively. (See Figure 11.11.) Being next to a male fetus has an effect on a female's blood levels of androgens prenatally. Vom Saal and Bronson (1980) found that females located between two males had significantly higher levels of testosterone in their blood than did females located between two females (or between a female and the end of the uterus). When they are tested as adults, 2M females are more likely to exhibit interfemale aggressiveness. Females of some primate species (for example, rhesus monkeys and baboons) are more likely to engage in fights around the time of ovulation (Carpenter, 1942; Saayman,

Figure 11.1.1

OM, 1M, and 2M Female Mouse Fetuses

Source: Adapted from vom Saal, F. S. (1983). Models of early hormonal effects on intrasex aggres!;ion in mice. In B. B. Svare (Ed.), Hormones and aggressive behavior. New York Plenum Press.

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sac

Oviducts (Fallopian tubes)

AGGRESSION IN FEMALES

Figure 11.10

Effects of 14 Days of Estradiol and Testosterone Adm inistration on lnterfemale Aggression in Rats

Source: Based on data from van de Poll, N. E.. Taminiau, M. S .. Endert, E., and Louwerse, A. L. (1988) Gonadal steroid influence upon sexual and aggressive behavior of female rats. International Journal of Neuroscience, 41, 271-286.

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1971). This phenomenon is probably caused by their increased sexual interest and consequent proximity to males. Another period of figh1ting occurs just before menstruation (Mallow, 1979; Sassenrath et al., 1973). During this time, females tend to attack othe1r females. In humans, progesterone levels in the luteal phase (before menstruation) appear to be related to aggression in women. Low concentrations of progesterone in the luteal phase were associated with high levels of selfreported aggression and irritability (Ziomkiewicz et al., 2012). Denson and colleagues (2018) synthesized the results of behavioral neuroscience studies of aggression in women. Figure 11.12 summarizes key findings related to prenatal neural and hormonal factors associated with aggression in women. Adult males of many species fight for territory or access to females. In laboratory rodents, androg•en secretion occurs prenatally, decreases, and then increases again at the time of puberty. Intermale aggressiveness also begins around the time of puberty, which suggests that the behavior is controlled by neural circuits that are stimulated by androgens. It has long been known that castratiom reduces aggressiveness, and injections of testosterone reinstate it (Beeman, 1947) . In Chapte:r 10 we saw that early androgenization has an organi:zational effect. The secretion of androgens early in development modifies the developing brain, making neural circuits that control male sexual behavior become more responsive to testosterone. Similarly, early androgenization has an organizational effect that stimulates the development of AGGRESSION IN MALES

Emotion

Figure 11.12

335

Aggression in Women

This figure presents a summary of factors associated with aggressive behavior in women. The left portion displays prenatal and early developmental factors that affect aggression. The center portion shows neural and hormonal processes associated with aggression. Highlighted text indicates uncertainty regard ing the robustness of the relationship with aggression in women. Note that this figure includes a limited set of factors and that many additional factors do not appear here (e.g., gemetic influences, neurotransmitter systems, societal factors). In addition, many of these factors are also related to male aggressive behavior. DLPFC = dorsolateral prefrontal cortex; DMPFC = dorsomedial prefrontal cortex; DACC =dorsal anterior cingulate cortex.

EEG Research Greater relative left frontal asymmetry

Prenatal drug, alcohol, and testosterone exposure; postnatal maternal depression

Prenatal/ early developmental factors

fMRI Research Activity in DLPFC, DMPFC, DACC, amygdala, putamen, caudate, thalamus, insula, ventral striatum, and hippocampus

Neural and honmonal factors

testosterone-sensitive neural circuits that facilitate interrnale aggression after activational hormone exposure at puberty. The organizational effect of androgens on intermale aggression (aggressive displays or actual fights between two males of the same species) is important, but it is not an all-or-none phenomenon. Prolonged administration of testosterone will eventually induce intermale aggression even in rodents that were castrated immediately after birth. Exposure to androgens early in life decreases the amount of exposure that is necessary to activate aggressive behavior later in life (vom Saal, 1983). Thus, early androgenization sensitizes the neural circuits: The earlier the androgenization, the more effective is the sensitization. (See Figure 11.13.) In Chapter 10 we also saw that androgens stimulate male sexual behavior by interacting with androgen receptors in neurons located in the medial preoptic area (MPA). This region appears to be important in mediating the effects of androgens on intermale aggression as well. Implanting testosterone in the MPA reinstated intermale aggression in castrated male rats (Bean & Conner, 1978). Presumably, the testosterone directly activated the behavior by stimulating the androgen-sensitive neurons located there. The MPA appears to be involved in several behaviors related

Figure 11.13 Organizational and Activational Effects of Test osterone on Social Aggression Treatment

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Activational Effect

to reproduction: male sexual behavior, maternal behavior, and intermale aggression. Males of most species more readily attack other males but us ually do not attack females. Their ability to discriminate the sex of the intruder appears to be based on the presence of particular pheromones. Intermale aggression was abolislhed in mice by cutting the vomeronasal nerve, which

336 Chapter 11 deprives the brain of inpu t from the vomeronasal organ (Bean, I982). And if the urine of female mice is painted on a male mouse, he will not be attacked if he is introduced into another male's cage (Dixon, I973; Dixon & Mackintosh, I971). A targeted mutation against proteins that are essential for the detection of pheromones by the vomeronasal organ abolishes a male mouse's ability to discriminate between males and females. Because male intruders were not recognized as rival males, they were not attacked. In fact, the mice with the targeted mutation attempted to copulate with the intruders (Prince et al., 20I3; Stowers et al., 2002). EFFECTS OF ANDROGEN S ON HUMAN AGGRESSIVE BEHAVIOR Testosterone is often the first thing people

associate with human aggressive behavior. However, the relationship between testosterone and human behavior is more complicated than it's often made out to be. As Sapolsky (20I7) notes: Additional studies show that testosterone promotes prosociality in the right setting. In one, under circumstances where someone's sense of pride rides on honesty, testosterone decreased men's cheating in a game. In another, subjects decided how much of a sum of money they would keep and how much they would publicly contribute to a common pool shared by all the players; testosterone made most subjects more prosocial. What does this mean? Testosterone makes us more willing to do what it takes to attain and maintain status. And the key point is what it takes. Engineer social circumstances right, and boosting testosterone levels during a challenge would make people compete like crazy to do the most acts of random kindness." (Sapolsky, 20I7, p. 107) Several lines of research support the conclusion that testosterone does not automatically increase aggression. For example, administering testosterone in lab settings increases activity of the amygdala, hypothalamus, and periaqueductal gray region (areas important in detecting a threat), but only in response to viewing angry faces (Goetz et al., 20I4; Hermans et al., 2008; Radke et al., 20I5; van Wingen et al., 2009). Other studies have reported that administering testosterone increased aggressive behavior and competitive motivation, but only among men and women who were already high in trait dominance (a characteristic of being assertive, forceful, and self-assured). A follow-up study found that testosterone only increased aggression among men who had traits of high dominance and low impulse control (Carre et al., 20I7). In another study, some participants who received testosterone were more prosocial and generous in a game that involved responding to high and low offers of money. The effects of testosterone depended on the context. In response to an unfair offer, testosterone increased punishment and aggression. In response to a generous offer, testosterone increased generosity (Dreher et al., 20I6).

Under diJfferent circumstances, repeated use of high doses of testiosterone can increase aggressive behavior in rodent models (Wood, 2008; Wood et al., 20I3). What mechanisms might be responsible for increased aggression? Testosterone does not seem to increase motivation for aggression or decrease impulse control directly. Instead, testosterone must increase aggression through another meams. Some research suggests testosterone increases aggression through disinhibition, meaning that a behavior that would typically be inhibited (e.g., attacking another individual) is not, making it more likely to occur (Wood et al., 2'.0I3). Taken together, the research on testosterone suggests that this hormone increases the behaviors that help an individual secure a high social status. Depending on the context and the traits of the individual, testosterone might increase aggression, or it might increase prosocial behaviors, (for review, see Carre & Archer, 20I8). Figure 11.14 illustrates the influence of testosterone on some of the different strategies used by rodents and humans to achieve and maintain high status. Notice the variety and flexibility available in the wide range of human social status behaviors that may be influenced by testosterone. The remainder of this module describes research on the organizational and activational effects of hormones, the environment, and alcohol, and their roles in human aggression. ORGANIZATl'O NA L EFFECTS Prenatal androgenization increases aggressive behavior in all species that have been studied, including primates. After puberty, androgens also begin to have activational effects. Boys' testosterone levels begin to incn~ase during the early teens, at which time aggressive behavior and intermale fighting also increase (Mazur, I983). Boys' social status changes during puberty, a nd testosterone affects their muscles as well as their brains, so we cannot be certain that the effect is hormonally produced or, if it is, that it is mediated by the brain. As we saw earlier in this chapter, the small amount of prenatal exposure to androgens that a 2M female rodent receives has measurable organizational effects on aggressive behavior. Cohen-Bendahan and colleagues (2005a) compared the proneness to aggression in I3-year-old female dizygotic twins who hadl shared the uterus with a brother (IM females) with those who had shared it with a sister (OM females). They found a modest but statistically significant increase in aggressiveness in the IM girls. The testosterone levels of the

l M and OM girls did not differ, so the increased aggressiveness may have been a result of increased prenatal exposure to androgens. It is impossible to rule out the possibility that being raised with a same-aged brother might have an effect on a girl's proneness to aggression too. As we saw in Chapter 10, girls with congenital adrenal hyperplasia (CAH) are exposed to unusually high levels of androgens-- produced by their own adrenal glandsduring prenatal development. The effects of this exposure

Emotion

Figure 11.14 Strategies Used

337

by Rodents and Humans to Achieve and Maintain High Social Status

High or acutely rising testosterone levels probably have a positive influence on th~3 status motive, and achievement of a high status position might then increase testosterone further. Other factors (psychological or physical) might facilitate and/or inhibit this motivation independently of testosterone. Heroic altruism Prosocial behavior Speech, gaze, body posture Social vigilance Antisocial behavior Physical aggression

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include a preference for boys as playmates, interest in toys and games that boys typically prefer, and, in adulthood, an increased prevalence of sexual attraction to other women. Parental socialization and biological differences contribute to sex-typical toy play, but not other characteristics such as spatial ability (Wong et al., 2012). Berenbaum and Resnick (1997) found that women and adolescent girls with CAH displayed higher levels of aggression, as measured by parents' ratings and paper-and-pencil tests. Scientifically rigorous evidence concerning the activational effects of androgens on aggression in adulthood is difficult to obtain in humans. In the past, authorities attempted to suppress aggression by castrating convicted male sex offenders. Investigators reported that aggressive attacks disappeared, along with the offender's sex drive (Hawke, 1951; Laschet, 1973; Sturup, 1961). However, the studies typically lack appropriate control groups and usually do not measure aggressive behavior directly. Some perpetrators of aggression, especially sexual assault, have been treated with synthetic steroids that inhibit the production of androgens by the testes. Treatment with drugs may be preferable to castration because the effects of drugs are reversible. However, the efficacy of treatment with antiandrogens has yet to be established conclusively. According to Walker and Meyer (1981), these drugs decrease sex-related aggression but have no effect on other forms of aggression. In fact, Zumpe and colleagues (1991) found that one of these drugs decreased sexual activity

ACTIVATIONAL EFFECTS

and aggression toward females when administered to male monkeys but actually increased intermale aggression. Another way to determine whether androgens affect aggressiveness in humans is to examine the testosterone levels of people who exhibit varying levels of aggressive behavior. However, even though this approach poses fewer ethical problems, it presents methodological ones. First, let's review some evidence. In a review of the literature, Archer (1994) found that most studies found a positive relationship between men's testosterone levels and their level of aggressiveness. For example, Dabbs and Morris (1990) studied 4,462 U.S. military veterans. The men with the highest testosterone levels had records of more antisocial activities, including assaults on other adults and histories of more trouble with parents, teachers, and classmates during adolescence. The largest effects were seen in men of lower socioeconomic status. Similar to testosterone's role in achieving social status, Mazur and Booth (1998) suggest that the primary social effect of androgens may be on dominance. If androgens enhance motivation to dominate others, that motivation may sometimes lead to aggression but not in all situations. For example, a person might strive to defeat others symbolically (through athleti•c competition or acquisition of symbols of status) rather than through direct aggression. Role of Environment In any event we must remember that correla.tion does not necessarily indicate causation. A person's environment can affect his or her testosterone level. For example, losing a competition causes a faU in blood levels of

338 Chapter 11

testosterone (Elias, 1981; Mazur & Lamb, 1980). Even winning or losing a game of chance carried out in a psychology laboratory can affect participants' testosterone levels: Winners feel better afterward and have a higher level of testosterone (McCaul et al., 1992). Bernhardt and colleagues (1998) found that basketball and soccer fans showed an increase in testosterone levels if their team won and a decrease if it lost. People adopting open, expressive postures (called "power poses") may experience an increase in testosterone levels and feelings of power, but not necessarily aggression (Carney et al., 2010). However, some researchers have critiqued the "power pose" research and failed to replicate the changes in testosterone (Crede & Phillips, 2017; Ranehill et al., 2015; Smith & Apicella, 2017). We cannot be sure in any correlational study that high testosterone levels cause people to become dominant or aggressive; perhaps their success in establishing a position of dominance increases their testosterone levels relative to those of the people they dominate. Anabolic Steroids As news reports have publicized, some athletes take anabolic steroids to increase their muscle mass and strength and, supposedly, to increase their competitiveness. Anabolic steroids include natural androgens and synthetic hormones with androgenic effects. We might expect that these hormones would increase aggressiveness, a response sometimes called "roid rage" in popular media. Anabolic steroids are used by less than 1 percent of the population in United States and other countries (e. g., Sweden, and Australia) (Dunn, 2015). Yates and colleagues (1992) found that male weight lifters who were taking anabolic steroids were more aggressive and hostile than those who were not. While, approximately 40 percent of anabolic steroid users report increased aggression, approximately 60 percent do not (Dunn, 2015). The role of anabolic steroid use in aggression is not yet clear, and we cannot be certain that steroid use is responsible for the increased aggressiveness; it could be that the men who were already more competitive and aggressive are more likely to choose to take steroids (Dunn, 2015; Yates et al., 1992). Alcohol An interesting set of experiments with another species of primates might have some relevance to h uman

Figure 11.1.5 Alcohol, Mating, and Aggressive Behavior in Monkeys The graph shows the effect of alcohol intake on frequency of aggressive behavior among dominant and subordinate male squirrel monkeys during the mating season and the nonmating season. Source: Based on c:lata from Winslow, J. T. , and Miczek, K. A. (1988).

Androgen dependemcy of alcohol effects on aggressive behavior: A seasonal rhythm in high-ranfling squirrel monkeys. Psychopharmacology, 95, 92-98.

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aggression and alcohol use. Evidence suggests that the effects of alcohol may interact with those of androgens. Winslow and Miczek (1985, 1988) found that alcohol increases intermale aggression in dominant male squirrel monkeys, but only during the mating season, when their blood level of testosterone is two to thre1e times higher than that during the nonmating season. 1hese studies suggest that the effects of alcohol interact both with social status and with testosterone. (See Figure 11.15.) This suggestion was confirmed by Winslow and colleagues (19B8), who tested monkeys during the nonmating season. They found that alcohol increased the aggressive behavior of dorninant monkeys if the monkeys were also given injections of tcestosterone. However, these treatments were ineffective in subordinate monkeys, which presumably had learned not to be aggressive. The next step will be to find the neural mechanisms that are responsible for these interactions.

Module Review: Aggression Research with Laboratory Animals LO 11.4

Distinguish the roles of serotonin and neural circuitry in animal models of aggression and predation.

Aggressive behaviors are species-typical and serve useful functions most of the time. The PAG appears to be involved in defensive behavior and predation. These

mechanisms are modulated by the hypothalamus and amygdala. The activity of serotonergic neurons appears to inhibit risk-taking behaviors, including aggression. Destruction of serotonergic axons in the forebrain enhances aggression, and administration of drugs that facilitatoe serotonergic transmission reduces it. Low CSF levds of 5-HIAA (a metabolite of serotonin) are correlated w ith increased risk-taking and aggressive

Emotion 339 behavior in monkeys. High levels of brain serotonin and 5-HIAA in rats and silver foxes are associated with reduced aggression.

Research with Humans LO 11.5 Evaluate the roles of heredity and serotonin in human aggression. Low CSF levels of 5-HIAA are correlated with increased risk-taking and aggressive behavior in humans. Genetic factors play a role in people's level of aggression and antisocial behavior.

social status, testosterone can increase generosity. When it does increase aggression, testosterone may do so through disinhibition. Androgens primarily affect offensive attack. They are not necessary for defensive behavio1rs, which are shown by females as well as males. Resea:rch suggests that the primary effect of androgens may be to increase motivation to achieve dominance and that increased aggression may be secondary to this effect.. It is not clear whether higher androgen levels promote dominance or whether successful dominance increases androgen levels.

Thought Question Hormonal Control of Aggressive Behavior LO 11.6

Critique the role of hormones in aggression.

Testosterone functions to increase behaviors related to obtaining and maintaining social status. Under conditions of threat, testosterone increases aggression. Under conditions in which generosity would increase

Impulse Control Many investigators believe that impulsive violence is a consequence of faulty emotional regulation. For many of us, frustrations may elicit an urge to respond emotionally, but we usually manage to calm ourselves and suppress these urges. The ventromedial prefrontal cortex-which includes the medial orbitofrontal cortex and the subgenual anterior cingulate cortex-plays an important role in regulating our responses to such situations.

Role of the vmPFC LO 11.7

Describe the role of the ventromedial p refrontal cortex in impulse control.

You read earlier about the role of the vmPFC in inhibiting a conditioned fear response. Similarly, the vmPFC is involved in inhibiting emotional behavior, such as impulsive violence or aggression. The importance of the vmPFC in control of emotional behavior is demonstrated by the effects of damage to this region. One famous case comes from the mid-1800s. Phineas Gage, the foreman of a railway construction crew, was using a steel rod to ram a charge of blasting powder into a hole that had been drilled in solid rock. Suddenly, the charge exploded and sent the rod into his cheek, through his brain, and out the top of his head. (See Figure 11.16.) He survived, but by many accounts he was a different man. Before his injury, Gage was described as serious, industrious, and energetic. Afterward, he was described as childish, irresponsible, and thoughtless of others. Some accounts suggested that he was unable to make or carry out plans, and his actions and mood appeared

From the point of view of evolution, aggressive behavior and a tendency to establish dominance have useful functions. In particular, they increase the likelihood that only the healthiest and most vigorous animals will reproduce. Can you think of examples of beneficial and detrimental effects of these tendencies among members of our own species?

to be prone to sudden changes. It was initially believed that his accident largely destroyed the vmPFC bilaterally (Damasio et al., 1994); however, some researchers have suggested that the damage was limited to the left vmPFC only (JRatiu and Ion-Florin, 2004). In addition, a reexamination of the historical evidence suggests that Gage may have made substantial recovery following the accident, with less impai1rment to his emotional and impulse control than initially believed, consistent with damage to only one half of the vm.PFC (Macmillan & Lena, 2010). Gage's controversial accident aside, damage to the vmPFC causes serious and often debilitating impairments of be~havioral control and decision making. These impai1rments appear to be a consequence of emotional dysregulation. People whose vmPFC has been damaged by disease or accident are still able to accurately assess the significance of particular situations but only in a theoretical sense. For example, patient E. R. experienced bilateral damage of the vmPFC produced by a benign tumor, which was successfully removed (Eslinger & Damasio, 1985). E. R. dlisplayed excellent social judgment and when he was given hypothetical situations involving moral, ethical, or practical dilemmas and asked what the people involved should do, he always gave sensible answers and justified them with carefully reasoned logic. However, his own life was a different matter. He spent his life's savings, lost one job after another, and was unable to distinguish between trivial decisions and important ones. Eventually, his wife left him and sued for divorce. Although E. R. "had learned and used normal patterns of social behavior before his brain lesion, and ... could recall such patterns ... real-life situations failed to evoke them" (p. 1737).

340 Chapter 11

Figure 11.16

Phineas Gage's Accident

The steel rod entered his left cheek and exited through the top of his head. Source: Everett Collection HistoricaVAlamy Stock Photo

Evidence suggests that the vmPFC serves as an interface between brain mechanisms involved in automatic emotional responses (both learned and unlearned) and those involved in the control of complex behaviors. This role includes using our emotional reactions to guide our behavior and in controlling the occurrence of emotional reactions in various social situations. Anderson and colleagues (2006) obtained ratings of emotional behaviors of patients with lesions of the vmPFC, such as frustration tolerance, emotional instability, anxiety, and irritability, from the patients' relatives. They also obtained ratings of the patients' real-world competencies, such as judgment, planning, social inappropriateness, and financial and occupational status, from both relatives and clinicians. They found a significant correlation between emotional dysfunction and impairments in real-world competencies. There was no relationship between cognitive abilities and realworld competencies, which strongly suggests that emotional problems lie at the base of the real-world difficulties exhibited by people with vmPFC damage. Raine and colleagues (1998) found evidence of decreased prefrontal activity and increased subcortical activity (including the amygdala) in the brains of convicted murderers. These changes were primarily seen in impulsive,

emotional murderers. Cold-blooded, calculating, predatory murderers-whose crimes were not accompanied by anger and rage-showed more typical patterns of brain activity. Presumably, increased activation of the amygdala reflected an increased tendency for display of negative emotions, and the decreased activation of the prefrontal cortex reflected a decreased ability to inhibit the activity of the amygdala and control the emotions. Similarly, Raine and colleagues (2000) found that people with antisocial personality disorder :showed an 11 percent reduction in volume of the gray matter of the prefrontal cortex. An interesting functional-imaging study by Nili and colleagues (2010) suggests that the vmPFC plays a role in brain mechanisms of courage. Nili and his colleagues scanned the b:rains of people who were or were not afraid of snakes. While the people were in the scanner, they could press buttons that controlled the action of a conveyer belt that brought a live snake toward or away from them. People who were not afraid of snakes brought the snake near them and showed no signs of fear. However, people who were afraid of snakes did show signs of fear as the snake approached. Some of the fearful people pressed the button that moved the snake away from them, but others brought the snake near to them, even though they were clearly afraid.

Emotion

Figure 11.17

341

Role of the vmPFC

The participants' task was to reach maximal proximity to either a live snake or a toy bear, by repeatedly choosing whether to bring the object closer or move it away, while undergoing fMR I brain scanning. A display of coura!~e was accompanied by activation of a region of the vmPFC, the subgenual anterior cingulate cortex. Source: Nili, U., Goldberg, H., Weizman , A., and Dudai, Y. (2010). Fear thou not: Activity of fro•ntal and temporal circuits in moments of real-life courage, Neuron, 66(6), 949-962.

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fear. A display of courage was accompanied by activation of a region of the vmPFC, the subgenual anterior cingulate cortex. Participants who succumbed to their fear- that is, those who moved the snake away-did not show activation of the subgenual anterior cingulate cortex. (See Figure 11.17.)

Brain Development and Impulse Control LO 11.8

Provide evidence for a developmental factor in impulse control.

Many investigators believe that impulsive violence is a consequence of faulty emotional regulation. The amygdala plays an important role in provoking anger and violent emotional reactions, and the prefrontal cortex plays an important role in suppressing such behavior by making us see its negative consequences. The amygdala matures early in development, but the prefrontal cortex matures much later, during late childhood and early adulthood. (See Figure 11.18.) As

Figure 11.18 •

Subject in scanner controlling the distance from the object on trolley

the prefrontal cortex matures, adolescents show increases in speed of cognitive processing, abstract reasoning ability, ability to shift attention from one topic to another, and ability to inhibit inappropriate responses (Yurgelun-Todd, 2007). In fact, a structural imaging study by Whittle and colleagues (2008) found that aggressive behavior during paren t-child interactions in adolescence was positively related to the volume of the amygdala and negatively related to the relative volum.e of the right medial prefrontal cortex.

Serotonin and Impulse Control LO 11.9

Explain the role of serotonin in impulse control regulation.

Earlier in this chapter we saw that decreased activity of serotone~rgic neurons is associated with aggression, violence, and risk taking. As we saw, decreased activity of the prefrontaJ cortex is also associated with antisocial behavior. These two facts appear to be linked. The prefrontal cortex receives a major projection of serotonergic axons. Research

Representation of Amygdala and Prefrontal Cortex Development over Lifespan

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342 Chapter 11 indicates that serotonergic input to the prefronta1 cortex activates this region. For example, a functional-imaging study by Mann and colleagues (1996) showed that fenfluramine, a drug that stimulates the release of 5-HT, increases the activity of the prefrontal cortex, which presumably inhibits the activity of the amygdala and suppresses aggressive behavior. Crockett and colleagues (2010) found that a single high dose of a 5-HT agonist decreased the likelihood of participants making a decision to cause harm in scenarios that presented moral dilemmas. It seems likely, therefore, that an abnormally low level of serotonin release can result in decreased activity of the prefrontal cortex and increased likelihood of utilitarian judgments (the next module includes more information about utilitarian judgments) or, in the extreme, antisocial behavior. Several studies have found evidence for deficits in serotonergic innervation of the PFC associated with impulsive behavior. New and colleagues (2002) found that a serotonin-releasing drug increased the activity of the orbitofrontal cortex in healthy, nonviolent participants but failed to do so in participants with a history of impulsive aggression. A functional-imaging study found evidence for lower levels of serotonin transporters in the medial prefronta l cortex of people with impulsive aggression (Frankie et al., 2005). Because serotonin transporters are found in the membrane of serotonergic terminal buttons, this study suggests that the medial prefrontal cortex of people in this sample contains decreased serotonergic input. As we saw earlier, impulsive aggression has been successfully treated with selective serotonin reuptake inhibitors such as fluoxetine. A functional-imaging study by New and colleagues (2004) measured regional brain activity of people with histories of impulsive aggression before and after 12 weeks of treatment with fluoxetine. They found that the drug increased the activity of the prefrontal cortex and reduced aggressiveness.

Moral Decision Making LO 11.10

D escribe the brain regions involved in em otional asp ects of moral decision maki ng involving impulse control.

Evidence suggests that emotional reactions guide moral judgments as well as decisions involving personal risks and rewards and that the prefrontal cortex plays a role in these judgments as well. In the past, moral judgments were believed to be a product of conscious, rational decision making. However, recent research on the role of neural mechanisms of emotion suggests that emotions play an important role-perhaps the most important role-in the formation of moral judgments. Consider the following moral dilemma (Thomson, 1986): You see a runaway trolley hurtling down a track leading to a cliff. There are five people on the track. Without your

intervention these people will soon die. However, you are standing near a switch that will shunt the trolley off to another track, where the vehicle will stop safely. But there is another person on that: track, and he will be killed if you throw the switch to save the five people on the other track. Should you stand by and watch the trolley kill the five people, or should you save them-and kill the man on the other track? Most people conclude that the better choice would be to throw the switch; saving five people justifies the sacrifice of one man. Tlhis decision is based on conscious, logical application of a rule that it is better to kill one person than five people. But consider a variation of this dilemma. As before, the trolley is hurtling toward doom, but there is no switch at hand to shunt it to another track. Instead, you are standing on a bridge ov•er the track. A very large man is standing there too, and if you give him a push, his body will fall onto the track and stop the trolley. (In this scenario, you are too small to stop the trolley, so you cannot save the five people by sacrificing yourself.) What should you do? (See Figure 11.19.) Most people feel repugnance at the thought of pushing the man off the bridge and balk at the idea of doing so, even though the result would be the same as the first dilemma: one person lost, five people saved. Whether we kill someone by sending a trolley his way or by pushing him off a bridge into the path of an oncoming trolley, he dies when the trolley strikes him. Butt somehow, imagining yourself pushing a person's body and causing his death seems more emotionally wrenching thai11 throwing a switch that changes the course of a runaway trolley. Thus, moral judgments appear to be guided by emotional reactions and are not simply the products of rational[, logical decision-making processes. In a functional-imaging study, Greene and colleagues (2001) presented people with moral dilemmas such as the one we just described and found that thinking about them activated several brain regions involved in emotional reactions, including the vmPFC. Making innocuous decisions, such as whether to take a bus or train to some destination, did not activate these regions. Perhaps, then, our reluctance to push someone to his death is guided by the unpleasant emotional reaction we feel when we contemplate tlhis action. Let's reconsider the contrast between the decision to throw a switch to save five lives and the decision to shove someon e onto the tracks to accomplish the same goal. Conside1ration of the first dilemma generates a much smaller emotional reaction than consideration of the sec-

ond dilemma does, and consideration of only the second dilemma strongly activates the vmPFC. We might expect that people with vmPFC damage, who show impairments of emotional reaction, might choose to push the man onto the track in the second dilemma. In fact, that is exactly what they doi. Koenigs and colleagues (2007) presented nonmoral, impersonal moral, and personal moral scenarios to patients with vmPFC lesions, patients with brain damage not including this region, and healthy controls.

Emotion

Figure 11.19

343

Moral Decision-Making Scenario: The Case of the T1rolley

In scenario (a) a person must decide to throw a switch to save five people or one person. In scenario (b) a person m ust decide to push a man off a bridge to save five people.

Table 11.2 lists examples of the scenarios that the investigators of the study presented to their participants. Koenigs and his colleagues predicted that patients with vmPFC lesions should make the same decisions as participants in the other two groups on the nonmoral and impersonal moral judgments, because these decisions are normally solved rationally, without a strong emotional component. Only the outcome, or utility, of the choice need be considered. However, the emotional deficits of

patients with prefrontal damage would be expected to lead to utilitarian judgments even in the case of personal moral judgments-and that is precisely what was seen. The patients with vrnPFC lesions were much more likely to say "yes" to the question posed at the end of the scenarios. Reluctance to push someone to his death even though that action would save the lives of others might be caused by the unpleasant thought of what it would feel like to commit that action and see the man fall to his death. If this

Table 11.2

Examples of Scenarios Involving Nonmoral, Impersonal Moral, and Personal Moral Judgments from the Study by Koenigs and colleagues (2007)

Source: Based on Keonigs, M., Young, l., Adolphs, R., et al. Damage to the prefrontal corte): increases utilitarian moral judgments. Nature, 2007, 446, 708-91 1. Brownies (Nonmoral scenario) You have decided to make a batch of brownies for yourself. You open your recipe book and find a recipe for brownies. The recipe calls for a cup of chopped walnuts. You don't like walnuts, but you do like macadamia nuts. As it happens:, you have both kinds of nuts available to you. Would you substitute macadamia nuts for walnuts in order to avoid eating walnuts? Speedboat (Impersonal moral scenario) While on vacation on a remote island, you are fishing from a seaside dock. You observe a gro•up of tourists board a small boat and set sail for a nearby island. Soon after their departure you hear over the radio that there is a violent storm brewing, a storm that is sure to intercept them. The only way that you can ensure their safety is to warn them by borrowing a nearby speedboat. The speedboat belongs to a miserly tycoon who would not take kindly to your borrowing his property. Would you borrow the speedboat in order to warn the tourists about the storm? Lifeboat (Personal moral scenario) You are on a cruise ship when there is a fire on board, and the ship has to be abandonecl. The lifeboats are carrying many more people than they were designed to carry. The lifeboat you're in is sitting dangerously low in the water-a few inches lower, and it will sink. The seas start to get rough, and the boat begins to fill with water. If nothing is done it will sink before the rescue boats arrive, and everyone on board will die. However, there is an injured person who will not survive in any case. If you throw that person overboard the boat will stay afloat and the remaining passengers will be saved. Would you throw this person overboard in order to save the lives of the remaining passengers?

344 Chapter 11 is true, then perhaps people with vmPFC lesions say that they are willing to push the man off the bridge because thinking about doing so does not evoke an unpleasant emotional reaction. In fact, Moretto and collegues (2009) found that people without brain damage showed physiological

signs of an unpleasant emotional reaction when they contemplated pushing the man off the bridge-and said that they would not push him. People with vmPFC lesions did not show signs of this emotional reaction-and said that they would pu:sh him.

Module Review: Impulse Control Role of the vmPFC LO 11.7

Describe the role of the ventromedial prefrontal cortex in impulse control.

The vmPFC plays an important role in emotional reactions. This region communicates with the dorsomedial thalamus, temporal cortex, ventral tegmental area, olfactory system, amygdala, cingulate cortex, lateral hypothalamus, and other regions of the frontal cortex, including the dorsolateral prefrontal cortex. People with vmPFC lesions show impulsive behavior and often display outbursts of inappropriate anger. They are able to explain the implications of complex social situations but often respond inappropriately when they find themselves in these situations. Decreased prefrontal activity and increased subcortical activity are associated with impulsive, violent behavior. People with antisocial personality disorder have reduced gray matter volume in the prefrontal cortex. The activity of the vmPFC increases when people show courageous behavior (impulse control)-letting a snake approach them even though they fear snakes.

aggressive behavior during adolescence was positively related to the vollume of the amygdala and negatively related to the relative volume of the right medial prefrontal cortex.

Serotonin and Impulse Control LO 11.9

Explain the role of serotonin in impulse control regulation.

Serotonergic input to the prefrontal cortex inhibits the amygdala and suppresses aggressive and impulsive behavior. Increasing serotonergic activity reduces impulsive behavior. The vmPFC of people with impulsive aggression contains less dense serotonergic input.

Moral Decision Making LO 11.10 Describe the brain regions involved in

emotional aspects of moral decision making involving impulse control. The vmPFC is involved in making moral judgments. When people make judgments that involve conflicts between utilitarian judgments and personal moral judgments, the vmPFC is activated. People with damage to the vmPFC display utilitarian moral judgments.

Brain Development and Impulse Control LO 11.8

Provide evidence for a developmental factor in impulse control.

The amygdala is part of a circui t involved in anger and violence and matures before the prefrontal cortex, which suppresses violent behavior. Research found that

Communication of Emotions As described earlier in this chapter, emotions are organized responses (behavioral, autonomic, and hormonal) that prepare an animal to deal with existing situations in the environment, such as events that pose a threat to the organism. For our earliest premammalian ancestors that is likely all there was to emotions. But over time, other responses, with new functions, evolved. Many species of animals (including our own) communicate their emotions to others through postural changes, facial expressions, and nonverbal sounds (such as sighs, screams, and growls). These expressions serve useful social functions: They tell other individuals how we feel and-more importantly- what we are likely to do. For

Thought Question Is there value in understanding the neural basis of moral behavior and decision making? How might this information be used by clinicians, police, judges, jury members, or educators?

example, such expressions of emotion warn a rival that we are angry and to stay away or tell friends that we are sad and would like some comfort and reassurance. This module examines such expression and communication of emotions.

Facial Expression of Emotions: Innate Responses LO 11.11

Describe evidence in support of emotional expressions as innate responses.

Charles Darwin (1872/1965) suggested that human expressions of emotion evolved from similar expressions in other animals. He said that emotional expressions are innate,

Emotion

unlearned responses consisting of a complex set of movements, principally of the facial muscles. A person's sneer and a wolf's snarl are biologically determined response patterns, both controlled by innate brain mechanisms, just as are coughing and sneezing. (Of course, people can sneer and wolves can snarl for quite different reasons.) Some of these movements resemble the behaviors themselves and may have evolved from them. For example, a snarl shows one's teeth and can be seen as an anticipation of biting. Darwin obtained evidence for his conclusion that emotional expressions were innate by observing his own children and by corresponding with people living in various isolated cultures around the world. He reasoned that if people all over the world, no matter how isolated from each other, show the same facial expressions of emotion, then these expressions must be inherited instead of learned. The logical argument goes like this: When groups of people are isolated for many years, they develop different languages. We can say that the words people use are arbitrary; there is no biological basis for using particular words to represent particular concepts. However, if facial expressions are inherited, then they should take approximately the same form in people from all cultures, despite their isolation from one another. And Darwin did, indeed, find that people in different cultures used the same patterns of movement of facial muscles to express a particular emotional state. Classic research by Ekman and his colleagues (Ekman & Friesen, 1971; Ekman, 1980) tends to confirm Darwin's hypothesis that facial expression of emotion uses an innate, species-typical repertoire of movements of facial muscles (Darwin, 1872/1965). For example, Ekman and Friesen (1971) studied the ability of members of an isolated tribe in New Guinea to recognize facial expressions of emotion produced by members of other cultures. They had no trouble doing so, and they produced facial expressions that were readily recognized by the researchers. Figure 11.20 shows four photographs taken from videotapes of a man from this tribe reacting to stories designed to evoke facial expressions of happiness, sadness, anger, and disgust. Because the same facial expressions were used by people who had not previously been exposed to each other, Ekman and Friesen concluded that the expressions were innate, unlearned behavior patterns. In contrast, different cultures use different words to express particular concepts; production of these words does not involve innate responses but must be learned. Other researchers have compared the facial expressions of blind and sighted people. They reasoned that if the facial expressions of the two groups are similar, then the expressions are innate for our species and do not require learning by imitation. In fact, the facial expressions of young blind and sighted children are very similar (Woodworth & Schlosberg, 1954; Izard, 1971). In addition, a study of the emotional expressions of people competing in (and winning or losing) athletic events in the 2004 Paralyrnpic Games found no

345

Figure 11.20 Facial Expressions in a New Guinea Tribesman The tribesman made faces when he heard the following stories: (a) "Your friend has come and you are happy." (b) " Your child has died." (c) "You are angry and about to fight." (d) "You see a dead pig that has beEm lying there a long time." Source: Paul Ekman Group, LLC

(a)

(b)

(c)

(d)

differences between the expressions of congenitally blind, nonco1ngenitally blind, and sighted athletes (Matsumoto & Willingham, 2009). Both the cross-cultural studies and the investiigations of blind people confirm the innate quality of these facial expressions of emotion. A study by Sauter and colleagues (2010) reached similar conclusions. The investigators cairried out a vocal version of the study by Ekman and Friesen. They presented European English-speakers and people living in isolated northern Namibian villages with recordings of sounds of nonverbal vocalizations to situations that would be expected to produce the emotions of anger, disgus:t, fear, sadness, surprise, or amusement. The participants were told a story and then heard two different vocalizations (sighs, groans, laughs, etc.), one of which would be appropriate for the emotion produced by the story. Members of both cultures had no difficulty choosing the correct vocalizations of members of their culture and the other culture.

Neural Basis of the Communication of Emotions: Recognition LO 11 .12

Summarize the neural basis of emotional recognition, including laterality, d irection of gaze, imitation, and d isgust.

Effective communication is a two-way process. That is, the ability to display one's emotional state by changes in

346 Chapter 11

expression is useful only if other people are able to recognize them. In fact, Kraut and Johnston (1979) unobtrusively observed people in circumstances that would be likely to make them happy. They found that happy situations (such as making a strike while bowling, seeing the home team score, or experiencing a beautiful day) produced only small signs of happiness when the people were alone. However, when the people were interacting socially with other people, they were much more likely to smile. For example, bowlers who made a strike usually did not smile when the ball hit the pins, but rather when they turned around to face their companions. Jones and colleagues (1991) found that even 10-month-old children showed this tendency to display emotion when an audience was present. Recognition of another person's facial expression of emotions is generally automatic, rapid, and accurate. Tracy and Robbins (2008) found that observers quickly recognized brief expressions of a variety of emotions. If they were given more time to think about the expression they had seen, the participants showed very little improvement. Rapid assessments are sometimes called "thin slice" judgments by researchers. Thin slice assessments of situations and behaviors with emotional content (such as deception or communication) have been found to be as accurate when exposure to content is less than 30 seconds, as when it is 300 seconds. Additional time to assess emotional content does not lead to greater accuracy in these examples either (Ambady and Rosenthal, 1992). Similar research in music reported accurate assessment of emotional content in songs after only 300-400 milliseconds of exposure (Krumhansl, 2010). People can express emotions through their body language, as well as through muscular movements of their face (de Gelder, 2006). For example, a clenched fist might accompany an angry facial expression, and a fearful person may run away. The sight of photographs of bodies posed in postures of fear activates the amygdala, just as the sight of fearful faces does (Hadjikhani & de Gelder, 2003). Meeren and colleagues (2005) prepared computer-modified photographs of people showing facial expressions of emotions that were either

Figure 11.21

congruent with the person's body posture (for example, a facial expression of fear and a body posture of fear) or incongruent (for example, a facial expression of anger and a body posture of fear). The researchers asked people to identify the facial expressions shown in the photos and found that the ratings were faster and more accurate when the facial and body expressions matched. In other words, when we look at other people's faces, our perception of their emotion is affected by their body posture as well as by their facial expression. LATERALITY OF EMOTIONAL RECOG NITION We recognize other people's feelings by means of vision and audition-seeing their facial expressions and hearing their tone of voice and choice of words. Many studies have found that the right hemisphere plays a more important role than the left hemisphere in comprehension of emotion. For example, Bowers and colleagues (1991) found that patients with right hemisphere damage had difficulty producing or describing mel!ltal images of facial expressions of emotions. Several fonctional-imaging studies have confirmed these results. For example, George and colleagues (1996) had participants listen to some sentences and identify their emotional content. In one condition, the participants listened to the meaning of the words and said whether they described a situation in which someone would be happy, sad, angry, or neutral. In another condition, the participants judged the

emotional stat,e from the tone of the voice. The investigators found that comprehension of emotion from word meaning increased the activity of the prefrontal cortex bilaterally, the left hemisphere more than the right. Comprehension of emotion from tone of voice increased the activity of only the right prefrontal cortex. (See Figure 11.21.) Heilman, Watson, and Bowers (1983) recorded a particularly interestimg case of a man with a disorder called pure word deafness, caused by damage to the left temporal cortex. (This syndrome is described in Chapter 14.) The man could not comprehend the meaning of speech but had no difficulty identifying the emotion being expressed by its intonation. This case, like the functional-imaging study by George and

Perception of Emotions

The PET scans indicate brain regions activated by listening to emotions expressed by meanings of words (red) or tone of voice (green). Source: Tracings of brain activity from George, M. S., Parekh, P. I., Rosinsky, N., Ketter, T. A., et al. (1996). Understanding emotional prosody activates right hemisphere regions. Archiwi!s of Neurology, 53, 665-670.

Right

Left

•

Meanings of words

•

Tone of voice

Emotion

colleagues (1996), indicates that comprehension of words and recognition of tone of voice are independent functions. ROLE OF THE AMYGDALA AND PREFRONTAL CORTEX As we saw in the previous module, the amygdala p lays a special role in emotional responses. It plays a role in emotional recognition as well. For example, several studies have found that lesions of the amygdala (the result of degenerative diseases or surgery for severe seizure disorders) impair people's ability to recognize facial expressions of emotion, especially expressions of fear (Adolphs et al., 1994, 1995; Calder et al., 1996; Young et al., 1995). In addition, functional-imaging studies (Morris et al., 1996; Whalen et al., 1998) have found large increases in the activity of the amygdala when people view photographs of faces expressing fear, but only small increases (or even decreases) when they look at photographs of happy faces. However, amygdala lesions do not appear to affect people's ability to recognize emotions in tone of voice (Adolphs & Tranel, 1999; Anderson & Phelps, 1998). Several studies suggest that the amygdala receives visual information that we use to recognize facial expressions of emotion d irectly from the thalamus and not from the visual association cortex. Adolphs (2002) notes that the amygdala receives visual input from two sources: subcortical and cortical. The subcortical input (from the superior colliculus and the pulvinar, a large nucleus in the posterior thalamus) appears to provide the

Figure 11.22

most important information for this task. Krolak-Salmon and colleagues (2004) recorded electrical potentials from the amygdala and visual association cortex through electrodes that had been implanted in people who were being evaluated for neurosurgery to alleviate a seizure disorder. They presen ted the people with p hotographs of faces showing neutral expressions or expressions of fear, happiness, or disgus t. They found that fearful faces produced the largest response and that the amygdala sh owed activity before the visual cortex did. The rapid response suggests that visual information that the amygdala receives directly from the subcortical visual system (which conducts information very rapidly) permits it to recognize facial expressions of fear. Some people with blindness caused by damage to the visual cortex can recognize facial expressions of emotion even though thei; have no conscious awareness of looking at a person's face, a phenomenon known as affective blindsight (Anders et al., 2004; de Gelder et al., 1999). Tamietto and colleagues (2009) confirmed that "emotional contagion" can take place even w ithout conscious awareness. They presented photographs of faces expressing happiness or fearfulness to the sighted and blind fields of people with unilateral visual cortex lesions. Although the people did not report seeing an emotional expression (or even a face) in their blind fields, they automatically made facial expressions of their own that matched those of the faces in the photographs. Figure 11.22 shows the contraction of a "smile muscle" and a "frown

Unconscious Imitation of Facial Expressions of Emotions

When pati ents with unilateral damage to the visual cortex saw photographs of happy or fearful faces, they smiled or frowned when the photographs were presented to thHir sighted or blind field, which indicates that visual information concerning emotional expressions can take place without conscious awareness. Source: Based on data from Tamietto, M., Castelli, L., Vighetti, S., Paola, P. , et al. (2009). Unseen facial and bodily expressions trigger fast emotional reactions. Proceedings of the National Academy of Sciences, USA, 106, 17661 - 17666.

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Chapter 11

Figure 11.23 Brain Pathway Showing Input from the Two Visual Pathways to the Amygdala The magnocellular pathway conveys monochromatic information about depth and motion. It projects to the amygdala and uses low spatial freque:ncy information to quickly identify emotional information. The parvocellular pathway conveys information about color and fine details. It projects to the fusiform face area and uses high spatial

frequency information. Parallel pathways

Dorsal (parietal) pathway Depth

Motion

Ventral (inferior temporal) pathway Form

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Magnocellular pathway I

Parvocellular pathway

muscle" Lmder these conditions. Note that the appropriate muscles contracted when the happy or fearful face was presented to either the sighted field ("seen stimuli") or the blind field ("LU1Seen stimuli"). As we saw in Chapter 6, the visual cortex receives information from two systems of neurons. The magnocellular system provides information about movement, depth, and very subtle differences in brightness in the scene before our eyes. This system appeared early in evolution of the mammalian brain and provides most mammals (dogs and cats, for example) with a monochromatic, somewhat fuzzy image of the world. The parvocellular system is found onJy in some primates, including humans. This system provides us with color vision and detection of fine details. The part of the visual association cortex responsible for recognition of faces, the fusiform face area, receives information primarily from the parvocellular system. The information that the amygdala receives from the superior colliculus and the pulvinar has its origin in the more primitive magnocellular system. (See Figure 11.23.) An ingenious fLmctional-imaging study by Vuilleumier and colleagues (2003) presented people with pictures of faces showing neutral or fearful expressions. Some of the pictures were normal, some had been filtered with a computer program so that they showed only high spatial frequencies, and some had been filtered to show only low spatial frequencies. (Chapter 6 described the concept of spatial frequencies.) As Figure 11.24 shows, high spatial frequencies show fine details of transitions between light and dark, and low spatial frequencies show fuzzy images. These photos primarily stimulate the parvocellular and magnocellular systems, respectively. Vuilleumier and his colleagues found that the fusiform face area was better at recognizing individual faces and primarily used high spatial frequency (parvocellular) information to do so. (See Figure 11.23.) In contrast, the amygdala

Figure 11.2'.4 Involvement of Magnocellular and Parvocellular Systems in Emotional Perception The figure shows the stimuli used by Vuilleumier and colleagues (2003). The mom primitive magnocellular system is sensitive to low

spatial frequencies (SF). and the more recently evolved parvocellular system is sensitive to high spatial frequencies. Source: From Vuilleiumier, P., Armony, J. l., Driver, J., and Dolan, R. J. (2003). Distinct spatial frequency sensitivities for processing faces and emotional expressions. Natur.e Neuroscience, 6, 624-631.

Broad SF

High SF

Low SF

Emotion

(and the superior colliculus and pulvinar, which provide it with visual information) was able to recognize an expression of fear based on low spatial frequency (magnocellular) information but not on high spatial frequency information. Krolak-Salmon and cvolleagues (2004) recorded electrical potentials from the amygdala and visual association cortex through electrodes that had been implanted in people who were being evaluated for neurosurgery to alleviate a seizure disorder. They presented the people with photographs of faces showing neutral expressions or expressions of fear, happiness, or disgust. They found that fearful faces produced the largest response and that the amygdala showed activity before the visual cortex did. The rapid response supports the conclusion that the amygdala receives visual information from the magnocellular system (which conducts information very rapidly) that permits it to recognize facial expressions of fear. So far, the evidence suggests that the amygdala plays an indispensable role in recognition of facial expressions of fear. However, a study by Adolphs and colleagues (2005) suggests that, under the appropriate conditions, other regions of the brain can perform this task. Adolphs and colleagues discovered that S. M., a woman with bilateral amygdala damage, failed to look at the eyes when she examined photographs of faces. Spezio and colleagues (2007) conducted a similar study, but this one measured S. M.'s eye movements while she was actually conversing with another person. Like the study by Adolphs and colleagues this one found that S. M. failed to direct her gaze to the other person's eyes. In contrast, she spent a large amount of time looking at the other person's mouth. (See Figure 11.25.) By themselves, eyes are able to convey a fearful expression. A functional-imaging study by Whalen and colleagues (2004) found that viewing the fearful eyes shown in Figure 11.26 activated the ventral amygdala, the region that receives the majority of the cortical and subcortical inputs to the amygdala. The fact that S. M. did not look at eyes suggests a cause for her failure to detect only this emotion. In fact, when

Figure 11.25

Eye Fixations After Amygdala Damage

The figure shows the numbers of fixations on a person's face made by a patient with bilateral amygdala damage compared to a control participant. Warmer colors indicate increasing numbers of fixations. Note that the patient does not look at the other person's eyes. Source: Based on Spezio, M. L. , Huang, P. -Y. S., Castelli, F. , and Adolphs, R. (2007). Journal of Neuroscience, 27, 3994-3997. Copyright 2007, The Society for Neuroscience.

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Participant w ithout amygdala lesion

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Figure 11.26 Role of the Whites of Eyes in Emotional Response The stimuli used in the study by Whalen and colleagues (2004) show that the whites of the eyes alone can convey the impression of a fearful ~3xpressi on. Source: Based on Whalen, P. J. , Kagan, J. , Cook, R. G., Davis, F. C. , Kim,

H., Polis, S., ... and Johnstone, T. (2004). Human amygdala responsivity to masked fearful eye whites. Science 306, 2061. Copyright 2004 American Association for the Advancement of Science.

Fear

Happiness

Adolphs and colleagues (2005) instructed S. M. to look at the eyes oif the face she was examining, she was able to recognize an expression of fear. However, unless she was reminded to do so, she soon stopped looking at eyes, and her ability to recognize a fearful expression disappeared again. PERCIEPTION OF DIRECTION OF GAZE Perrett and his colleagues (1992) discovered an interesting brain function that may be related to recognition of emotional expression. They found that neurons in the monkey's superior temporal sulcus (STS) are involved in recognition of the direction of another monk1~y's gaze-or even that of a human. They found that some neurons in this region responded when the monkey looked at photographs of a monkey's face or a human face but only when the gaze of the face in the photograph was oriented in a particular direction. For example, Figure 11.27 shows the activity level of a neuron that responded when a human face was looking upward. Why is gaze important in recognition of emotions? First, it is important to know whether an emotional expression is directed toward you or toward someone else. For example, an angry expression directed toward you means something very different from a similar expression directt~d toward s omeone else. And if someone else shows signs of fear, the expression can serve as a useful warning, but only if you can figure out what the person is looking at. In fact, Adams and Kleck (2005) found that people more readily recognized anger if the eyes of another person were directed toward the observer and fear if they were directed somewhere else. As Blair (2008) notes, an angry expression directed toward the observer means that the other person wants the observer to stop what he or she is doing. The neoco1rtex that lines the STS seems to provide such information. Lesions there disrupt monkeys' ability to discriminate tthe direction of another animal's gaze, but they do not impair the monkeys' ability to recognize other animals' faces (Campbell et al., 1990; Heywood & Cowey, 1992). As we saw in Chapter 6, the posterior parietal cortex-the endpoint of the dorsal stream of visual analysis-is concerned with perceiving the location of objects in space.

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Chapter 11

Figure 11.27

A Gaze Direction Cell

The graph shows the responses of a single neuron in the cortex lining in the superior temporal sulcus of a monkey's brain. The cell fired most vigorously when the monkey was presented a photograph of a face looking upward. Source: Based on Perrett, D. I., Harries, M. H., Mistlin, A. J., et al. (1992). Social signals analyzed at the single cell level: Someone is looking at me, something touched me, something moved. International Journal of

Comparative Psychology, 4,

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A functional-imaging study by Pelphrey and colleagues (2003) had people watch an animated cartoon of a face. When the direction of gaze changed, increased activity was seen in the right STS and posterior parietal cortex. Presumably, the connections between neurons in the STS and the parietal cortex enable the orientation of another person's gaze to direct one's attention to a particular location in space. Adolphs and colleagues (2000) discovered a possible link between somatosensation and emotional recognition. They compiled computerized information about the locations of brain damage in 108 patients with localized brain lesions and correlated this information with the patients' ability to recognize and identify facial expressions of emotions. They found that the most severe damage to thjs ability was caused by damage to the somatosensory cortex of the right hemisphere. (See Figure 11.28.) They suggest that when we see a facial expression of an emotion, we unconsciously imagine ourselves making that expression. Often, we do more than imagine making the expressions-we actually imitate what we see. Adolphs and colleagues suggest that the somatosensory representation of what it feels like to make the perceived expression provides cues we use to recognize the emotion being expressed in the face we are viewing. In support of this hypothesis, Adolphs and his colleagues report that the ability of patients with right hemisphere lesions to recognize facial expressions of emotions is correlated with their ability to perceive somatosensory stimuli. That is, patients with somatosensory impairments (caused by right-hemisphere lesions) also had impairments in recognition of emotions.

Figure 11.2'.8 Brain Damage and Recognition of Facial Expmssions of Emotion This computer-generated image shows performance of participants with localized brain damage on recognition of facial expressions of emotion. The collored areas outline the site of the lesions. Lesions that resu lted in g1ood performance are shown in shades of blue; those that result1~d in poor performance are shown in red and yellow. Source: From Adol1Phs, R., Damasio, H., Tranel, D., Cooper, G., and Damasio, A. R. (2000). A role for somatosensory cortices in the visual recognition of emotion as revealed by three-dimensional lesion mapping. The Journal of Neuroscience, 20, :2683-2690.

Right heimisphere

Left hemisphere

Hussey and Safford (2009) reviewed a considerable amount of evidence that supports this hypothesis (the so-called! simulationist hypothesis). For example, neuroimaging studies have shown that brain regions that are activated when particular emotional expressions are observed are also activated when these expressions are imitated. In addition, a study by Pitcher and colleagues (2008) used transcranial magnetic stimulation to disrupt the normal aoctivity of brain regions involved in visual perception o:f faces or perception of somatosensory feedback from one's own face. They found that disruption of either region impaired people's ability to recognize

Emotion

facial expressions of emotion. Finally, a study by Oberman and colleagues (2007) had people hold a pen between their teeth, which interfered with smiling. When they did so, they had difficulty recognizing facial expressions of happiness, but not expressions of d isgust, fear, and sadness, which involve the upper part of the face more than smiling does. We are beginning to understand the neural circuit that provides this form of feedback. Research has found that mirror neurons play an important role in the control of movement (Gallese et al., 1996; Rizzolatti et al., 2001; Rizzolatti & Sinigaglia, 2010). Mirror neurons are activated when an animal performs a particular behavior or when it sees another animal performing that behavior. Presumably, these neurons are involved in learning to imitate the actions of others. These neurons, which are located in the ventral premotor cortex of the frontal lobe, receive input from the superior temporal sukus and the posterior parietal cortex. This circuit is activated when we see another person perform a goal-directed action, and feedback from this activity helps us to understand what the person is trying to accomplish. Carr and colleagues (2003) suggest that the mirror neuron system, which is activated when we observe facial movements of other people, provides feedback that helps us to understand how other people feel. In other words, the mirror neuron system may be involved in our ability to empathize with the emotions of other people. A neurological disorder known as Moebius syndrome provides further support for this hypothesis. Moebius syndrome is caused by defective development of nerves involved in the movement of facial muscles. Because of this paralysis, people affected with this syndrome cannot make facial expressions of emotion. In addition, they have difficulty recognizing the emotional expressions of other people (Cole, 2001). Perhaps their inability to produce facial expressions of emotions makes it impossible for them to imitate the expressions of other people, and the lack of internal feedback from the motor system to the somatosensory cortex may make the task of recognition more difficul t. In Chapter 8 you read about research on audiovisual neurons-neurons that respond to the sounds of particular actions and to the sight of those actions. Warren and colleagues (2006) obtained evidence that audiovisual neurons play a role in communication of emotions, too. The investigators asked volunteers to make emotional sounds in response to written scenarios that presented situations expected to evoke triumph, amusement, fear, and disgust. The volunteers were asked not to make verbal responses such as "yuck" or "yippee" but to restrict themselves to nonverbal vocal responses. These sounds were presented to participants while they underwent fMRI scanning. The scans showed that hearing the emotional vocalizations activated the same regions of the brain that were activated by facial expressions of these emotions. When we hear other people make nonverbal emotional sounds, our mirror

351

neurom system is activated, and the feedback from this activatio•n may contribute to our recognition of the emotions being expressed by these sounds. PERCIEIVING DISGUST Several studies have found that

damage to the insular cortex and basal ganglia impair people's ability to recognize facial expressions of a very specific emotion: disgust (Calder et al., 2000; Sprengelmeyer et al., 1996; Sprengelmeyer et al., 1997). In addition, a functional-imaging study by Wicker and colleagues (2003) found that both smelling a disgusting odor and seeing a face of a person showing an expression of disgust activate the insular cortex. Disgust is an emotion provoked by something that tastes or smells bad- or by an action that we consider to be in bad taste. Disgust produces a very characteristic facial expression. As we saw in Chapter 7, the in:sula contains the primary gustatory cortex, so perhaps it is not a coincidence that this region is also involved in recognition of "bad taste." A functional-imaging study by Thielscher and Pessoa (2007) asked participants to press one of two levers to indicate whether the facial expression they saw was one of d isgust or fear. The expressions varied in intensity, and one of them was actually neutral, indicating neither disgust nor fear. Nevertheless, the participants were asked to press one of the levers on every trial, indicating disgust or fear. When the pairticipants saw faces expressing disgust, the insular cortex and part of the basal ganglia were activated. What was particularly interesting was that even when the participants were watching a neutral expression, if they pressed the "disgust" lever, the "disgust" regions of the brain were activated. The results of an online survey presented on the British Broadcasting Corporation Science website suggest that the emotion of disgust has its origins in avoidance of disease. The survey presented pairs of photos and asked people to indicate which photos were more disgusting. The people who responded indicated that the one that appeared to hold a potential threat of disease was more disgusting. For example, a yellow liquid that has soaked a tissue looks more like a body fluid than a blue liquid does. (See Figure 11.29.)

Neural Basis of the Communication of Emotions: Expression LO 11.13

Summarize the neural basis of emotional expression, including laterality, laughter, and humor.

We saw in the previous submodule that the amygdala is involved in the recognition of other people's facial expression of emotions. Research indicates that it is not involved in the expression of facial emotions, as shown in the following case.

352 Chapter 11

Figure 11.29

Disease and Disgust

The figure shows pairs of photographs with high and low relation to the threat of disease used in the online survey presented on the BBC Science website. The numbers in red or green indicate the mean ratings (range of 1 [least disgusting] to 5 (most disgusting]) made by people who completed the survey. Source: From Curtis, V., Aunger, R. , and Rabie, T. (2004). Evidence that disgust evolved to protect from risk of disease. Biology Letters, 271, S131-S133.

fact, she couldn't even identify it in herself. When she saw a photograph of herself showing fear, she could not tell what emotion her face had been expressing. However, she had no difficulty recognizing individual faces, and she could easily identify male and female faces and accurately judge their ages. What is particularly interesting is that the amygdala lesions d id not impair S. P.'s ability to produce her own facial expressions of fear. She had no difficulty accurately expressing fear, anger, happiness, sadness, disgust, and surprise. She coulld express emotion, but not recognize it. Facial exp:ressions of emotion are automatic and involuntary (although. they can be modified by display rules). It is not easy to produce a realistic facial expression of emotion when we do not really feel that way. In fact, Ekman and Davidson have confirmed an early observation by a nineteenthcentury neurologist, Guillaume-Benjamin Duchenne de Boulogne, thatt genuinely happy smiles, as opposed to false smiles or social smiles people make when they greet someone else, involve contraction of a muscle near the eyes, the lateral part of the orbicularis oculi-now sometimes referred to as Duchenne's muscle (Ekman, 1992; Ekman & Davidson, 1993). As Duo:henne put it, "The first [zygomatic major muscle] obeys the will but the second [orbicularis oculi] is only put in phy by the sweet emotions of the soul; the ... fake joy, the deceitful laugh, cannot provoke the contraction of this latter muscle" (Duchenne, 1862/1990, p. 72). (See Figure 11.30.) The difficulty actors have in voluntarily producing a convincing facial expression of emotion is one of the reasons that led Constantin Stanislavsky to develop his

Figure 11.3:0

An Artificial Smile

The photograph shows Dr. Duchenne electrically stimulating muscles in the face of a volunteer, causing contraction of muscles around the mouth that become active during a smile. As Duchenne discovered, however, a true gmile also involves muscles around the eyes.

Disease irrelevant

Disease relevant

Anderson and Phelps (2000) reported the case of S. P., a 54-year-old woman whose right amygdala was removed to treat a serious seizure disorder. Because of a preexisting lesion of the left amygdala, the surgery resulted in a bilateral amygdalectomy. After the surgery, S. P. lost the ability to recognize facial expressions of fear. In

Emotion

system of method acting, in which actors attempt to imagine themselves in a situation that would lead to the desired emotion. Once the emotion is evoked, the facial expressions follow naturally (Stanislavsky, 1936). This observation is confirmed by two neurological disorders with complementary symptoms (Hopf et al., 1992; Michel et al., 2008; Topper et al., 1995; Urban et al., 1998). The first, volitional facial paresis, is caused by damage to the face region of the primary motor cortex or to the fibers connecting this region with the motor nucleus of the facial nerve, which controls the muscles responsible for movement of the facial muscles. (Paresis, from the Greek "to let go," refers to a partial paralysis.) The interesting thing about volitional facial paresis is that the patient cannot voluntarily move the facial muscles but will express a genuine emotion with those muscles. For example, Figure ll.3la shows a woman trying to pull her lips apart and show her teeth. Because of the lesion in the face region of her right primary motor cortex, she could not move the left side of her face. However, when she laughed (Figure 11.31b), both sides of her face moved normally.

Figure 11.31

Emotional and Vo liti onal Pa resis

(a) A woman with volitional facial paresis caused by a right hemisphere lesion tries to pull her lips apart and show her teeth. Only the right side of her face responds. (b) The same woman shows a genuine smile. (c) A man with emotional facial paresis caused by a left-hemisphere lesion shows his teeth. (d) The same man is smiling. Only the left side of his face responds. Source: From Hopf, H. C., Mueller-Fore!!, W., and Hopf, N. J., Neurology, 1992, 42, 1918-1923.

(a)

(b)

(c)

(d)

353

In contrast, emotional facial paresis is caused by damage to• the insular region of the prefrontal cortex, to the white matter of the frontal lobe, or to parts of the thalamus. This system joins the system responsible for voluntary movements of the facial muscles in the medulla or caudal pons. People w ith this disorder can move their face muscles voluntarily but do not express emotions on the affected side of the face. Figure ll.31c shows a man pulling his lips apart to show his teeth, which he had no trouble doing. Figure ll.3ld shows him smiling; as you can see, only the left side of his mouth is raised. He had a stroke that damaged the white matter of the left frontal lobe. These two syndromes clearly indicate that different brain mechamisms are responsible for voluntary movements of the facia l muscles and automatic, involuntary expression of emotions involving the same muscles. LATERALITY OF EMOTIONAL EXPRESSION As we saw in the previous submodule, the right hemisphere plays a more significant role in recognizing emotions in the voice or facial expressions of other people-especially negative emotions. The same hemispheric specialization appears to be true for expressing emotions. When people show emotions with their facial muscles, the left side of the face usually makes a more intense expression. For example, Sackeim and Gur (1978) cut p hotographs of people who were expressing emotions into right and left halves, prepared mirror images of each of them, and pasted them together, producing so-called chimerical faces (from the mythical Chimera, a fire-breathing monster, part goat, part lion, and part serpent). They found that th.e left halves were more expressive than the right ones. Because motor control is contralateral, the results suggest that th.e right hemisphere is more expressive than the left. Moscovitch and Olds (1982) made more natural observations of people in restaurants and parks and found that the left side of their faces appeared to make stronger expressions of emotions. They confirmed these results in the laboratory by analyzing videotapes of people telling sad or humorous stories. A review of the literature by Borod and colleagues (1998) found dozens of other studies that obtain.e d similar results. Left hemisphere lesions do not usually impair vocal expressions of emotion. For example, people with Wernkke's aphasia (described in Chapter 13) usually modulate their voice according to mood, even though the words. they say make no sense. In contrast, right hemisphern lesions do impair expression of emotion, both facially .and by tone of voice. Using the chimerical faces technique, Hauser (1993) found that rhesus monkeys, like humans, express emotions more s trongly in the left sides of their faces. Analysis of videotapes further showed that emotional expressions also begin sooner in the left side of the face. These findings suggest that hemispherical specialization for emotional expression a1ppeared before the emergence of our own species.

354 Chapter 11

Figure 11.32 Humor and Violation of Social Norms The graph shows the activation of the right ventromedial prefrontal icortex and the left orbitofrontal cortex, as measured by fMRI, by exposure to humorous cartoons with increasing funniness and increasing violati on of social norms. vmPFC = ventromedial prefrontal cortex, OFC = orbital frontal cortex Source: Based on data from Goel, V., and Dolan, R. J. (2007). Social regulatic•n of affective experience of humor. Journal of Cognitive Neuroscience, 19, 1574- 1580.

6

vmPFC

3 4

2

c

c

0

~

> u 25

Obese

>30

Altogether her body mass index was reduced to 35, along with a dramatic recluction in the volume of visceral and subcutaneous adipose tissue (see Figure 12.24; Bli..iher et al., 2013). This weight loss had important health implications for A J. Following surgery, previously elevated measures of liver enzymes (indicative of poor liver function) and insulin resistance (a predictor of developing type II diabetes) returned to within normal ranges.

The case study of A. J. highlights the current challenges we face in overcoming obesity. Effectively treating obesity is difficult, despite the availability of many different interventions. For some individuals, strict regulation of diet and a rigorous exercise program is effective, but often it is not. For other individuals, gastric surgery (such as A. J.'s sleeve gastrectomy, or the Roux-en-Y gastric bypass that you will read about later in the chapter) is an effective treabment, but these surgeries are not guaranteed to work either. The challenges presented by obesity are complex, and we will look more closely at the factors that lead to obesity and that also might prove effective in combating it. Gastric surgic.al procedures, for example, don't just change the amount of food consumed, they also impact hunger and satiety siignals in the hypothalamus. Patients have reported reduced feelings of hunger, fewer food cravings (Rieber et al., 2013), and reduced ghrelin and leptin levels (Yousseif et al., 2014) following sleeve gastrectomy.

Reduction in Adipose Tissue 24 Months After Gastric Surg·ery

This cross section of A. J.'s waist using an imaging technique shows the reduction in adipose tissue surrounding her organs (in red) and in subcutaneous adipose tissue (blue) before gastric surgery (Pre-OP) and at 6-, 12-, and 24-month follow-up time points. Source: Based on Bluher, S., Raschpichler, M., Hirsch, W., and Till, H. (2013). A case report and review of the literature of laparoscopic sleeve gastrectomy in morbidly obese adolescents: Beyond metabolic surgery and visceral fat reduction. Metabolism, 62(6), 761-767.

Pre-OP

6 months

1:2 months

24 months

Ingestive Behavior

Possible Causes

389

In. a longitudinal study of college students across seven

semes ters, Small and colleagues (2013) found that students reduced their intake of fruits and vegetables and the number of days that they engaged in vigorous physical activity from their first to their fourth year of college. Students living off campus were the least likely to consume fruits and vegetables and to engage in vigorous exercise. In contrast, students conswned fewer sugar-sweetened beverages over time. On a broader scale, some parts of the U.S. are considered food deserts, or areas where fresh fruits, vegetables, whole grains, an d other staples of a healthy diet are not readily available, and there may be few, if any, grocery stores or markets. The absence of healthy food options in these .areas can contribute to reliance upon cheap, highly processed foods from convenience stores or fast-food chains:, adding to a host of health problems, including rising obesity rates (Walker et al., 2010). 1

LO 12.21 Compare the roles of environment, physical

activity, and genetics in obesity. What causes obesity? Genetic differences-and their effects on development of the endocrine system and brain mechanisms that control food intake and metabolism-appear to be responsible for the majority of cases of extreme obesity. But, as we just saw, obesity rates have been rising dramatically over recent decades. Rapid changes in the gene pool are unlikely to account for the majority of this overall increase in weight gain throughout the world's population. Environmental changes (which occur more quickly than genetic changes in a population) that influence people's behavior are a significant contributing cause. ENVIRONM ENTAL FACTORS Body weight is the result of the difference between two factors: calories consumed and energy expended. If we consume more calories than we expend as heat and work, we gain weight. If we expend more than we consume, we lose weight. In many societies, inexpensive, convenient, good-tasting, high-calorie food is readily available, which promotes an increase in intake. Fast-food restaurants are close at hand, parking is convenient (or even unnecessary at restaurants with drivethru windows), and portion sizes have increased. People eat out more often than they used to, and often do so at inexpensive fast-food restaurants. Many prepared foods contain high-fructose corn syrup (Bray et al., 2004). Fructose, unlike glucose, does not stimulate insulin secretion or enhance leptin production, so this form of sugar is less likely to activate the brain's satiety mechanisms (Teff et al., 2004). Different environments can also influence food intake. For example, the transition to college life is often associated with changes in eating and physical activity patterns. Many students are familiar with the idea of the "freshman 5 (or 15)"-gaining 5 pounds (or more) during the first year of college. This phenomenon was partially confirmed in a sample of Canadian college students. Seventy percent of the students in the study gained weight during their 4 years in college, averaging gains of 5.3 ± 4.7 kg (11.7 ± 9.1 lb.). While this weight gain was consistent with expected growth for males and females from 18 to 20 years of age, it is important to note that BMI and percentage body fat also increased in this group. Furthermore, the percent of obese individuals in the sample increased from 18 percent at the beginning of the 4-year study to 31 percent at th e end (Gropper et al., 2012). A study in a sample of American college students revealed that female students gained 1.8 ± 2.9 kg (4.0 ± 6.3 lb.) while male students gained 1.6 ± 3.9 kg (3.5 ± 8.5 lb.). Both groups experienced significantly increased BMI. The significant weight gains in this study all occurred within the first 4 months of college (HolmDenoma et al., 2008).

PHYSllCAL ACTIVITY FACTORS Another modern trend

contributing to the obesity epidemic involves changes in peop l•~'s expenditure of energy. The proportion of people employed in jobs that require a high level of physical activity has decreased considerably, which means that on the average we need less food than previous generations did. Our hunter-gatherer ancestors probably consumed about 3,000 lkcal per day and expended about 1,000 kcal in their everyday activities. People with sedentary occupations in today''s industrialized societies consu me a little less than their ancestors- about 2,400 kcal- but they use only about 300 kcal in physical activity (Booth & Neufer, 2005). We expend energy in two basic ways: through physical activity and through the production of heat. Not all physical activity can be categorized as "exercise." A study by Levine and ct0lleagues (1999) fed nonobese people a diet for 8 weeks that contained 1,000 calories more than they needed to sustain their weight. Approximately 39 percent of the ca loriE~S were converted into fat tissue, and approximately 26 percent went into lean tissue, increased resting metabolic rate, and the energy required to digest the extra food. The rest, approximately 33 percent, went into an increase in involuntary activity: muscle tone, postural changes, and fidgeting. Levine an d his colleagues referred to this phenomenon as "nonexercise activity thermogenesis," or NEAT. The amount of fat tissue that a person gained was inversely related to their level of NEAT. Levine and colleagues (2005) measured NEAT levels in a group of people with sedentary lifestyles that included both lean and moderately obese individuals. The investigators found that the people who were overweight remained seated 2.5 hours per day more than the lean people. More recent work by Levine and colleagues has begun to include recommendations for increasing NEAT to promote physical health and better understand the neural and physiological basis of NEAT behaviors- many of which overlap with the brain

390 Chapter 12 mechanisms of eating regulation described in this chapter (Villablanca et al., 2015) . Recently, some researchers have suggested that work stations and environments can be redesigned to increase NEAT by facilitating standing or walking on a treadmill rather than sitting at a desk. In fact, a 1-year trial in an office that replaced its traditional chair-based desks with treadmill desks revealed that employees engaged in more NEAT, lost weight, and reduced their waist circumference (Keopp et al., 2013). A review of 23 sitting, standing, and treadmill desk use studies suggested some physiological benefits of treadmill desks; however, significant gaps in this area of research make it challenging to make recommendations (MacEwen et al., 2015). GENETIC FACTORS Differences in body weightperhaps reflecting physiological differences in metabolism, activity levels (including NEAT), or appetite-have a strong hereditary basis. Twin studies suggest that between 40 percent and 70 percent of the variability in body fat is due to genetic differences. Twin studies have also found strong genetic effects on the amount of weight that people gain or lose when they are placed on high- or low-calorie diets (Bouchard et al., 1990; Hainer et al., 2001). Heredity appears to affect people's metabolic efficiency. However, until recently, variations in only two genes were found to cause obesity in humans: the gene for the MC4 receptor and the FTO gene (fat mass and obesity related gene), which codes for an enzyme that acts in hypothalamic regions related to energy balance, such as the PVN, and the arcuate nucleus (Olszewski et al., 2009; Willer et al., 2009). A massive study with 145 authors (Willer et al., 2009) discovered six new genetic loci that are associated with BMI. However, these genes are very rare, so none of them can account for the prevalence of obesity in the general population. The high level of heritability of obesity must be explained, then, as the additive effects of a large number of genes, each of which has a small individual effect on BMI. Just as cars differ in their fuel efficiency, so do living organisms, and hereditary factors can affect the level of efficiency. People differ in this form of efficiency. Those with an efficient metabolism have calories left over to deposit in the long-term nutrient reservoir, and these calories accumulate in the form of increased adipose tissue. Researchers have referred to this condition as a "thrifty phenotype." In contrast, people with an inefficient metabolism (a "spendthrift phenotype") can eat large meals without gaining much weight. A fuel-efficient automobile is desirable, but a fuel-efficient body runs the risk of becoming obese-at least in an environment where food is cheap and plen tiful. Why are there genetic differences in metabolic efficiency? As we saw earlier in this chapter, natural selection for mechanisms that helped our ancestors to avoid starvation was much stronger than natural selection for mechanisms that helped them to avoid becoming obese. Perhaps

individual differences in metabolic efficiency reflect the nature of the environment experienced by their ancestors. Perhaps people whose ancestors lived in regions where food was scarce or subject to periods of famine are more likely to have inherited efficient metabolisms. This hypothesis has received support from some epidemiological studies. Ravussin and colleagues (1994) studied two populations of Indigenous Pima people. One group lives in the southwestern United States and the other in northwestern Mexico. Members of the two groups share the same genetic background, speak the same language, and have commont historical traditions. The two groups separated 700-1,00IO years ago and now live under very different environmental conditions. Many Pima in the southwestern United States eat a high-fat American diet and weigh an average of 90 kg 1(198 lb). In contrast, the lifestyle of the Mexican Pima remained largely unchanged until relatively recently. These individuals engaged in subsistence farming and ate a low-fat diet- and weigh an average of 64 kg (141 lb.). The rate of diabetes in the American group was more than five times higher. As members of the Mexican group have begun to have a more modem, sedentary lifestyle and consume more processed foods, rates of obesity have begun to increase (Esparza-Romiero et al., 2015). These findings have been interpreted to demonstrate that genes that promote an efficient metabolism are beneficial in environments in which people expend many calories in daily life and consume foods that are not calorie-dense but that these same genes can pose a liability when people live in an environment where access to physical activilty is limited and more diverse, traditional food options are replaced with high-calorie, low-nutrient items. Leptin As we saw earlier, study of the ob mouse led to the discovery of leptin, the hormone secreted by well-nourished adipose tissue. So far, researchers have found several cases of familial obesity caused by mutations of genes: responsible for production of leptin or the leptin receptor (Farooqi & O'Rahilly, 2005). Treatment of people who aLre leptin-deficient with injections of leptin has dramatic effects on body weight. (See Figure 12.25.) Unfortunately~ leptin has no effect on people who lack leptin receptors. In any case, mutations of the genes for leptin or leptin receptors are very rare, so they do not explain the vast majority of cases of obesity. When leptin was discovered, researchers hoped that this naturally occutrring peptide could be widely used to treat obesity. In fact, a drug company paid a large sum of money for the rights tto develop this compound. However, it turns out that most people who are obese already have a high blood level of lleptin, and increasing this level with injections of the peptide has little or no effect on their food intake. Several investigators have suggested that a fall in blood levels of leptin should be regarded as a hunger signal. Starvation decreases the blood level of leptin, which

Ingestive Behavior

Figure 12.25

391

Hered itary Leptin D eficiency

The photographs show three pati ents with hereditary leptin deficiency before 1(a) and after (b) treatment with leptin for 18 months. The faces of the patients are obscured for privacy. Source: From Licinio, J., Caglayan, S., Ozata, M., et al. (2004). Phenotypic effects of leptin replacement on morbid obesity, d iabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proceedings of the National Acad.e my of Science, USA, 101, 4531-4536.

(a)

removes an inhibitory influence on NPY I AGRP neurons and an excitatory influence on CARTI a -MSH neurons. That is, a low level of leptin increases the release of orexigenic peptides and decreases the release of anorexigenic peptides. And as Flier (1998) suggests, people with a thrifty metabolism should show resistance to a high level of leptin, which would permit weight gain in times of plenty. People with a spendthrift metabolism should not show leptin resistance and should eat less as their level of leptin rises.

Treatment LO 12.22 Evaluate the roles of reinforcement, stress, su rgery, pharmacology, and behavioral in terventions in treating obesity. Obesity is difficult to treat. The enormous financial success of diet books and weight reduction p rograms attests to the challenges people encounter in losing weight. Many programs help people to lose weight initially, but then the weight is quickly regained (Kramer et al., 1989). To better understand the challenges involved in weigh t loss, the following sections will explore the roles of reinforcement, stress, surgery, pharmacology, and behavioral interventions in treating obesity. Evidence suggests that the physiological mechanisms that make it difficult for people to reduce their caloric intake are related to the mechanisms that make it difficult for people to stop taking drugs of abuse. Overeating shares many attributes with compulsive behaviors. For example, although some overweight people who participate in treatment programs succeed in eating less and losing weight, many return to the former behaviors and regain the weight they lost. Similarly, people who succeed in stopping their use of a d rug often

(b)

return to their former behavior and begin using the drug again. In both cases, stress and anxiety can cause reinstatement of the eating or drug taking, apparently by means of similar brain mechanisms (Nair et al., 2009). Both dopamine, which plays an important role in reinforcement, and corticotrophin-releasing hormone (CRH), which plays an important role in stress, are involved in relapse of food- and drug-seeking behavior. Cottone and colleagues (2009) found that rats that had become accustomed to a tasty, high-calorie diet showed signs of withdrawal symptoms, accompanied by increased CRH secretion and increased activation of the central nucleus of the amygdala when their access to the diet was curtailed. In fact, in some ways, changing behaviors associated with a "food addiction" is more difficult than clhanging behaviors associated with substance abuse. It is pos!>ible to stop taking a drug altogether and stay away from people and places associated with obtaining and abusing the drug, but it is not possible to completely stop eating. The extraordinary difficulty in reducing caloric intake for a sustained period of time (often a lifetime) has led to the development of many interventions. The next sections will describe some surgical, pharmacological, and behavioral methods that have been devised to reduce eating behavior to lose weight.

ROLE OF REINFORCEMENT AND STRESS

Surgeons have become in volved in trying to help people w ho are obese lose weight. The procedures they have developed (called bariatric surgen;) are designed to reduce the amount of food that can be eaten during a meal or to interfere with absorption of calories from the intestines. Bariatric surgery has been aiimed at the stomach, the small intestine, or both. One form of bariatric surgery is a special form of gastric bypass called the Roux-en-Y gastric bypass, or RYGB. S URG I CAL I N TERVEN TI ONS

392

Chapter 12

Similar to sleeve gastrectomy (described in A. J.'s case at the beginning of this module), this procedure produces a small pouch in the upper end of the stomach. However, in this procedure, the stomach pouch is attached to a lower portion of the intestine. The effect is to produce a small stomach whose contents enter the jejunum (second portion of the small intestine), bypassing the duodenum (first portion of the small intestine). Digestive enzymes that are secreted into the duodenum pass through the upper intestine and meet up with the meal that has just been received from the stomach pouch. (See Figure 12.26.) The RYGB procedure works well, although it often causes an iron and vitamin 8 12 deficiency, which may be treated by increased intake of these substances. In the United States alone, approximately 200,000 bariatric surgeries are performed each year. Brolin (2002) reported that the average postsurgical loss of excessive weight of obese patients was about 35 percent of their initial weight. Even patients who sustained smaller weight losses showed improved health, including reductions in hypertension and diabetes. A metaanalysis of 147 studies by Maggard and colleagues (2005) reported an average weight loss of 43.5 kg (approximately 95 lb.) 1 year after RYGB surgery and 41.5 kg after 3 years. And although the biological response to starvation is very strong, RYGB surgery does not induce these changes. Instead, after surgery people report that they feel less hungry and their level of exercise increases (Berthoud et al., 2011). Similar to the sleeve gastrectomy, one important reason for the success of the RYGB procedure appears to be that it disrupts the secretion of ghrelin. The procedure also increases blood levels of PYY (Chan et al., 2006; Reinehr et al., 2007).

Figure 12.26

Both of these changes would be expected to decrease food intake: A decrease in ghrelin should reduce hunger, and an increase in PYY should increase satiety. A plausible explanation for the decreased secretion of ghrelin could be disruption of communication between the upper intestine and the stomach; as you will recall, although ghrelin is secreted by the stomach, the upper intestine controls this secretion. Presumably, because the suirgery decreases the speed at which food moves through the small intestine, more PYY is secreted. Another type of intervention for obesity-drug treatment-is the subject of active research programs by the pharmaceutical industry. Possible ways in which drugs could help people lose weight are to suppress appetite and reduce the amount of food they eat, or to prevent some of the food they eat from being digested. PHARMACOLOGICAL INTERVENTION

Some serotonergic agonists suppress eating. However, ;a drug used for this purpose, fenfluramine, was found to have dangerous side effects, including pulmonary hypertension andl damage to the valves of the heart, so the drug was withdrawm from the market in the United States (Blundell & Halford, 1998). Fenfluramine acts by stimulating the release of 5-HT. Another drug, sibutramine, has similar effects on eating, but a studly of people who were taking the drug found increased incidlence of heart attacks and strokes, so this drug, too, was withdrawn from the market (Li & Cheung, 2011). As we mentioned earlier, the fact that marijuana often elicits a craving for highly palatable foods led to the discovery that the endocannabinoids have an orexigenic effect. The drug rirnonabant, which blocks CBI cannabinoid receptors, was found to suppress appetite, produce a Suppress Appntite

Roux-en-Y Gastric Bypass (RYGB)

This procedure reduces the size of the stomach, bypasses the duodenum, and suppresses the secretion of ghrelin. (a) The stomach and small intestine before surgery. (b) The small pouch made from the stomach and the connection to the roux limb of the small intestine (the second part of the small intestine, downstream of the duodenum).

Gall bladder

Gall bladder

Roux limb (50- 100 cm of jejunum) Stomach

Duodenum Jejununn (15-20 cm)

(a)

(b)

Ingestive Behavior

significant weight loss, lower blood levels of triglycerides and insulin, and increase blood levels of HDL ("good" cholesterol), with apparently minimal adverse side effects (Di Marzo & Matias, 2005). However, use of rimonabant was subsequently found to be associated with depressive mood disorders, anxiety, and increased suicide risk, so it is no longer on the market as an antiobesity treatment (Christensen et al., 2007). As we will see in Chapter 19, rimonabant has also been shown to help people stop smoking. Although the drug is not approved for this purpose either, its efficacy suggests that the craving for nicotine, like the craving for food, involves the activity of endocannabinoids in the brain. A compound extracted from the roots of a vine may function to make cells more sensitive to the effects of leptin, and decrease eating behavior. The compound, named Celastrol, was ineffective in ob mice without leptin receptors, but produced weight loss in overweight wildtype mice fed a high-fat diet (Liu et al., 2015). Follow-up research has identified additional leptin-sensitizing compounds that may provide additional obesity treatment strategies (Lee et al., 2016). As we have seen, appetite can be stimulated by activation of NPY, MCH, orexin, and ghrelin receptors, and it can be suppressed by the activation of leptin, CCK, CART, and MC4 receptors. Appetite can also be suppressed by activation of inhibitory presynaptic Y2 autoreceptors by PYY. Most of these orexigenic and anorexigenic chemicals also affect metabolism: Orexigenic chemicals tend to decrease metabolic rate, and anorexigenic chemicals tend to increase it. Do these discoveries hold any promise for the treatment of obesity? Is there any possibility that researchers will find drugs that will stimulate or block these receptors, thus decreasing people's appetite and increasing the rate at which they burn rather than store their calories? Drug companies certainly hope so, and they are working hard on developing medications that will do so. Table 12.4 lists some of the anti-obesity drugs that have been approved-and withdrawn-so far. Some of these drugs are described in the next section of this module. Prevent Digestion Another drug, orlistat, interferes with the absorption of fats by the small intestine. As a result, about a third of the fat in the person's diet passes through the digestive system and is excreted with the feces. Unfortunately, as a result, the drug induces gastrointestinal side effects in 15 percent to 30 percent of users. A double-blind, placebo-controlled study by Hill and colleagues (1999) found that orlistat helped people to maintain weight loss they had achieved by participating in a conventional weight-loss program. People who received the placebo were much more likely to regain the weight they had lost. Treatment with orlistat also reduces the incidence of type II diabetes, and has beneficial effects

393

Table 12.4 Anti-obesity Drugs Approved by the U.S. Food and Drug Administration

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100 kcal per day could prevent weight gain in most people. The effort would require a relatively small change in behavior for most people-about 14 minutes of walking each day. Other behavioral interventions for weight loss include in-person or online health-coaching programs, cognitive behavioral therapies, and incentive programs. The variety of methods-surgical, pharmacological, and behavioral-that therapists and surgeons have developed to treat obesity attests to the tenacity of the problem.

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The basic difficulty, beyond that caused by having an efficient metabolism, is that eating is pleasurable and satiety signals are easy to ignore or override. By learning more about the physiology of hunger signals, satiety signals, and the reinforcement provided by eating, many hope that researchers and clinicians will be able to develop safe and effective interventions that attenuate the signals that encourage us to eat and strengthen those that encourage us to stop eating.

Module Review: Obesity Possible Causes LO 12.21 Comp are the roles of environmen t, physical activity, and gen etics in ob esity.

Environmental factors can affect how many calories are expended through physical exercise and ingested in calorie-dense foods. In many places, inexpensive, convenient, good-tasting, high-calorie food is readily available, which promotes an increase in intake. Reduced physical activity contributes to obesity, alon g with less "nonexercise activity thermogenesis," or NEAT. Interactions between genetic and environmental factors are illustrated by the example of Pima peoples living in the United States and Mexico. A high percentage of Pima who live in the United States and consume a highfat diet become obese and, as a consequence, develop diabetes. In contrast, Pima living in Mexico, who engaged

in subsistence farming and ate a low-fat diet, remained thin, and had a lower incidence of obesity. Obesity is s trongly affected by heredity. Some p eople have inherited a thrifty metabolism, which makes it difficult for them t:o lose weight. One of the manifestations of a thrifty metabolism is a low level of nonexercise activity thermogenesis, or NEAT. Obesity in humans is related to a hereditary absence of leptin or leptin receptors only in a few families. In general, people who are obese have very high levels of leptin in their blood. However, they show resistance to lthe effects of this peptide, apparently because the transport of leptin through the blood-brain barrier is reduced. The most significant simple genetic cause of severe obes:ity is mutation of the gene for the MC4 receptor and the FTO gene. The MC4 receptor responds to the orexigen AGRP and the anorexigen a-MSH, and the FTO gene codes for an enzyme that acts in hypothalamic

Ingestive Behavior

regions involved in energy balance. In addition, mutations that inactivate the genes responsible for the production of leptin or leptin receptors result in obesity.

Treatment LO 12.22 Evaluate th e roles of rein forcement, s tress, surgery, pharmacology, and b eh avioral interventions in treating obesity. Stress and anxiety can cause reinstatement of eating or drug taking, apparently by means of similar brain mechanisms. Both dopamine, which plays an important role in reinforcement, and corticotrophin-releasing hormone (CRH), which plays an important role in stress, are involved in relapse in food and drug seeking behaviors. Researchers have evaluated many behavioral, surgical, and pharmacological treatments for obesity, but no universally successful program has yet been found. The RYGB procedure, a special form of gastric bypass operation, is one

Eating Disorders Eating disorders include anorexia nervosa, bulimia nervosa, and binge eating. Each of these disorders include extreme changes in eating behavior. Individuals with eating disorders are at an increased risk of mortality, particularly those diagnosed with anorexia nervosa (Arcelus et al., 2011). As you read the case of N. B. below, consider the changes to eating behavior that are described, and any possible biological correlates. N. B. was a 17-year-old who spent much of her time thinking about food, controlling her weight through dieting, and comparing nutritional labels. She maintained a low-calorie diet and reported feeling hungry most of the time. She occasionally binged and stole food. When she was 14, she began to diet in response to a period of weight gain. She adopted rigid eating patterns, engaged in compulsive exercise and sought treatment from a mental health professional. At age 16, she was hospitalized due to extremely low body weight. After being discharged, N. B. began restricting her food intake again, as well as stealing food, bingeing, and purging. She was prescribed a drug that was an antagonist at serotonin and norepinephrine receptors but the treatment was ineffective. Finally, N. B. began a cognitive behavioral therapy intervention that reduced the frequency of her bingeing and restricted eating, and she began to gain weight (Martin-Murcia et al., 2011).

The case study of N. B. highlights several important aspects of eating disorders that will be explored in the following module. As you will read, the prevalence of some eating disorders is higher among females, and several eating d isorders include many of the symptoms that N. B. displayed: restricted eating, excessive exercise, eating large

395

form of bariatric surgery. The effectiveness of this operation is probably due primarily to its suppression of ghrelin secretion and stimulation of PYY secretion. Two drugs initially appeared to show some promise in the treatment •of obesity. Fenfluramine, a serotonin agonist, and rimonabant, a cannabinoid antagonist, suppress appetite, but adverse side effects have prevented their use. At present many pharmaceutical companies are trying to apply the results of the discoveries of orexigens and anorexigens described in this chapter to the development of antiobesity drugs. Another drug, orlistat, prevents the absorption of calories from fat.

Thought Question If you had unlimited resources, what strategies would you develop to treat obesity or the associated negative health consequences? Explain who might benefit the most from your intervention and why you selected it.

amow1ts of food in a short period of time (bingeing), and engaging in compulsive exercise or other behaviors such as vorniting to reduce the number of calories consumed (purging). Eating disorders are challenging to treat, and many individuals undergo repeated interventions in an effort to reduce their symptoms. Many eating disorder interventions have a low success rate. While the exact causes of eating disorders are unknown, it is likely that a variety of environmental and genetic elements are contributing factors. The Diagnostic and Statistical Manual of Mental Disord'ers of the American Psychiatric Association (fifth editioin; DSM) groups several related diagnoses together in the category "Feeding and Eating Disorders." These disordlers are characterized by several distinct criteria, includling a persistent pattern of eating behavior that impairs physical health or psychosocial functioning. The DSM does not consider obesity a mental illness at this time. Most people, if they have an eating problem, tend to overeat. However, some people, especially adolescent women, have the opposite problem: They eat too little, even to the point of starvation. This disorder is called anorexia nervosa. Another eating disorder, bulimia nervosa, is characteri2:ed by a loss of control of food intake. People with bulimiia nervosa periodically gorge themselves with food, especi.ally dessert or snack food, and especially in the afternoon or evening. These binges are usually followed by selfinduced vomiting or the use of laxatives, along with feelings of depression and guilt. With this combination of bingeing and purging, the net nutrient intake (and consequently, the body weight) of people with bulimia can vary, though a large proportion eat an overall typical amount of food and

396 Chapter 12

Table 12.5

Criteria for Eating Disorders

Source: Based on American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (DSM-5®). Washington, DC: American Psychiatric Association.

Restricted eating that leads to low body weight

Episodes of binge eating

Episodes of binge eating

Fear of gaining weight

Compensatory behaviors to prevent gaining weiglht that follow binge eating

Distress related to binge eating

Persistent behavior to prevent weight gain

Critical evaluation of body weight or shape

No use of compensatory behaviors

Disturbance in self-perception or failure to perceive seriousness of low body weight

maintain an average body weight (Kaye et al., 2000; Weltzin et al., 1991). Episodes of bulimia are seen in some patients with anorexia nervosa. A third disorder, binge-eating disorder, is characterized by eating a large quantity of food in a relatively short period of time (bingeing) and a loss of control over eating behavior. Unlike bulimia nervosa, binge-eating disorder is not associated with compensatory purging behavior. A lifetime history of binge-eating disorder is associated with obesity. The criteria for diagnosis of three important eating disorders are included in Table 12.5. The incidences of eating disorders are estimated at 0.5 percent to 2 percent for anorexia nervosa, 1 percent to 3 percent for bulimia nervosa, and 2 percent to 7 percent for binge-eating disorder. Women are 10 to 20 times more likely than men to develop anorexia nervosa and approximately 10 times more likely to develop bulimia nervosa (see Klein & Walsh, 2004). The lifetime prevalence of binge-eating disorder does not appear to vary between men and women (Hudson et al., 2007). Eating disorders are associated with decreases in health-related quality of life, high rates of hospitalization, and visits to emergency departments. The annual health care costs for eating disorders ranged from approximately $1,000 (approximately €880) to $64,000 (approximately €56,500) per person (Agh et al., 2016). The suicide rate in patients w ith anorexia is higher than that of the rest of the population (Pompili et al., 2004).

Possible Causes LO 12.23 Compare the roles of brain chan ges, starvation, excessive exercise, and genetic factors in eating disorders. The literal meaning of the word anorexia suggests a loss of appetite, but people with this disorder are usually interested in-even preoccupied with- food. They may enjoy preparing meals for others to consume, collect recipes, and even hoard food that they do not eat. Although people with anorexia are very interested in food, they express an intense fear of becoming obese, which continues even if they become dangerously thin. Many exercise by cycling, running, or almost constant walking and pacing.

BRAIN CHANGES Anorexia is associated with loss of gray and white matter in the brain (Seitz et al., 2016). Some reports demonstrate the presence of enlarged ventricles and widened sulci in tlhe brains of patients with anorexia, which indicate shrinkage of brain tissue (Artmann et al., 1985; Golden et al., 1996; Herholz, 1996; Katzman et al., 2001; Kingston et al., 1996). Some research suggests that this tissue loss can be reversed wiith successful treatment of the eating disorder (Golden et al., 1996; Seitz et al., 2016). (See Figure 12.28.) STARVATION Many researchers and clinicians have concluded that anorexia nervosa and bulimia nervosa are symptoms of an underlying mental d isorder. However, some evidence sugg;ests just the opposite: that the symptoms of eating disorde~rs are actually symptoms of starvation. A famous study carried out at the University of Minnesota by Ancel Keys artd his colleagues (Keys et al., 1950) recruited 36 physically amd psychologically healthy young men to observe the effects of semistarvation. For 6 months, the men ate approximately 50 percent of what they had been eating previously and, as a result, lost approximately 25 percent of their original body weight. As the volunteers lost weight, they began displaying disturbing symptoms, including preoccupation with food and eating, ritualistic eating, erratic mood, impaired cognitive performance, and physiological changes such as decrea1sed body temperature. They began hoarding food and nonfood objects and were unable to explain (even to themselves} why they bothered to accumulate objects for which they had no use. At first, they were gregarious, but as time went on, they became withdrawn and isolated. These men were not diagnosed with eating disorders, yet, once they lbegan to experience starvation, they displayed many of the symptoms that are commonly associated with eating disorde:rs. This has been interpreted as support for the claim that the symptoms of eating disorders arise from starvation rather tlnan an underlying mental disorder. The obsessions with food and weight loss and the compulsive rituals tlhat people witlh anorexia nervosa develop suggest a possible linkage with obsessive-compulsive disorder (described in more detail in Chapter 17). However, the fact that these obsessions and compulsions were seen in the men of the Minnesota study-none of whom showed these symptoms previously-suggests that they are effects rather than causes

Ingestive Behavior

Figure 12.28

397

Brain Comparison of Individuals with Anorexia

(a) Patient w ith anorexia nervosa, showing enlarged sulci (yellow circle), tl1ird ventricle (red circle), and lateral ventricle (green circle). (b) Healthy control patient showing typical anatomy in same regions. Source: Based on Golden, N. H., Ashtari, M., Kohn, M. R., Patel, M., Jacobson, M. S., Fletcher, A., and Shenker, I. R. (1996). Reversibility of cerebral ventricular enlargement in anorexia nervosa, demonstrated by quantitative magnetic resonance imaging, Journal of Pediatrics, 128(2), 296-301.

(a)

of the eating disorder. Both anorexia and semistarvation include symptoms such as mood swings, depression, and insomnia. Even hair loss is seen in both conditions. Although binge eating is a symptom of anorexia, eating very slowly is, too. Patients with anorexia tend to linger over a meal, and so did the volunteers in the Minnesota study. "Toward the end of starvation some of the men would dawdle for almost two hours over a meal which previously they would have consumed in a matter of minutes" (Keys et al., 1950, p. 833). EXCESSIVE EXERCISE As we saw, excessive exercising is a prominent symptom of anorexia (Zandian et al., 2007). In fact, Manley and colleagues (2008) reported that many fitness instructors recognize that some of their clients may have an eating disorder and have expressed concern about ethical or liability issues in permitting such clients to participate in their classes or facilities. Studies with animals suggest that the increased activity may actually be a result of the fasting. When rats are allowed access to food for 1 hour each day, they will spend more and more time running in a wheel if one is available and will lose weight and eventually die of emaciation (Smith, 1989). One explanation for the increased activity of rats on a semistarvation diet is that it reflects an innate tendency to seek food when it becomes scarce. Normally, hungry rats would extend their activity by exploring the environment and searching for food, but because of their confinement the tendency to explore is expressed through wheel running. The fact that starving rats increase their activity suggests that the excessive activity of patients with anorexia may be a symptom of starvation, not a weight-loss strategy. Blood levels of NPY are elevated in patients with anorexia. Nergfudh and colleagues (2007) found that infusion

(b)

of NPY into the cerebral ventricles further increased the time spent running in rats on a restricted feeding schedule. Norm.ally, NPY stimulates eating (as it does in rats with unlimited access to food), but under conditions of starvation it stimulates wheel-running activity instead. The likely explanation for this phenomenon is that, if food is not present, NPY increases the animals' activity level, which would normally increase the likelihood that they would find food. Increased levels of NPY may also play a role in the obsession with food that is often seen in patients with anorexia. G EN ETIC FACT O RS By now, you may be wondering w!hy anorexia develops in the first place. Even if the sympltoms of anorexia are largely those of s tarvation, what :initiates the behavior that leads to starvation? The simple answer is that we still do not know. One possibility is a genetic predisposition for this behavior. There is good 1evidence, primarily from twin studies, that hereditary factors play an important role in the development of anorexia nervosa (Kortegaard et al., 2001; Russell & Treasure, 1989; Walters & Kendler, 1995). Jn fact, between 58 percent and 76 percent of the variability in the occurrence of anorexia nervosa appears to be under control of genetic factors (Klein & Walsh, 2004). In addition, the incidence of anorexia nervosa is higher in girls who were born prematurely or who sustained birth trauma during compllicated deliveries (Cnattingius et al., 1999), which suggests that biological factors independent of heredity may play a role. Perhaps some young women (and a small number of young men) go on a diet to bring their body weight closer to what they perceive as ideal. Once they get set on this course and begin losing weight, physiological and endocrinological changes bring about the symptoms

398 Chapter 12

Figure 12.29

Reactions of Young Men and Women t10 Fasting

The graph shows food intake and eating rate during a buffet lunch after a 24-hour period of fasting or after a period during which they ate meals at their normal times. Source: Data from Sodersten, P., Bergh, C., and Zandian, M. (2006). Undemtanding eating d isorders. Hormones and Behavior, 50, 572-578.

58

600 ~ Not food deprived

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400

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48

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of starvation previously outlined, and the vicious cycle begins. In fact, at the end of the Minnesota semistarvation study when the volunteers were permitted to eat normally again, Keys and his colleagues found that a few volunteers displayed symptoms of anorexia, engaging in dieting behavior and complaining about the fat in their abdomens and thighs (Keys et al., 1950). This phenomenon suggests that strongly restricted access to food may contribute to inducing anorexia in people (men, in this case) with a predisposition to this disorder. The fact that anorexia nervosa is seen primarily in young women has prompted both biological and social explanations. Most psychologists favor the latter, concluding that the emphasis that most modern industrialized societies places on slimness-especially in women-is responsible for this disorder. Another possible cause could be the changes in hormones that accompany puberty. Whatever the cause, young men and women differ in their response to even a short period of fasting. Sodersten and colleagues (2006) had high school students visit their laboratory at noon one day, where they were given all the food they wanted to eat for lunch. Seven days later, they returned to the laboratory again. This time, they had been fasting since lunch on the previous day. The men ate more food than they had the first time. However, the women actua!Jy ate less than they had before. (See Figure 12.29.) Apparently, at least under some circumstances, women may not compensate for a period of food deprivation by eating more food.

Treatment LO 12.24 List s tra tegies used in eating disorder intervention s.

Eating disorders are very difficult to treat successfully. As illustrated in the case of N. B., many patients undergo

W1Jmen

Men

repeated rounds of treatment, including hospitalization. Eating disorder treatment strategies include a variety of cognitive behavioral therapies, pharmacological therapies, and some novel alternative therapies. COGNITIVE BEHAVIO RAL THERAPY Cognitive behavioral theraipy, considered by many clinicians to be the most effective approach to treating eating disorders, has a success rate of less than 50 percent and a relapse rate of 22 percent dming a 1-year treatment period (Pike et al., 2003). Cognitive behavioral therapy may be more effective than other psychotherapies in treating symptoms of bulimia in particular (Hofmann et al., 2012; Linardon et al., 2017). PHARMACOLOGY Researchers have tried to treat anorexia nervosa with many drugs that increase appetite in laboratory animals or in people without eating disorders-fo:r example, antipsychotic medications, drugs that stimulate adrenergic a2 receptors, I-DOPA, and THC. Unfortunately, these drugs have been largely unhelpful in treating anorexia nervosa (Mitchell, 1989). The fact that people with anorexia are usually obsessed with food (and show high levels of neuropeptide Y and ghrelin) suggests that the disorder is not caused by the absence of hunger. Researchers have had more success treating bulimia nervosa; several studies suggest that serotonin agonists such as fluoxetine (an SSRI antidepressant drug) may aid in the treatment of this disorder (Advokat & Kutlesic, 1995; Kaye

et al., 2001). However, fluoxetine does not help patients with anorexia (Attia et al., 1998). The drug lisdexamfetamine (LOX) may be useful for treating binge-eating disorder. LOX is an amphetamine that reduces binge eating (McElroy et al., 2016) and relapse in binge-eating disorder (Hudson et al.., 2017; for review, see Heo & Duggan, 2017), as well as changes brain activation associated with palatable food cues (Fleck et al., 2019).

Ingestive Behavior 399

ALTERNATIVE THERAPIES Bergh, Sodersten, and their colleagues (Court et al., 2008; Zandian et al., 2007) have

devised a novel treatment protocol for anorexia. The patients are taught to eat faster by placing a plate of food on an electronic scale attached to a computer that displays the time course of their actual and ideal intake. After the meal, the patients are kept in a warm room, which reduces their anxiety and their activity level. Remarkably, this treatment strategy has resulted in a 75 percent success rate, with a 10 percent relapse rate after treatment and 0 percent mortality. The remaining 15 percent of patients did not complete the treatment for various reasons (e.g., lack of insurance coverage; Bergh et al., 2013). Future research investigating this strategy and replicating these results could provide strong evidence for this approach to treating eating d isorders. Another line of research has investigated the efficacy of deep brain stimulation of the cingulate cortex. One year

of cingulate stimulation produced improvements in mood, BMI, and neural circuitry in individuals diagnosed with anorexia nervosa that had not responded to previous treatment attempts (Lipsman et al., 2017). Other researchers are investigating the effects of oxytocin administration on reducing the distress caused by eating in individuals with anorexia nervosa. Among individuals diagnosed with anorexia nervosa receiving treatment in a hospital, Russell and colleagues (2018) reported some reductions in eating disorder symptoms as well as lower baseline cortisol concentrations in response to a stressful situation (consuming a high-calorie snack) after 4 weeks of treatment with oxytocin. Eating disorders are serious conditions; understanding their causes is more than an academic matter. We can hope 1that research on the biological and social control of eating and metabolism and the causes of compulsive behaviors will help us to understand these disorders.

Module Review: Eating Disorders Possible Causes LO 12.23 Compare the roles of brain changes, starvation, excessive exercise, and genetic factors in eating disorders.

Eating disorders are associated with enlarged ventricles and reduced brain volume. Some research suggests that preoccupation with food and eating, ritualistic eating, erratic mood, excessive exercising, impaired cognitive performance, and physiological changes such as decreased body temperature are symptoms of starvation and not the underlying causes of anorexia. Birth complications are associated with eating disorders. Twin studies supp ort a role for heredity in eating disorders.

alternative therapies. The success rates for most eating disorder treatments are low; however, some alternative therapies have shown higher success rates.

Thought Question Anorexia has both environmental and physiological contributing factors. After reading the last module of this chapter, wh at do you think is the cause of the sex difference in the incidence of this d isorder (that is, the fact that the majority of people with anorexia are female)? Is it caused entirely by social factors (such as the emphasis on thinness in societies), biological factors, or does the combination p lay a significant role?

Treatment LO 12.24 List strategies used in eating disorder interventions.

Interventions for eating disorders include cognitive behavioral therapy, p harmacological treatments, and

Chapter Review Questions 1. Explain the characteristics of a regulatory mechanism.

2. Describe the fluid compartments of the body, and explain the control of osmometric and volumetric thirst. 3. Discuss the neural control of thirst. 4. Describe the characteristics of the short- and longterm reservoirs and the absorptive and fasting phases of metabolism. 5. Discuss social and environmental factors and hunger signals that are responsible for starting a meal. 6. Discuss the factors responsible for stopping a meal.

7. Describe research on the role of the brain stem and hypothalamus in hunger. 8. Describe research on the role of the hypothalamus in satiety. 9. Discuss the factors that may contribute to obesity. 10. Discuss some surgical, pharmacological, and behavioral treatments of obesity. 11. Discuss the physiological factors that may contribute to eating disorders.

Chapter 13

Learning and Memory

This stained section of hippocampal tissue shows glial cells (cyan), neurofilaments (green), and DNA (yellow).

Chapter Outline Overview of Learning and Memory

Types of Learning Types of Memory Stimulus-Response Learning

Classical Conditioning Operant Conditioning Motor Learning Role of the Cortex

Role of the Basal Ganglia Perceptual Leaming Role of the Cortex

Retaining Perceptual Information in Short-Term Memory

Relationatl Learning Role of the Hippocampus

Role of the Cortex Amnesia Role of the Hippocampus

Stimulus-Response Learning Motor Learning Perceptual Learning Relational Learning Long-Term Potentiation Induction of Long-Term Potentiation

Role of NMDA Receptors Role of AJMPA Receptors Role of Synaptic Changes

400

Learning and Memory 401

-

LO 13.1

LO 13.2

LO 13.3

Learning Objectives Compare characteristics of stimulusresponse, motor, perceptual, and relational learning. Contrast characteristics of sensory, short-term, and long-term memory. Describe the roles of the amygdala, AMPA receptors, and NMDA receptors in classical conditioning.

LO 131.10

Describe the role of the cortex in semantic memory.

LO 131.11

Compare the role of the hippocampus in memory consolidation and retrieval.

LO 131.12

Describe the stimulus-response learning ability of patients with hippocampal damage.

LO 131.13

Describe the motor learning ability of patients with hippocampal damage.

LO 13.4

Outline the neural mechanisms of operant conditioning.

LO 131.14

Describe the perceptual learning ability of patients with hippocampal damage.

LO 13.5

List the contributions of various cortical regions to motor learning.

LO 131.15

Describe the role of the hippocampus in relational learning.

LO 13.6

Explain the role of the basal ganglia in motor learning.

LO 131.16

Identify the events required for LTP to occur.

LO 13.7

Explain the roles of cortical regions in perceptual learning.

LO 131.17

Compare the relationship between NMDA and AMPA receptors in LTP.

LO 13.8

Contrast the roles of cortical regions in retaining perceptual information in short-term memory.

LO 131.18

Describe how AMPA receptors contribute to LTP.

LO 13.9

Describe the role of the hippocampus in relational learning.

LO 131.19

List the synaptic changes that accompany LTP.

H. M. initially appeared to have surprisingly few symptoms following surgery to remove part of his temporal lobes in an effort to control severe seizures. Figure 13.1 depicts the t issue that was removed in the surgery. H. M. had been experiencing severe seizures for many years, and they d id not respond

he could recall older memories very well. He showed no personchange after the operation, and he was generally polite and good-natured. However, after his surgery, H. M. was unable to learn new facts. He did not know the names of people he had met since

to medications. He opted for a surgery to remove tissue from the temporal lobes responsible for triggering the seizures. The goal of the surgery was to remove the tissue and reduce the seizures. The surgery was successful in reducing his seizures, and his intellectual ability and his immediate verbal memory were intact after the operation. He could repeat seven numbers forward and five numbers backward, and he could carry on conversations, rephrase sentences, and perform mental arithmetic. When he was tested on tasks of motor learning, such as tracing a shape in a mirror, following a target, or tapping his fingers, he improved with practice. He was unable to remember events that occurred during several years preceding his brain surgery, but

the operation (performed in 1953, when he was 27 years old). His family moved to a new house after his operation, and he never learned how to navigate the new neighborhood. He was aware of his condition and said:

alit~1

Every day is alone in itself, whatever enjoyment I've had, and whatever sorrow I've had . ... Right now, I'm wondering. Have I done or said anything amiss? You see, at this moment everything looks clear to me, but what happened just before? That's what worries me. It's like waking from a dream; I just don't remember. (Milner, 1970, p. 37)

402

Chapter 13

H. M. could remember a small amount of verbal information as long as he was not distracted. Constant rehearsal could keep information in his immediate memory for a long time. However, rehearsal did not appear to have any long-term effects. If he was distracted for a moment, he would completely forget whatever he had been rehearsing. He could complete repetitive tasks very well. Because he so quickly forgot what previously happened, he did not easily become bored. On December 2, 2008, H. M., whom we now know as Henry Molaison, died at the age of 82. Researchers had the privilege of studying H. M. throughout his life. What they

Figure 13.1

learned from his experience has been instrumental in enhancing our tJLnderstanding of how memories are formed and of the brain regions involved. H. M.'s contributions to the study of learning and memory continue today. His brain has been preserved, and researchers continue to learn from it. (See Figure 13.1.) You'll read more about H. M.'s ongoing contributions to our understanding of learning and memory later in the chapter. Experiences change us. Encounters with our environment alter our behavior by modifying our nervous system. As many investigators have said, an understanding of the

Bilateral Amygdala Damage in Patient H. M.

Note the lesions in H. M.'s temporal lobe and hippocampus that differ from a typical brain.

Typical brain

H. M.'s brain

(a)

(b)

Learning and Memory

403

Figure 13.2 The Steps of Learning and Memory Encoding (learning)

Jll

Consolidation (memory)

physiology and memory is the ultimate challenge to neuroscience research. The brain is complex, and so are learning and remembering. However, despite the difficulties, the long years of research finally seem to be paying off. New approaches and new methods have evolved from old ones, and real progress has been made in understanding the anatomy and physiology of learning and remembering. In this chapter, we will explore how we learn and how we remember. The first module begins with an overview of learning and memory processes. Subsequent modules will focus on types of learning: stimulus-response, motor, perceptual, and relational. Then we will consider impairments to learning and memory before concluding w ith a look at the role of long-term potentiation in forming memories.

Overview of Learning and Memory Learning allows us to acquire new information and refers to the process by which experiences change our nervous system and our behavior. Long-term changes in the nervous system following learning are referred to as memories. Memories persist over time and are formed when something is learned. Experiences shape the way we perceive, perform, think, plan, and behave. Learning something new and creating a memory physically changes the structure of the nervous system, altering neural circuits that participate in perceiving, performing, thinking, planning, and behaving. Learning, memory, and their effects on behavior are only possible through plasticity. As you will read in this chapter, the nervous system demonstrates synaptic plasticity among existing neurons in learning and forming memories. You'll learn more about synaptic plasticity in the final module of the chapter. Exciting new research is also revealing the role of the creation of new neurons (neurogenesis) in learning and memory. The information-processing model of memory provides an overall summary of the basic steps linking learning to memory. In this model, learning produces changes in the nervous system by encoding the new information to be learned. The encoding process includes consolidation, which strengthens changes associated with the initial information that is learned, helping to make a more permanent change to the nervous system (i.e., a memory). After being consolidated, the memory is stored and maintained via these persistent

Storage memory)

Jll

Retrieval (memory)

changes in the nervous system. Finally, retrieval is the process of accessing and using the information stored in the neural chang1~s that make up a memory to engage in a behavior. (See Figure 13.2.)

Types of Learning LO 13.1

Compare characteristics of stimulus-response, motor, perceptual, and relational learning.

Learniing can take at least four basic forms: stimulusresponse learning, motor learning, perceptual learning, and relational learning. We will introduce each of these four types of learning in this module, and return to each of them in greater detail in subsequent modules of the chapter. STIMllJLUS-RESPONSE LEARNING Stimulus-response leamiing is the ability to learn to perform a particular behavior when a particular stimulus is present. Stimulus-response learning establishes connections between circuits involved in perception and those involved in movement. The behavior could be an automatic response such as a defensive reflex, or it could be a complicated sequence of movements. Stimulus-response learning includes two major categories of learning that psychologists have studied extensively: classical conditioning and operant conditioning. Conditioning is a term that refers to learning from exposures to stimuli to produce a lasting change in behavior. Classical Conditioning Classical conditioning is a form of learning in which an unimportant stimulus acquires the properties of an important one. It involves an association between i!wo stimuli. A stimulus that previously had little effect on behavior becomes able to evoke a reflexive, species-typical behaviior. For example, an eyeblink response can be conditioned to a tone. If we direct a brief puff of air toward an eye, the eye will automatically blink. The response is called an unconditioned response (UR) because it occurs without any speciall training. The stimulus that produces it (the puff of air) is calle:d an unconditioned stimulus (US). Now we begin the training. We present a series of brief tones (auditory stimuli), each followed very quickly (500 msec later) by a puff of air. After several trials the eye begins to close in response to the tone, even before the puff of air occurs. We can measure the eyeblink response using EMG electrodes connected to a computer. Classical conditioning has occurred; the conditioned stimulus (CS)-the tone-now elicits the conditioned response (CR)-the eyeblink. (See Figure 13.3.)

404

Chapter 13

Figure 13.3 Classical Conditioning Example In eyeblink conditioning, a puff of air (US) causes the eye to blink (UR). The puff of air is paired with a tone (CS) for several trials. After pairing, the tone alone elicits a blink (CR). Air jet tube

Headgear is arranged for eye··blink conditioning.

Electrode connected to computer with EMG recording software

Puff of air to eye causes eye to blink.

,

I

Audio speaker

'11' After pairing air puff with tone!, tone alone comes to elicit a blink.

When classical conditioning takes place, what kinds of changes occur in the brain? Figure 13.4 shows an example of a neural circuit that could account for this type of learning. To make it simpler, let's assume that the US (the puff of air) is detected by a single neuron in the somatosensory system (the green neuron) and that the CS (the tone) is detected by a single neuron in the auditory system (the purple neuron). We will also assume that the response-the eyeblink- is controlled by a single neuron in the motor system. Leaming actually involves many thousands of neurons-sensory neurons, interneurons, and motor neurons-but the basic principle of synaptic change can be represented by this simple figure. Let's see how this circuit works. If we present a tone, at first, the individual makes no reaction because the synapse connecting the auditory neuron with the neuron in the motor system is weak. However, if we present a puff of air to the eye, the eye blinks. This reaction occurs because nature has provided the individual with a strong synapse between the somatosensory neuron and the motor neuron that causes a blink. To establish classical conditioning, we first present the tone and then quickly follow it with a puff of air. After we repeat these pairs of stimuli several times, the tone produces the blink all by itself (no puff needed), and the synapse between the auditory neuron and the motor neuron is strengthened. Donald Hebb (1949) proposed a rule that might explain how neurons are changed by experience in a way that would cause cha.nges in behavior. The Hebb rule says that if a synapse repeatedly becomes active at about the same time that the postsynaptic neuron fires, changes will take place in the structure or chemistry of the synapse that will strengthen it. How would the Hebb rule apply to our circuit? If the tone is presented first, then the weak auditory synapse becomes active. If the puff is presented immediately afterward, then the strong somatosensory synapse

becomes activ1e and makes the motor neuron fire. The act of firing then strengthens any synapse with the motor neuron that has just been active. In this example, that is the synapse between the auditory and motor neurons. After several pairings of the two stimuli and after several increments of strengthening,. the synapse between the auditory and motor neurons becomes strong enough to cause the motor neuron to fire by itself. Learning has occurred. (See Figure 13.4.) When Hebb formulated his rule, he had no way to determine whether it was correct. Now, finally, enough progress has been made in laboratory techniques that the strength of individual synapses can be determined, and investigators are studying the physiological bases of learning. We will see the results of some of these approaches later in this chapter. Operant Conditioning The second major class of stimulusresponse learning is operant conditioning (also called

Figure 13.4, A Simple Neural Model of Classical Conditioning When the tone is presented just before the puff of air to the eye, the auditory synapso is strengthened.

Neuron in somatosensory system\ Somatosensory synapse (strong) \

Puff of airto - - • the eye

~Bli nk Tone

--•

I

Neuron in auditory system

./

Auditory synapse (weak)

Motor neuron

Learn ing and Memory

consequences (a reinforcing stimulus), the behavior tends to occur more frequently; when it is followed by unfavorablle consequences (a p unish ing stimulus), it tends to occur less frequently. For example, a response that enables a hungry organism to find food will be reinforced, and a response that causes pain will be p unished. (Psychologists often refer to these stimuli as reinforcers and punishers.)

Table 13.1 Classical and Operant Cond itioning

Types of Behavior

Involuntary (reflexive), unlearned

Voluntary, learned

Type of Association

Association between two stimuli (ex: tone and puff of air)

Association between the stimulus and the response (ex: tone and pressing a lever)

instrumental conditioning). Operant conditioning is a form of learning in which a reinforcing or punishing outcome follows a specific behavior in a specific situation. The reinforcer increases the likelihood of the behavior occurring again in the future, while the punisher decreases it. Differences Between Classical and Operant Conditioning Operant conditioning and classical conditioning differ in important ways: They involve different types of behavior (involuntary and voluntary) as well as different types of associations. Table 13.1 summarizes these differences, and each difference is described in the text that follows. Classical conditioning involves automatic reflexes that do not have to be learned. Operant conditioning involves brand-new behaviors that have been learned. Classical conditioning involves an association between two stimuli (for example, a tone and a puff of air). Operant conditioning involves an association between a stimulus and a response (such as a tone and lever-pressing behavior). One easy way to remember this difference is that operant conditioning involves operating something in the environment, such as pressing a lever. There is nothing to "operate" in classical conditioning; the organism simply engages in a reflexive behavior. Operant conditioning permits an organism to change its behavior according to the consequences of that behavior. For example, when a behavior is followed by favorable

Reinforcement Let's consider the process of reinforcement. Reinforcement causes changes in an individual's nervo1us system that increase the likelihood that a specific stimulus will elicit a particular response behavior. For example, if a teacher enters a new classroom for the first time, they may not immediately know which switches operate the lights they want to turn on. They may try pressing several switches (if they are available) or moving around the room, looking for ways to turn on the lights. However, if the teacher presses the correct switch and the lights turn on immediately afterward, the likelihood of the teacher pressi.Jng that switch in the future increases. The process of reinforcement strengthens a connection between neural circuits involved in perception (the sight of the switch) and those involved in movement (the act of pressing the switch). As we will see later in this chapter, the brain contains reinforcement mechanisms that control this process. Figure~ 13.5 illustrates how reinforcement helps strengthen the connections between the perceptual and motor system using the example of a rat pressing a lever to receive a reinforcing stimulus (food). Test yourself by mapping the steps of the classroom light switch example onto this model. MOTOR LEARNING The second major category of learning, motor learning, is actually a component of stimulusresponse learning. Motor learning is the establishment of chang:es (responses) within motor systems following a stimulus. Motor learning cannot occur without sensory stimulus from the environment. For example, most skilled

Figure 13.5 A Simple Neural Model of Operant Conditioning

When rat presses lever, - - - -• it receives food

Reinforcing stimulus (e.g., food)

Reinforcement system

Stimulus (e.g ., sight of lever)

Neural circuit that detects a particular stimulus

Perceptual System

405

Reinforcement system / strengthens this connection

! L.

Neural circuit that controls a particular behavior

Motor System

----+

Behavior (e.g., lever p ress)

406

Chapter 13

Figure 13.6 An Overview of Perceptual , Stimulus-Response, and Motor Learning Perceptual learning S-R learning

I

Changes in Stimulus

movements involve interactions with objects, such as bicycles, video game controllers, tennis racquets, knitting needles, and keyboards. Motor learning differs from other forms of learning primarily in the degree to which new forms of behavior are learned; the more novel the behavior, the more the neural circuits in the motor systems of the brain must be modified. Perceptual learni ng is the ability to learn to recognize stimuli that have been perceived before. The primary function of this type of learning is the ability to identify and categorize objects and situations. Unless we have learned to recognize something, we cannot learn how we should behave with respect to it. Each of our sensory systems is capable of perceptual learning. For example, we can learn to recognize objects by their visual appearance, the sounds they make, how they feel, or how they smell. We can recognize people by the shape of their faces, the movements they make when they walk, or the sound of their voices. When we hear people talk, we can recognize the words they are saying and, perhaps, their emotional state. As we shall see, perceptual learning appears to be accomplished primarily by changes in the sensory association cortex. That is, learning to recognize complex visual stimuli involves changes in the visual association cortex, learning to recognize complex auditory stimuli involves changes in the auditory association cortex, and so on. A particular learning situation can involve varying amounts of all three types of learning that we have described so far: perceptual, stimulus-response, and motor. For example, if we teach an animal to make a new response whenever we present a stimulus it has never seen PERCEPTUAL LEARN ING

before, the animal must learn to recognize the stimulus (perceptual learning) and make the response (motor learning), and a connection must be established between these two new memories (stimulus-response learning). If we teach the animal to make a response that it has already learned whenever we present a new stimulus, only perceptual learning and stimulus-response learning will take place.

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neural circuit that detects - - + a particular stimulus Perceptual System

Motor learning

neural circu that control a particular behavior

----.

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The three forms of learning we have described so far consist primarily of changes in one sensory system, between one sensory system and the motor system, or in the motor system. (See Figure 13.6.) But most learning is usually more complex than that. The fourth form of learning, relational learning, involves learning the relationships among individual stimuli. For example, a somewhat more complex form of perceptual learning involves connections between different areas of the association cortex. When we hear the sound of a cat meowing in the dark, we can imagine what a cat looks like and what it would feel like if we touched its fur. Thus, the neural cir•cuits in the auditory association cortex that recognize the meow are somehow connected to the appropriate circuits in the visual association cortex and the somatosensory association cortex. These interconnections, too, are accomplished as a result of learning. Perceptioin of spatial location-spatial learning- also involves learning about the relationships among many stimuli. For example, consider what we must learn to become familiar with the contents of a room. First, we must learn to recognize each of the objects. In addition, we must learn the relative locations of the objects with respect to each other. As a result, when we find ourselves in a particular place in the room, our perceptions of these objects and their locations relative to us tell us exactly where we are. As we wilUsee in a later module of this chapter, a special system th.at involves the hippocampus and associated structures appears to perform coordinating functions required for many types of learning that go beyond simple perceptual, stimulus-response, or motor learning. RELATIONAL LEARNING

Types of Memory LO 13.2

Contrast characteristics of sensory, short-term, andl long-term memory.

Researchers describe the process of forming memories as occurring in three general stages: the sensory, short-term, and long-term stages of memory. (See Figure 13.7.) Information is first processed by sensory memory. Sensory memory is a brief period of time SENSORY MIBMORY

Learning and Memory

407

Figure 13.7 The Learning Process Maintenance rehearsal Attention Sensory input

Sensory memory

h

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! Unattended information is lost.

(ranging from fractions of a second to a few seconds) during which the initial sensation of environmental stimuli is initially remembered. Sensory memory occurs in each of the senses and allows an individual to retain the experience of the sensation slightly longer than the original stimulus. Sensory memory is often experienced as a brief period in which sensory experiences can be remembered as repeating or "echoing." For example, have you ever had the experience of reading or being completely involved in a task when someone interrupts you to ask a question or tell you something? Immediately you say "What?" because you were so involved in your task that you didn't hear them. Almost as soon as you say the word "What," you experience an echo of their voice and know the answer to your own question. This is an example of echoic memory for auditory sensory memory. Only a small fraction of information passes from sensory memory to the second stage of memory formation. The second stage is short-term memory. If information is meaningful or salient enough to be passed on from sensory memory, it will move to the short-term memory stage. This stage is longer than sensory memory, but still limited to seconds or minutes. The memory capacity of short-term memory is limited to a few items, such as the digits in a PIN or the letters in a name. The length of short-term memory can be extended through rehearsal. For example, you might be able to remember the digits in a security code longer if you repeat them to yourself until you enter them. The capacity of short-term memory can be expanded through techniques such as chunking (grouping pieces of information together, like the sections of a Social Security number or phone number). SHORT-TERM MEMORY

LONG-TERM MEMORY The third and final stage of memory is long-term memory. This stage is relatively permanent and can last for minutes, hours, days, or decades. Information that will be retained from short-term memory is consolidated into long-term memory. The conversion of short-term memories in to long-term memories has been

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Long-term memory

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Figure 13.8 Consolidation Consolidation Sensory information

I

Long-term memory Rehearsal

called consolidation, because the memories are "made solid." (See Figure 13.8.) Not all information from shortterm memory makes it to long-term memory. Long-term memories can be retrieved throughout a lifetime and strengthened with increased retrieval. Nondeclarative Memory There are two major categories of long-term memory: nondeclarative and declarative memory. Nondeclarative memory, or implicit memory, includes memories that we are not necessarily conscious of. Nondeclarative memories appear to operate automatically. They do not seem to require memorization or include facts or experiences; instead, they control behaviors. For example, think about when you learned a new skill like riding a bicyde or driving a car. You did so consciously and developed declarative memories about your attempts: who helped you learn, where you were, and how you felt. But you also formed nondeclarative memories; you learned to ride o:r drive. You learned to make automatic adjustments with your hands and body. The acquisition of specific motoric behaviors and skills is probably the most important form of nondeclarative memory. Driving a car, turning the pages of a book, playing a musical instrwnent, dancing, throwing and catching a ball, sliding a chair backward as we stand up- all of these skills involve coordination of movements with sensory information received from tlhe environment and from our own moving body parts. We do not need to be able to describe these activities in order to perform them. We may not even be aware of all the movements we make while we are performing them.

408 Chapter 13

Table 13.2 Examples of Declarative and Nondeclarative

Figure 13.9 Types of Memory

Memory Tasks umanmemo

Declarative Memory Tasks Remembering past experiences Finding your way in new environment

Nondeclarative Memory Tasks Learning to recognize broken drawings

Sensory memory (< 1 sec)

Learning to recognize pictures and objects

I

!

Long-term memory

hort-tenn mem (< 1 min)

(lifetime)

Learning to recognize faces Learning to recognize melodies Classical conditioning

Declarative memory

Nondeclarative memory

(facts, events)

(skills, tasks)

Operant conditioning Learning a sequence of button presses

Semantic memory (facts, concepts)

Declarative Memory The other category of memory, declarative memory, or explicit memory, includes memory of events and facts that we can think and talk about (Squire et al., 1989). Declarative memories are not simply verbal memories. For example, think about some event in your life, such as your last birthday. Think about where you were, when the event occurred, what other people were present, what happened, and so on. Although you could describe ("declare") this episode in words, the memory itself would not be verbal. In fact, it would probably be more like a video clip running in your head, one whose starting and stopping points-and fast forwards and rewinds-you could control. (See Table 13.2.) Evidence suggests that declarative memory includes distinct forms of episodic and semantic memories.

Episodic memories involve context; they include information about when and under what conditions a particular episode occurred and the order in which the events in the episode took place. Episodic memories are specific to a particulair time and place because a given episodeby definition--occurs only once. Semantic memories involve facts, but they do not include information about the context in which the facts were learned. In other words, semantic memories are less specific than episodic memories. For example, knowing that the sun is a star involves a less specific memory than being able to remember when, where, and from whom you learned this fact. Semantic memories cani be acquired gradually, over time. Episodic memories must be learned all at once. (See Figure 13.9.)

Module Review: Overview of Learning and Memory Types of Learning LO 13.1

Compare characteristics of stimulusresponse, motor, perceptual, and relational learnin g.

Stimulus-response learning, including classical and operant conditioning, consists of connections between perceptual and motor systems. Classical conditioning occurs when a neutral stimulus is followed by an unconditioned stimulus (US) that naturally elicits an unconditioned response (UR). After this pairing, the neutral stimulus becomes a conditioned stimulus (CS); it now elicits the response by itself, which we refer to as the conditioned response (CR). Operant conditioning occurs when a response is followed by a reinforcing or punishing stimulus. Motor learning, although it may primarily involve changes within neural circuits that control movement, is guided by sensory stimuli

and is a form of stimulus-response learning. Perceptual learning consists primarily of changes in perceptual systems that make it possible for us to recognize stimuli so that we can respond to them appropriately. Relational learning, the most complex form of learning, includes the ability to recognize objects through more than one sensory modality, to recognize the relative location of objects in the environment, and to remember the seque:nce in which events occurred during particular episodes.

Types of M emory 1

LO 13.2

Contrast characteristics of sensory, sh ortterm, and long-term memory.

Sensory memory is very brief and involves remembering an initial sensation. A small fraction of information from sensory memory passes on to short-term memory,

Learning and Memory

which lasts seconds or minutes and is limited to a few items. Short-term memory capacity can be extended with rehearsal or chunking. Long-term memory is relatively permanent, and memories can be retrieved throughout a lifetime and strengthened with increased retrieval. Long-term memory includes declarative and nondeclarative memory.

Stimulus-Response Learning The first module of this chapter introduced four basic types of learning: stimulus-response, motor, perceptual, and relational learning. The following modules explore each of these types of learning in greater detail, including what is known of their neural basis. Within each of these modules, learning produces memories as the information to be learned proceeds through sensory, short-term, and finally long-term memory stages. We begin by exploring the neural structures and systems that underlie classical and operant conditioning.

Classical Conditioning LO 13.3

Describe the roles of the amygdala, AMPA receptors, and NMDA receptors in classical conditioning.

Neuroscientists have studied the anatomy and physiology of classical conditioning using many models, such as the gill withdrawal reflex in Aplysia (a marine invertebrate) and the eyeblink reflex in the rabbit (Carew, 1989; Lavond et al., 1993). Here, we will describe the conditioned emotional response to illustrate the underlying neural activity responsible for conditioning response. (See Chapter 11 for an additional example of conditioned emotional response.) ROLE OF THE AMYGDALA The amygdala is important in classically conditioned emotional responses. An aversive stimulus such as an electrical shock produces a variety of behavioral, autonomic, and hormonal responses:

Figure 13.10

Thought Question Do you ride a bike or drive a car? What other complex behaviors have you learned? Choose one and identify the different types of learning and memory involved in the behavior.

freezing, increased blood pressure, secretion of adrenal stress hormones, and avoiding the stimulj associated with the shock. While much of our understanding of the neural basis of conditioned emotional responses comes from research with rodent models in the lab, this same general process can be found in many different applications, such as electrical fencing for pets or livestock. In these examples, a classically conditioned emotional response is established by pairing a neutral stimulus (such as the sight of a fence or flags placed around the perimeter of an area) with an aversive stimulus (such as a brief shock or surprising vibratioin delivered through a collar as an animal approaches a fenc1? boundary). (See Figure 13.10.) After being processed by the sensory cortex, information about the CS (for example, the sight of the fence) reaches the lateral nucleus of the agdala. This nucleus also receives information about the US (the shock) from the somatosensory system. These two sources of information converge in the lateral nucleus, which means that synaptic changes responsible for learning could take place in this location. A hypothetical neural circuit is shown in Figure 13.11 to illustrate classical conditioning of a tone and shock in a rodent model (also see Figure 13.3). The lateral nucleus of the amygdala contains neurons whose axons project to the central nucleus. Terminal buttons from neurons that transmit auditory and somatosensory information to the lateral nucleus form synapses with dendritic spines on these neurons. When a rodent encounters a painful shock stimulus, somatosensory input activates strong synapses in the lateral nucleus. As a result, the neurons in this nucleus begin firing, which activates

Applied Examples of Classical Conditionin,g

Electric fencing for livestock and pets uses classical conditioning. The unconditioned stimulus (shock or other aversive stimuli) and response (avoiding the location of the shock) are conditioned to a previously neutral stimulus (sight of a fence or flags) to produce the conditioned response (avoiding the fence or flags).

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Figure 13.11

Cond itioned Emotional Responses

The figure shows the probable location of the changes in synaptic strength produced by the classically conditioned emotional response that results from pairing a tone with a shock (aversive stimulus).

Basal nucleus

responses: hypothalamus, midbrain, pons, and medulla

neurons in the central nucleus, evoking an unlearned (unconditioned) emotional response. If a tone is paired with the painful stimuJus, the weak synapses in the lateraJ amygdala are strengthened. The synaptic changes responsible for this type of learning take place within this circuit. ROLE OF GLUTAMATE The evidence from many studies indicates that the changes in the lateral amygdala responsible for acquisition of a conditioned emotional response involve a series of synaptic changes called long-term potentiation (LTP). Long-term potentiation is described in detail in the final module of this chapter. LTP involves

Figure 13.12

NMDA recepitors and their relationship to increasing the number of AMPA receptors at the synapse. NMDA and AMPA receptors are described in Chapter 4. Briefly for now, LTP is accomplished through the activation of l\JMDA receptors and the insertion of additional AMPA receptors into the postsynaptic membrane. These synaptic changes in the glutamate system serve to increase the EPSP to the postsynaptic cell. For example, Rumpel and colleagues (2005) paired a tone with a shock and established a conditioned emotional response. They found that tlhe learning experience caused additional AMPA receptors to be inserted postsynaptically and increased EPSPs to dendritic spines of synapses between lateral amygdala neurons and axons that provide auditory input. They a lso found that a procedure that prevented the insertion of AMPA receptors into the dendritic spines also prevented the conditioned emotional response. In addition, Migue:s and colleagues (2010) found that blocking steps involved in LTP in the lateral amygdala impaired the establishment of a conditioned emotional response. In fact, the magnitude of the deficit was directly related to the decrease in post:synaptic AMPA receptors, and presumably the decrease in EPSPs. The results of these studies support the conclusion that LTP among glutamate synapses in the lateral amygdala plays a critical role in the establishment of conditioned emotional responses. (See Figure 13.12.) Additional details about synaptic changes associated with LTP will be discussed later in this chapter. For greater detail on the proicess of inserting AMPA receptors, look ahead to Figure 13.3~).

Overview of NMDA and AMPA Receptors in LTP Associated with Classical Conditioning Presynaptic neuron

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The NMDA receptor is activated by glutamate binding, but only after depolarization removes inhibitory Mg2• from the channel.

Postsynaptic neuron After clas~;ical conditioning

Mg2+ expelled from channel In LTP, additional AMPA receptors are inserted into the postsynaptic membrane, helping to enhance depolarization.

Learning and Memory 411

Operant Conditioning LO 13.4

Outline the n eural m echanisms of operant condition in g.

Operant conditioning is one of the means by which we (and other animals) learn from interacting with our environment. If, in a particular situation, we make a response that has favorable outcomes, we will tend to make the response again. This section first describes the neural pathways involved in operant conditioning and then discusses the neural basis of reinforcement. ROLE OF BASAL GANG LIA As we saw in the first module of this chapter, operant conditioning entails the strengthening of connections between neural circuits that detect a particular stimulus and neural circuits that produce a particular response. The circuits that are responsible for operant conditioning begin in various regions of the sensory association cortex, where perception takes place, and end in the motor association cortex of the frontal lobe, which controls movements. But what pathways are responsible for these connections, and where do the synaptic changes responsible for the learning take place? There are two major pathways between the sensory association cortex and the motor association cortex: direct transcortical connections (connections from one area of the cerebral cortex to another) and connections via the basal ganglia and thalamus. (A third pathway, involving the cerebellum and thalamus, also exists, but the role of this pathway in operant conditioning has until very recently received little attention from neuroscientists.) The first two pathways appear to be involved in operant conditioning, but they play different roles. (See Figure 13.13.)

Transcortical Pathways In conjunction with the hippocampal formation, the transcortical connections are involved in the acquisition of declarative, episodic memories-complex perceptual memories of sequences of events that we experience or that are described to us. The transcortical connections are also involved in the acquisition of complex behaviors that involve deliberation or instruction. For example, a person learning to drive a car with a manual transmission might say, "Let's see, push in the clutch, move the shift lever to the left and then away from me-there, it's in gear-now let the clutch come up-oh! It died-I should have given it more gas. Let's see, clutch down, turn the key.... " A memorized set of rules (or an instructor sitting next to us) provides .a script for us to follow. Of course, this process does not have to be audible or even involve actual movements of the speech muscles; a person can think in words with neural activity that does not result in overt behavior. At first, performing a behavior through observation or by following a set of rules is slow and awkward. And because so many of the brain's resources are involved in recalling the rules and applying them to our behavior, we cannot respond to other stimuli in the environment-we must ignore events that might distract us. But then, with practice, the behavior becomes much more fluid. Eventually, we perform it without thinking and can easily do other things at the same time, such as talking with passengers as we drive our car. Basal Ganglia Pathways Evidence suggests that as learned behaviors become automatic and routine, they are "transferred" to the basal ganglia. The process seems to work like this: As we deliberately perform a complex behavior, the basal ganglia receive information about the stimuli that are present and the responses we are making. At first the basal

Figure 13.13 Stimulus and Response Pathways Primary motor cortex 4 Finally, information goes to the primary motor cortex where the response behavior is initiated. Information from transcortical pathways is transferred to the basal ganglia as the behavior becomes automatic. The

3 Information then goes to the premotor and supplementary motor cortex.

caudate and putamen receive information from the frontal lobes about movements.

2 Information then goes to the globus pallidus. Putam en

412 Chapter 13

ganglia are passive "observers" of the situation, but as the behaviors are repeated again and again, the basal ganglia begin to learn what to do. Eventually, they take over most of the details of the process, leaving the transcortical circuits free to do something else. We need no longer think about what we are doing. Returning to the example of driving a car with a manual transmission, as the driver practices, processing is transferred to the basal ganglia, and the driver no longer needs to deliberately think through each step. Instead, the driver fluidly and automatically starts the engine, shifts gears, and drives the car. The caudate nucleus and the putamen (two parts of the basal ganglia) receive sensory information from all regions of the cerebral cortex. They also receive information from the frontal lobes about movements that are planned or are actually in progress. (This means that the basal ganglia have all the information they need to monitor the progress of someone learning to drive a car.) The outputs of the caudate nucleus and the putamen are sent to another part of the basal ganglia: the globus pallidus (a third part of the basal ganglia). The outputs of this structure are sent to the frontal cortex: to the premotor and supplementary motor cortex, where plans for movements are made; and to the primary motor cortex, where they are executed . (See Figure 13.14.) The transfer of memories from brain systems involved in acquisition of behavior sequences to those involved in storage of automatic procedures can be observed in the basal ganglia. For example, research with animal models has revealed that the area of the rat brain that corresponds to the caudate nucleus in humans and other primates is reciprocally connected with the prefrontal cortex. The area of the

Figure 13.14 Diagram of the Basal Ganglia and Their Connections Black arrows represent excitatory connections. Red arrows represent inhibitory connections. Supplementary motor area

Premotor cortex

Primary somatosensory cortex

rat brain that corresponds to the primate putamen is reciprocally connected to sensory and motor regions of the cortex. Yin and colleagues (2009) and Thom and colleagues (2010) found that the rat caudate analogue was involved in early learning of new skills, but that as practice continued and the behavior became more habitual and automatic, the putamen analogue began to take over control of the animal's behavior. Lesions of the basal ganglia disrupt operant conditioning but do not affect other forms of learning. For example, Fernandez-Ruiz and colleagues (2001) lesioned portions of the caudate nucleus and putamen that receive visual information from the ventral stream in monkeys. They found that the lesions impaired the monkeys' ability to learn to make a visually guided operant response, but did not affect other forms of learning. Williams and Eskandar (2006) trained monkeys to move a joystick in a particular direction (left, right, forward, or backward) when they saw a particular visual stimulus. Correct respornses were reinforced with a sip of fruit juice. As the monkeys learned the task, the firing rate of neurons in the caudate nucleus increased. The activity of caudate neurons was correlated. with the animals' rate of learning. When the investigators further activated the caudate neurons through electrical stimllllation during the reinforcement period, the monkeys learned a stimulus-response association more quickly. These results provide further evidence for the role of the basal ganglia in operant conditioning. Learning provides a means for us to profit from exiperience-to make responses that provide favorable outcomes. When good things happen (that is, when reinforcing stimuli occur), reinforcement mechanisms in the brain become active, and the establishment of synaptic changes is facilitated. The discovery of the existence of such reinforcement mechanisms occurred by accident. REINFORCEMENT

Neural Circuits Involved in Reinforcement In 1954, James Olds, a young assistant professor, and Peter Milner, a graduate student, attempted to determine whether electrical stimulation of the reticular formation would facilitate maze learning in rats. The reticular formation is a large structure between the brainstem and midbrain that contains many different nuclei and pathways (see Chapter 3 for review). Olds and Milner planned to turn on the stimulator briefly each time an animal reached a choice point in the maze. The researchers applied a brief electrical current into that region around the reticular formation when the animals

entered one corner of their enclosure. The a.nimals quickly returned to the location following the stimulation. They returned to the original corner more and more quickly after each successive stimulation was applied (Olds, 1973). Realizing that they were on to something big, Olds and Milner decided to stop their original experiment and study the phenomenon they had discovered. Subsequent research discovered that although there are several different

Learning and Memory

413

Figure 13.15 The Ventral Tegmenta l Area and the Nucleus Accumbens Diagrams of sections through a rat brain show the location of these regiions. Source: Adapted from Swanson, L. W. (1992). Brain maps: Structure of the rat brain. New York: Elsevier, 1992.

Hippocampal formation

Corpus callosum

SeptaI area Basal ganglia

Anterior commissure

Nucleus accumbens

reinforcement mechanisms, the activity of dopaminergic neurons plays a particularly important role in reinforcement. As we saw in Chapter 4, the mesolimbic system of dopaminergic neurons begins in the ventral tegmental area (VTA) of the midbrain and projects rostrally to several forebrain regions, including the amygdala, hippocampus, and nucleus accumbens (N AC). (See Figure 13.15.) Neurons in the NAC project to the ventral part of the basal ganglia, which, as we just saw, are involved in learning. The mesocortical system also plays a role in reinforcement. This system also begins in the ventral tegmental area but projects to the prefrontal cortex, the limbic cortex, and the hippocampus. Because the stimulation of several regions of the brain is reinforcing, the mesolimbic system is only one of several reinforcement pathways. In their study, Olds and Milner had inadvertently activated these pathways when they stimulated the reticular pathway, causing the animal's behavior during the stimulation (being in the comer of the enclosure) to be reinforced, and more likely to occur in the future. Role of Dopamine in Reinforcement Chapter 5 described a research technique called microdialysis, which enables an investigator to analyze the contents of the interstitial fluid within a specific region of the brain. Researchers using this method have shown that reinforcing electrical stimulation of the m edial forebrain bundle or the ventral tegmental area or the administration of cocaine or amphetamine causes the release of dopamine in the nucleus accumbens (Moghaddam & Bunney, 1989; Nakahara et al., 1989; Phillips et al., 1992). The medial forebrain bundle connects the ventral tegmental

tegmental area

nigra

area with the nucleus accumbens. (See Figure 13.16.) Microdialysils studies have also found that the presence of natural reinforcers, such as water, food, or a sex partner, stimulates the reliease of dopamine in the nucleus accumbens. It appears that th.e effects of reinforcing brain stimulation are similar in many ways to those of naturally occurring reinforcers.

Figure 13.16 Dopamine and Reinforcement ReleasH of dopamine in the nucleus accumbens, measured by microdialysis, was produced when a rat pressed a lever that delivered electrical stimulation to the ventral tegmental area. Source: Based on data from Phillips, R. G., and LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditio1ning. Behavioral Neuroscience, 1992, 106, 274-285.

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414 Chapter 13

Functional-imaging studies have shown that reinforcing events also activate the human nucleus accumbens. For example, Knutson and colleagues (2001) found that the nucleus accumbens became more active (and, presumably, dopamine was being released there) when people were presented with stimuli that indicated that they would be receiving money. Like classical conditioning, operant conditioning involves strengthening synapses among neurons that have just been active. However, operant conditioning involves three elements: a discriminative stimulus, a response, and a reinforcing stimulus. How are the neural manifestations of these three elements combined, and what role does dopamine play? Let's consider a hungry rat learning to press a lever and obtain food. As in classical conditioning, one element (the discriminative stimulus-in this case the sight of the lever) activates only weak synapses on motor neurons responsible for a movement that causes a lever press. The second element-the particular circumstance that happened to induce the animal to press the lever-activates strong synapses, making the neurons fire. The third element comes into play only if the response is followed by a reinforcing stimulus. U it is, the reinforcement mechanism triggers the secretion of a neurotransmitter or neuromodulator throughout the region in which the synaptic changes take place. This chemical is the third element; only if it is present can weak synapses be strengthened. Dopamine serves such a role. Several studies have shown that long-term potentiation is essential for operant conditioning and that dopamine is an essential ingredient in long-lasting long-term potentiation. Knecht and colleagues (2004) taught people a vocabulary of artificial words. The learning took place gradually, during five daily sessions. In a double-blind procedure, some participants were given L-DOPA 90 minutes before each session, and others were given a placebo. L-DOPA is the precursor for dopamine, so administration of this drug increases the release of dopamine in the brain. The participants who received the L-DOPA learned the artificial vocabulary faster and remembered it better than those who received the placebo. In that same vein, Tsai and colleagues (2009) used optogenetic stimulation in mice to specifically activate dopaminergic neurons in the VTA and found that the stimulation reinforced performance on an operant task. Functions of the Reinforcement System A reinforcement system must perform two functions: detect the presence of a reinforcing stimulus (that is, recognize that something good has just happened) and strengthen the connections between the neurons that detect the discriminative stimulus (such as the sight of a lever) and the neurons that produce the operant response (a lever press). (Refer back to Figure 13.5.) Assuming that this proposed mechanism is correct, several questions remain: What activates the dopaminergic neurons in the midbrain, causing their terminal buttons to release dopamine? What role does the release of dopamine

play in strengthening synaptic connections? Where do these synaptic changes take place? Research that suggests some preliminary answers to these questions is discussed in the rest of tlhis module. Detecting RBinforcing Stimuli Reinforcement occurs when neural circuits detect a reinforcing stimulus and cause the activation of dopaminergic neurons in the ventral tegmental area. Detecting a reinforcing stimulus is not a simple matter. A stimulus that serves as a reinforcer in one situation may not in another. For example, the presence of food will reinforce the behavior of a hungry animal but not that of an animal that has just eaten. The reinforcement system is not automatically activated when particular stimuli are present. Its activation also depends on the state of the animal or the environment the stimuli occur in. Studies by Schultz and his colleagues, recording the activity of dopaminergic neurons in the nucleus accumbens, have discovered that the reinforcement system appears to be activated by unexpected reinforcing stimuli. For example, Mirenowicz and Schultz (1994, 1996) taught monkeys an operant task that required them to make a response when they heard an auditory stimulus. During training, dopaminergic neurons in the VTA responded rapidly when the reinforcing stimulus (a tasty liquid) was delivered. However, once the animals learned the task, the VTA neurons became active when tlhe auditory stimulus was presented but not when the reinforcing stimulus was delivered. In addition, if a reinforcing stimulus does not occur when it is expected, the activity of doparninergic neurons suddenly decreases (Day et al., 2007). A functional-imaging study by Berns and colleagues (2001) found similar results with humans. Figure 13.17 shows that when a small amount of tasty fruit juice was squirted in people's mouths unpredictably, the nucleus accumbens was activated, but when the delivery of fruit juice was predictable, no such activity occurred. Schultz rund his colleagues suggest that activation of the dopaminergic neurons of the VTA communicates to other circuits in the brain that an event related to a potentially reinfmcing stimulus has just occurred. In other words, the activity of these neurons sends a signal that there is something to be learned. If the delivery of the reinforcer is already expected, then there is nothing that needs to be learned. A functional-imaging study by Knutson and Adcock (2005) found that anticipation of a reinforcing stimulus (the opportunity to win some money) increased the activation of the ventral tegmentum and some of its projection regions (including the nucleus accumbens) in humans. The investigators found that the participants were more likely to remember pictures that they had seen while they were anticipating the chance to win some money. (See Table 13.3.) Role of the Prefrontal Cortex The prefrontal cortex provides an important input to the ventral tegmental area.

Learning and Memory

Figure 13.17

Expected and Unexpected Reinforcers

The functional MRI scans show the effects of expected and

Table~

13.3

415

Activity of VTA Neurons in Response

to Reinforcers

unexpected reinforcers (sips of fruit juice) on activity of the nucleus accumbens (arrows) in humans. Source: Based on Berns, G. S., McClure, S. M., Pagnoni, G., and Montague, P.R. (2001). Predictability modulates human brain response to reward . Journal

of Neuroscience, 21, 2793-2798. Used with permission.

Walkin1;i by a vending machine, you aocidentally bump into it. A cancly bar falls out. You type your password into an email program, and your email a1ccount opens.

Unexpected reward

Expected reward

Module Review: LO 13.3

Describe the roles of the amygdala, AMPA receptors, and NMDA receptors in classical conditioning.

When a stimulus (CS) is paired with a shock (US), the two types of information converge in the lateral nucleus of the amygdala. Classical conditioning changes the response of neurons to the CS in the lateral nucleus of the amygdala. The mechanism of synaptic plasticity in this system appears to be NMDA-mediated long-term potentiation. LTP is accomplished through the activation of NMDA receptors and the subsequent insertion of additional AMPA receptors into the postsynaptic membrane. Blocking aspects of LTP in the lateral nucleus prevents establishing conditioned emotional responses.

Operant Conditioning LO 13.4

Outline the neural mechanisms of operant conditioning.

Operant conditioning involves strengthening connections between neural circuits that detect stimuli and

Active

Expected

Inactive

The terminal buttons of the axons connecting these two areas secrete glutamate, an excitatory neurotransmitter, and the activity of these synapses makes dopaminergic neurons in the ventral tegmental area fire in a bursting pattern, which greatly increases the amount of dopamine they secrete in the nucleus accumbens (Gariano & Groves, 1988). The prefrontal cortex is generally involved in devising strategies, making plans, evaluating progress made toward goals, and judging the appropriateness of one's own behavior. Perhaps the prefrontal cortex turns on the: reinforcement mechanism when it determines that the ongoing behavior is bringing the organism nearer to its goals and that the present strategy is working.

Stimulus-Respons~3

Classical Conditioning

Unexpected

Learning

neural circuits that produce responses. One of the locations of these changes appears to be the basal ganglia, especially the changes responsible for learning of automated! and routine behaviors. The basal ganglia receive senso:ry information and information about plans for movement from the neocortex. The mesolimbic and mesocort:ical pathways are responsible for reinforcement in op1erant conditioning. The prefrontal cortex may be involved in activating the mesolimbic pathway to achieve goals.

Thought Question Have you ever worked hard on a problem and suddenly thought of a possible solution? Did the thought make you feel excited and happy? What might we find if we examined your nucleus accumbens, and why might we find that?

416 Chapter 13

Motor Learning Motor learning typically involves learning a novel sequence of motor behaviors over repeated trials. The cerebellum, thalamus, basal ganglia, and motor cortex are involved in motor learning across many different tasks (Hardwick et al., 2013). Chapter 8 describes the brain regions involved in the control of voluntary movement in greater detail, and the following module provides an introduction to the role of two key areas involved in motor learning: the cortex and basal ganglia.

Role of the Cortex LO 13.5

List the contributions of various cortical regions to motor learning.

The primary motor cortex is responsible for controlling the movements of the body and is organized somatotopically. As you read in Chapter 8, several adjacent areas of the cortex are critical in organizing complex, learned movements. For example, the supplementary motor area is involved in performing previously learned, automatic series of behaviors. The premotor cortex is involved in motor learning and memory that is guided by sensory information. The ventral premotor cortex is home to mirror neurons that facilitate motor learning when observing another individual. Motor learning typically involves a period of fast learning when the motor movements to be learned show rapid improvement during initial trials. The memory of this motor behavior is improved in the period of time following the initial trials when no additional practice occurs, called between-session learning. This improvement is made through consolidation and reconsolidation of the memory. Further improvement in motor learning occurs following sleep. REM and slow-wave sleep are associated

with enhanced aspects of motor learning in some motor learning tasks and may promote LTP (Censor et al., 2012).

Role of the Basal Ganglia LO 13.6

Explain the role of the basal ganglia in motor learning.

What brain regions are responsible for the acquisition of nondeclarative motor memories? As we saw earlier in this chapter, perceptual memories involve the sensory regions of the cerebrall cortex. The basal ganglia appear to play an essential role in stimulus-response and motor learning. Several experiments have shown that people with diseases of the basaI ga1nglia have deficits that can be attributed to d ifficulty in leaming automatic responses. For example, Owen and colleagues (1992) found that patients with Parkinson's disease were impaired on learning a visually cued operant conditioning task, and Willingham and Koroshetz (1993) found that patients with Huntington's disease failed to learn a sequence of button presses. Parkinson's disease and Huntington's disease both involve degeneration of the basal ganglia and are described in d etail in Chapter 15. Table 13.4 summarizes examples of motor learning associated with activity in the motor cortex and basal ganglia.

Table 13.4 Examples of Activity of Motor Cortex and Basal Ganglia in Motor Learning Learning to type your name on a keyboard

Learning an automatic sequence of button presses in respcnse to seeing a stimulus

Learning a dance> by watching another person

Learning to fasten your seatbelt when hearing a tone

Module Review: Motor Learning Role of the Cortex

Thought Question

LO 13.5

How can motor learning improve, even when an individual is not actively engaged in practicing the motor behavior? Explain the roles of between-session learning and sleep in motor learning and motor memory.

List the contributions of various cortical regions to motor learning.

The primary motor cortex is responsible for executing motor behaviors, and input from the premotor area and supplementary motor area help to refine motor learning.

Role of the Basal Ganglia LO 13.6

Explain the role of the basal ganglia in motor learning.

The basal ganglia are responsible for learning automatic motor behaviors, such as in stimulus-response paradigms.

Learning and Memory

Perceptual Learning Learning enables us to adapt to our environment and to respond to changes in it. In particular, it provides us with the ability to perform an appropriate behavior in an appropriate situation. Situations can be as simple as responding to the sound of a doorbell or as complex as the social interactions of a group of people. Perceptual learning involves learning to recognize things. Perceptual learning can involve learning to recognize entirely new stimuli, or it can involve learning to recognize changes or variations in familiar stimuli. For example, if a friend gets a new hairstyle or replaces glasses with contact lenses, our visual memory of that person changes. We also learn that particular stimuli are found in particular locations or contexts or in the presence of other stimuli. We can even learn and remember particular episodes: sequences of events taking place at a particular time and place. The more complex forms of perceptual learning will be discussed in a later module of this chapter, which is devoted to relational learning. The following module will describe the roles of the cortex in learning to recognize stimuli and how the memories of those stimuli are formed.

Role of the Cortex LO 13.7

Explain the roles of cortical regions in perceptual learning.

We will first describe the role of the cortex in learning to recognize stimuli, then provide evidence of cortical activity in later remembering stimuli. Finally, the role of the cortex will be discussed in the context of retaining perceptual information in short-term memory. In mammals with large and complex brains, objects are recognized visually by circuits of neurons in the extrastriate cortex. Visual learning can take place very rapidly, and the number of items that can be remembered is enormous. In fact, Standing (1973) showed people 10,000 color slides and found that they could recognize most of the slides weeks later. Other primates are capable of remembering items that they have seen for just a few seconds, and the experience changes the responses of neurons in their extrastriate cortex (Rolls, 1995). As we saw in Chapter 6, the striate cortex receives information from the lateral geniculate nucleus of the thalamus. After the first level of analysis in the striate cortex; the information is sent to the extrastriate cortex. After analyzing particular attributes of the visual scene, such as form, color, and movement, subregions of the extrastriate cortex send the results of their analysis to the next level of the visual association cortex, which is divided into two "streams." The ventral stream, which is involved with object recognition, continues ventrally into the inferior temporal cortex. The LEARNING

417

dorsal stream, which is involved with perception of the location of objects, continues dorsally into the posterior parietal cortex. Most investigators agree that the ventral stream is involved with the what of visual perception, and the dorsal stream is involved with the where. (See Figure 6.14.) Many studies have shown that lesions that damage the inferior temporal cortex-the end of the ventral streamdisrupt the ability to discriminate among visual stimuli. These lesions impair the ability to perceive (and learn to recognize) particular kinds of visual information. As we saw in Chapter 6, people with damage to the inferior temporal cortex may have excellent vision but be unable to recognize familiar, everyday objects such as scissors, cell phones, or light bulbs-and faces of friends and relatives. MEMORY Perceptual learning involves changes in synaptic connections in the extrastriate cortex that establish new neural circuits. At a later time, when the same stimulus is seen again and the same pattern of activity is transmitted to the cortex, these circuits become active again. This activity constitutes the recognition of the stimulusthe readout, or replay, of the visual memory. For example, Yang and Maunsell (2004) trained monkeys to detect small differences in visual stimuli whose images were projected onto a specific region of the retina. After the training was compllete, the monkeys were able to detect differences much smaller than those they could detect when the training forst started. However, they were unable to detect these differences when the patterns were projected onto other 1regions of the retina. Recordings of single neurons in the extrastriate cortex showed that the response properties of neurons that received information from the "trained" region of the retina-but not from other regions-had become sensitive to small differences in the stimuli. Neural cir1cuits in that region alone had been modified by the training. (See Figure 13.18.) Let's look at some evidence from studies with humans that supports the conclusion that activation of neural circuits in the sensory association cortex constitutes the "replay" of a perceptual memory. Many years ago, Penfield and Perot (1963) discovered that when they stimulated the extrastriate and auditory association cortex as patients were undergoing seizure surgery, the patients reported memories of images or sounds-for example, images of a familiar street or the sound of the patient's mother's voice. (You will recall from the opening case in Chapter 3 that seizure surgery is performed under a local anesthetic so that the su:rgeons can test the effects of brain stimulation on the patients' cognitive functions.) Damage to regions of the brain involved in visual perception not only impairs the ability to recognize visual stimuli but: also disrupts people's memory of the visual properties of familiar stimuli. For example, Vandenbulcke and colleagues (2006) found that Patient J. A., who had sustained

418

Chapter 13

Figure 13.18 Role of the Extrastriate Cortex in Perceptual Learning

of Movement

Activation of neural circu its in the sensory association cortex constitutes the "readout" of perceptual memory. Seeing a specific visual stimulus results in a unique pattern of neural activity in the extrastriate cortex. The same visual stimulus, if seen again later, will

The bars represeint the level of activation, measured by fMRI, of MT/MST, a region of the visual association cortex that responds to movement. Participants looked at photographs of static scenes or scenes that implied motion similar to the ones shown here.

stimulate the same neural activity in the extrastriate cortex.

Figure 13.1.9

Evidence of Retrieval of Visual Memories

Source: Based on data from Kourtzi, A., and Kanwisher, N. (2000). Activation in human MT/MST by static images with implied motion. Journal of Cognitive Neuroscience, 12, -48- 55.

Dorsal stream

Primary --7::~ visual pathway

(ij

2.5

c:

O>

.iii

2

.~ Q)

Ventral stream

g> 1.5

0

c

co ~

Long-term depression

c

~-10

~

- 20 10 3 5 Frequency of stimulati on of Schaffer collateral axons (Hz)

50

spines.. Long-term depression appears to involve the opposite: a decrease in the number of AMPA receptors in these spines (Carroll et al., 1999). And just as AMPA receptors are inserted into dendritic spines during LTP, they are removed from the spines in vesicles during LTD (Liischer et al., 1999). In field CAl, long-term depression, like long-term potentiationi, involves the activation of NMDA receptors, and its establishment is disrupted by APS. How can activation of the same receptor produce opposite effects? An answer was suggested by Lisman (1989), who noted that sustained, low-frequency stimulation of synapses on pyramidal cells

440 Chapter 13 in this region that produces LTD would cause a modest but prolonged increase in intracellular Ca2+, whereas the intense, high-frequency stimulation that produces LTP would cause a much greater increase in Ca2+. Perhaps small and large increases in intracellular calcium ions trigger different mechanisms. Evidence in favor of this hypothesis was obtained by a study by Liu and colleagues (2004). NMDA receptors come in at least two forms. One form contains one type of subunit, and the other contains a different type of subunit. Liu and his colleagues found that LTP was prevented by a drug that blocked one type of NMDA receptor and that LTD was prevented by a drug that blocked the other type of NMDA receptor. Receptors that produce LTP permit an influx of large amounts of Ca2+ if they are stimulated repeatedly in a short amount of time. In contrast, receptors that produce LTD permit less calcium to enter the cell, but if they are stimulated slowly over a long period of time, they permit the buildup of a modest but prolonged increase in intracellular calcium.

OTHER FORMS OF LONG -TERM POTEN TIATIO N

Long-term pot:entiation was discovered in the hippocampal formation and has been studied more in this region than in others, but it also occurs in many other regions of the brain. In some but not all of these regions, LTP is initiated by stimulation of NMDA receptors. For example, in the hippocampal formation, Nl\IDA receptors are present in highest concentrations in field CAl and in the dentate gyrus. However, very few NMDA receptors are found in the region of field CA3 that receives mossy fiber input from the dentate gyrus (Monaghan & Cotman, 1985). High-frequency stimulation of the mossy fibers produces LTP that gradually decays over a period of several hours (Staubli, Larson, & Lynch, 1990). APS, the drug that blocks NMDA receptors and prevents the establishment of LTP in CAl neurons, has no effect on LTP in field CA3. In addition, long-term potentiation in field CA3 appears to involve only presynaptic changes; no alterations are seen in th1e structure of dendritic spines after LTP has taken place (Reid et al., 2004).

Module Review: Long-Term Potentiation Induction of Long-Term Potentiation

Role of AM:PA Receptors

LO 13.16 Identify the events required for LTP to occur.

LO 13.18 Describe how AMPA receptors contribute to ILTP.

A circuit of neurons passes from the entorhinal cortex through the hippocampal formation. High-frequency stimulation of the axons in this circuit strengthens synapses; it leads to an increase in the size of the EPSPs in the dendritic spines of the postsynaptic neurons. The only requirement for LTP is that the postsynaptic membrane be depolarized at the same time that the synapses are active. The perforant pathway must be depolarized either by exposu re to stimuli in the environment or by delivery of a burst of pulses.

AMPA receptors are ionotropic receptors present on the postsynaptic :membrane and help to depolarize the cell by controlling a sodi um ion channel. AMPA receptors are also required for LTP. When glutamate binds to the AMPA receptor, the resulting depolarization removes the Mg 2+ ion from the NMDA receptors, allowing Ca2 + to enter the c1~ll. A result of calcium signaling is the insertion of additional AMPA receptors in the postsynaptic membrane, strengthening the depolarization of the membrane. This enhanced depolarization is responsible for strengthening the synapses involved in LTP.

Role of NMDA Receptors LO 13.17 Compare the relationship between NMDA and AMPA receptors in LTP.

NMDA and AMPA receptors are present on the postsynaptic membrane and are required to establish LTP. NMDA and AMPA receptors are both ionotropic receptors that respond to glutamate and are found in the hippocampus. NMDA receptors are blocked by an ion of magnesium at rest, and require depolarization to remove the Mg2+ ion. AMPA receptors contribute this local depolarization to facilitate removal of the Mg 2+ ion. Once open, NMDA receptors allow Ca2+ ions to enter the cell, triggering intracellular events responsible for LTP and the recruitment of additional AMPA receptors to the terminal membrane.

Role of Syn aptic Changes LO 13.19 List the synaptic changes that accompany LTP.

LTP may involve presynaptic changes in existing synapses, such as an increase in the amount of glutamate that is released by the terminal bu tton. Presynaptic changes may be signaled from the postsynaptic cell via retrograde messengers. The establishment of LTP includes changes in the size and shapE! of postsynaptic dendritic spines into fatter, mushroom-shaped spines. Establishing LTP can cause the growth of new dendritic spines. Long-lasting LTP requires protein synthesis. The gene that codes for the production of the enzyme PKM-zeta is constantly produced in the nucleus and transported to dendritic spines, where its translation is blocked by the action of another enzyme, Pinl.

Learning and Memory

Thought Question Have you heard of clicker training? It's a form of training that pairs a unique sound (a "click" from a small noise maker) with a treat or other positive reinforcer and is used to train animals. After several pairings with food,

441

eventually the click" itself becomes reinforcing, and it can bE~ used to reinforce the behavior that precedes the click. )Explain what has happened in the hippocampus of the aniimal to induce LTP in the circuits associating the reinfo:rcer with a behavior. Describe the steps of LTP and explain how the brain is changed in this form of learning. /1

Chapter Review Questions 1. Describe the four basic forms of learning: perceptual learning, stimulus-response learning, motor learning, and relational learning. 2. Describe research on the role of the visual cortex in visual perceptual learning. 3. Describe research on perceptual short-term memory. 4. Discuss the physiology of the classically conditioned emotional response to aversive stimuli. 5. Describe the role of the basal ganglia in operant conditioning.

6. Discuss how the reinforcement system may detect reinforcing stimuli and strengthen synaptic connections. 7. Discuss the role of the hippocampal formation in episodic, semantic, and spatial memories and the role of the prefrontal cortex in evaluating the accuracy of memories. 8. Discuss research on the induction of long-term potentiation and the roles of NMDA and AMPA receptors.

Chapter 14

Human Communicaltion

Scanning electron microscope image of a neuron in the cortex.

Chapter Outline Language Production and Comprehension: Brain Mechanisms

La teraliza tion Language Production and Comprehension in the Brain Bilingualism Prosody Voice Recognition Disorders of Language Production and Comprehension

Disorders of Language Production: Broca' s Aphasia 442

Disorders. of Language Comprehension: Wernicke"s Aphasia Conductit::m Aphasia Aphasia in People Who Are Deaf Stuttering;

Disorders of Reading and Writing Pure Alexia Toward ain Understanding of Reading Toward ain Understanding of Writing

Human Communication

m

443

Learning Objectives

LO 14.1

Contrast language-related functions of the left and right hemispheres.

LO 141.7

Describe the symptoms and biological basis of Wernicke's aphasia.

LO 14.2

Identify brain regions involved in language production and comprehension.

LO 141.8

Describe the symptoms and biological basis of conduction aphasia.

LO 141.9

Compare common and languagespecific brain regions for bilingual language processing.

Describe the symptoms and biological basis of aphasia in people who are deaf.

LO 141.10

Describe the biological basis of and treatment strategies for stuttering.

LO 14.4

Identify brain structures and functions involved in prosody.

LO 141.11

Identify the symptoms and biological basis of pure alexia.

LO 14.5

Identify the brain regions involved in recognizing voices.

LO 141.12

Describe the biological basis of acquired and developmental dyslexia.

LO 14.6

Describe the symptoms and biological basis of Broca's aphasia.

LO 14.13

Explain the biological basis of phonological and orthographic dysgraphia.

LO 14.3

While driving her car to visit some friends, R. F., a 39-year-old woman, was hit by an intoxicated driver who ignored a stop

trying (without success) to read some words that I (N. C.) had typed. Suddenly, she said, "Hey! You spelled this one wrong."

sign. The left side of R. F.'s skull was fractured, and the bone fragments caused considerable damage to her brain. A neurosurgeon repaired the damage as best he could, but R. F. remained in a coma for several weeks. After considerable recovery, she had difficulty remembering the names of even the most common objects, and she could no longer read. Although R. F. could not read, she could match words with pictures, which indicated that she could still perceive words. This fact was made especially apparent one day when she was

I looked at the word and realized that she was right; I had. But although she saw that the word was misspelled, she still could not say what it was, even when she tried very hard to sound it out. That evening I made up a list of 80 pairs of words, one spHlled correctly and the other incorrectly. The next day I gave her a pencil and asked her to cross out the misspelled words. She was able to go through the list quickly and easily, correctly identifying 95 percent of the misspelled words. She was able to reac1 only five of them.

The case of R. F. illustrates several intriguing aspects of language processing in the brain. Her ability to perceive words and their spelling, but not sound out words or recognize them as specific words, reveals that different pathways and brain structures are responsible for the various components of speech production and comprehension, including reading and writing. Language and communication are important aspects of human social behavior. Our cultural evolution has been possible because we can communicate with others to share and record ideas. Language enables our discoveries to be cumulative. Knowledge gained by one generation can be passed on to the next. The basic function of language is seen in its effects on other people. When we communicate with someone, we almost always expect our message to induce the person to engage in some sort of behavior. Sometimes, the

behavior is advantageous, as when we ask for an object or for hellp in performing a task. At other times we are asking for a social exchange: some attention and perhaps some conve:rsation. Although many people use speech as a form of language to communicate, keep in mind that language encompasses written, symbolic, and gestural forms of communication as well. While many examples in this chapter come from research on speech, research is expanding to help us better understand the brain's involvement in different forms of communication. To begin to understand human communication, this chapter is organized with an introduction to the fundamental brain mechanisms of language production and comprehension, which will allow us to better understand the subsequent modules on disorders of language production and comprehension, and reading and writing.

444 Chapter 14

Language Production and Comprehension: Brain Mechanisms Much of our understanding about the brain mechanisms of language comes from observing the effects of brain injuries on people's verbal behavior. One category of language disorders that has been studied extensively is aphasia. Aphasia is a disturbance in the comprehension or production of language, caused by brain damage. Not all language disturbances are aphasias. To receive a diagnosis of aphasia, a patient must have difficulty comprehending, repeating, or producing meaningful language, and this difficulty must not be caused by sensory or motor deficits or by lack of motivation. For example, the inability to speak caused by deafness or paralysis of the speech muscles is not considered to be aphasia. In addition, the deficit must be relatively isolated. This means that the individual must appear to be aware of what is happening in their environment and to recognize that others are attempting to communicate. Two examples of specific aphasias that are discussed in this chapter are Broca's and Wernicke's aphasias. Broca's aphasia is an expressive aphasia resulting from damage to Broca's area in the left frontal lobe. Individuals with Broca's aphasia have difficulty producing language, through either verbal communication or sign languages such as American Sign Language (ASL). Wernicke's aphasia is a receptive aphasia caused by damage to Wernicke's area in the left temporal gyrus. (Look ahead to Figure 14.2.) This aphasia results in speech comprehension deficits. In individuals who primarily communicate using ASL, damage to this area results in deficits in comprehending signs (Campbell et al., 2007). Other information about the brain mechanisms of language comes from studies using functional-imaging techniques to assess language processes in healthy volunteers. In general, these studies have confirmed or complemented what we have learned by studying patients with brain damage.

Lateralization LO 14.1 Contrast language-related functions of the left and right hemispheres. The results of imaging and lesion studies have helped to identify unique brain regions involved in language-related functions. In the case of language, brain regions are distinguished based on function rather than on neuroanatomical differences. Language is largely a lateralized function. Most language disturbances occur after damage to the left side of

the brain, whether people are left-handed or right-handed. In approximately 90 percent of the total population, the left hemisphere is dominant for speech and language functions. Using an imaging procedure to measure changes in ce1rebral blood flow while people performed a verbal task, Knecht and colleagues (2000) assessed the relationship betwie en handedness and lateralization of speech mechanisms i1n people without any known brain damage. They found that right hemisphere speech dominance was seen in only 4 percent of right-handed people, in 15 percent of ambidextrnus people, and in 27 percent of left-handed people. This pattern h as been replicated in additional studies (Nenert et al., 2017). Using a similar verbal task in a sample of children and adults, Szaflarski and colleagues (2006) demonstrated that language lateralization corresponded with age, with the strongest indications of left hemisphere lateralization ,occurring in early adulthood. The degree of lateralization then appeared to decrease into older adulthood; howevcer, age-related declines in lateralization of language have not been found in all studies (Nenert et al., 2017). Figure 14.l shows combined representations of left hemisphere activation among children and adults during the verbal task in the study by Szaflarski and colleagues (2006). The images in the figure are reversed, with the left hemisphere on the right side of the image. Although the circuits that are primarily involved in language comprehension and production are typically located in one hemisphere (usually the left hemisphere), the opposite hemisphere also plays a role in speech and language. When we hear and understand words and when we talk about or think about our own perceptions or memories, we are using neural circuits in addition to

Figure 14.1. Left Hemisphere Activation in a Verb Generation Task The left hemisphcere was selectively activated when right-handed children and adults were asked to think of verbs that were associated with nouns they heard during the study (for example, chair, spoon). The images in th1e figure represent combined activity from all participants in thie study.

Human Communication 445 those directly involved in speech. For example, damage to the right hemisphere makes it difficult for a person to read maps, perceive spatial relations, and recognize complex geometrical forms. People with such damage also have trouble talking about things like maps and complex geometrical forms or understanding what other people have to say about them. The right hemisphere also appears to be involved in organizing a narrative--selecting and assembling the elements of what we want to say (Gardner et al., 1983). As we saw in Chapter 11, the right hemisphere is involved in expressing and recognizing emotion in the tone of voice. It is also involved in control of prosody- the rhythm and stress found in speech. Therefore, both hemispheres of the brain contribute to our language abilities. The importance oflateralization is also revealed through studies of patients who have undergone a surgical procedure known as the split-brain operation. This procedure involves surgically severing the corpus callosum, largely isolating each cerebral hemisphere. The split-brain surgical operation is sometimes used to treat very severe seizure disorders, when neurons in one side of the brain become uncontrollably overactive, and the overactivity is transmitted to the other side of the brain by the corpus callosum. After the split-brain operation is performed, the two disconnected hemispheres operate independently; their sensory mechanisms, memories, and motor systems can no longer exchange information. Something that patients may notice after the operation is that their left hand seems to have a "mind of its own." For example, patients may find themselves putting down a book held in the left hand, even if they have been reading it with great interest. This conflict occurs because the right hemisphere, which controls the left hand, cannot read and therefore finds holding the book boring. At other times patients may surprise

Figure 14.2

themselves by making gestures (with the left hand) when they had not intended to. A psychologist once reported that a man with a split brain attempted to hit his wife with one hand and protect her with the other. You might think that disconnecting the brain hemispheres would be devastating, but the effects of the splitbrain operation are not immediately obvious to the casual observer. This is because in many circumstances, stimuli are coinveyed to both hemispheres simultaneously. For example, looking directly a picture of an apple using both eyes, the visual stimulus is conveyed through both the right and left visual fields and the left hemisphere is able to cor:rectly answer "apple" when the person is asked to identiJfy the picture. Only one hemisphere-as you just read, iin most people, the left-controls language production and comprehension. If the information does not reach the left hemisphere, then the person cannot communicate about it. The right hemisphere of a person with a split brain appears able to understand instructions reasonably well, but it is incapable of producing language; therefore, any sltimuli that reach the right hemisphere cannot be communicated, or at least not through language. For example, if the picture of an apple is shown only to the left visual field and conveyed only to the right hemisphere, withoiut a language-processing center in the right hemisphere, the person cannot verbally identify the image (or use a :nonverbal sign or gesture to identify it). In fact, the person will not even report being aware that the stimulus was seen. However, if the person is allowed to select a matching item from a list or draw a picture of the stimulus with their left hand, they will correctly identiJfy an apple. If you then ask the person why they selected or drew the apple, they will not have a conscious reason for selecting it (consciousness in this sense requires the use of language).

Testing the Effects of the Split-Brain Operation

Experiments with split-brain patients have helped to illuminate the lateralized nature of brain function. Split-brain patients have undergone surgery to cut the corpus callosum, the main bundle of neuronal fibres connecting the two sides of the brain.

A word is flashed briefly to the right field of view, and the patient is asked what he saw.

Now a word is flashed to the left field of view, and the patient is asked what he saw.

FACE Corpus callosum versa.

Left

Because the left hemisphere is dominant for verbal processing, the patient's answer matches the wordl.

The right hemisphere cannot share information with the left, so the patient is unable to say what he saw, but he can draw it (with the left hand).

446

Chapter 14

The effects of cutting the corpus callosum reinforce the conclusion that we become conscious of something only if information about it is able to reach the parts of the brain responsible for language in the left hemisphere. If the information does not reach these parts of the brain, then that information does not reach consciousness. We still know very little about the physiology of consciousness, but studies of people who have undergone the splitbrain operation are beginning to provide us with some useful insights.

Language Production and Comprehension in the Brain LO 14.2 Identify brain regions involved in language production and comprehension. As you read, independent, but interacting, brain regions are involved in language production and comprehension. The following section summarizes the roles of several key language regions in the brain. LANGUAGE PRODUCTION Language production requires multiple factors. For example, being able to produce meaningful language requires several abilities. First, the person must have something to communicate about. Let us consider what this means. To use speech as a form of communication, we can talk about something that is currently happening or something that happened in the past. When we talk about something that is happening, we are talking about our perceptions: things we are seeing, hearing,

Figure 14.3

feeling, smelling, and so on. When we talk about something that happened in the past, we are talking about our memories. Both perceptions of current events and memories of events that occurred in the past involve brain mechanisms in the posterior part of the cerebral hemispheres (the occipital, temporal, and parietal lobes). Along with some parts of the p1refrontal cortex, these regions are largely responsible for iour having something to say and our ability to tell a story about it (D' Argembeau, 2013; Levine, 2004; Mar, 2004). We can also talk about something that did not happen and use our imagination to make up a story (or to tell a lie). We know very little about the neural mechanisms that are responsible for imagination, but it seems likely that they invo1lve the mechanisms responsible for perceptions and memories because when we make up a story, we usually base it on knowledge that we originally acquired through pew~ption and have retained in our memory. Regardless of whether we are communicating about something that happened, or something we imagined, converting our thoughts into language requires several important brain regions. LANGUAGE COMPREHENSION The brain mechanisms involved in recognizing words and comprehending their meaning worlk a little like a dictionary. (See Figure 14.3.) Dictionaries contain entries (the words) an d definitions (the meanings of the words). In the brain, we h ave at least two types of Emtries: auditory and visual. That is, we can look up a word according to how it sounds or how it looks (in writing). Let's consider one type of entry: The sound of

The "Dictionary " in the Brain

Wernicke's area contains the auditory entries of words; the meanings are c:ontained as memories in the sensory association areas. Black arrows represent comprehension of words - the activation of memories that correspond to a word 's meaning. Red arrows represent translation of thou9hts or perceptions into words. Wernicke's area (word recognition) Broca's area (speech production)

Meanings of wiords

Perceptions and ;:::::::::=-memories Primary auditory cortex

Posterior language - - area (interface between Wernicke's area and perceptions and memories)

~ Perceptions and Caudate region

memories

Human Communication

a word. When we hear a familiar word, how do we understand its meaning? First, we must recognize the sequence of sounds that constitute the word: We find the auditory entry for the word in our "dictionary." These entries are stored in Wernicke's area in the auditory association cortex of the left temporal lobe. As you have already read, Wernicke's area is required for comprehension and production of meaningful language. It is possible to produce speech when Wernicke's area has been damaged, but the speech often does not make sense to the listener. Next, memories associated with the word are activated. Wernicke's area is connected through the posterior language area to neural circuits that contain these memories. Language conveys more than simple words denoting objects or actions. It also conveys abstract concepts, some of them quite subtle. Studies of patients with brain damage (Brownell et al., 1983, 1990; Lundgren & Brownell, 2016) suggest that comprehension of the more subtle, figurative aspects of language involves the right hemisphere in particular-for example, understanding the meaning behind metaphors, proverbs such as "People who live in glass houses shouldn't throw stones," or moral stories. Functional-imaging studies confirm these observations (Yang, 2014). Nichelli and colleagues (1995) found that judging the moral of Aesop's fables (in contrast to judging more superficial aspects of the stories) also activated regions of the right hemisphere. Sotillo and colleagues (2005) found that a task that required comprehension of metaphors such as "green lung of the city" (a park) activated the right superior temporal cortex. (See Figure 14.4.) Pobric and colleagues (2008) found that temporarily disrupting the right superior temporal cortex by using TMS impaired people's ability to understand

Figure 14.4

Evaluating Metaphors

These images of neural activity were produced by evaluating the meaning of metaphors. Source: Based on Sotillo, M., Carretie, L., Hinojosa, J. A. , Tapia, M., Mercado, F., Lopez-Martin, S., and Albert, J. (2005). Neural activity associated with metaphor comprehension: spatial analysis. Neuroscience Letters, 373, 5-9.

L

Caudal - - - - • Rostral

447

novel metaphors, such as a "conscience storm." The use of TMS had no effect on the participants' ability to understand conventional metaphors, such as "sweet voice," that they had already heard, or literal expressions such as "snow storm."

Bilingualism LO 14.3 Compare common and language-specific brain regions for bilingual language p rocessing. The majority of people in the world are bilingual or multilingual. Are the brains of people who are bilingual different from those of people who are monolingual? What brain structures are involved in communkating in second (or third, or fourth, or fifth) languages? Bi.lingual patients with lesions sometimes display aphasia symptoms in one language and not another, or specific deficits affecting (for example) speech in one language and writing in another. This led early researchers to conclude that different languages were processed by different brain structures. Imaging techniques such as fMRI and PET allow researchers to more closely examine the brain regions involved in communication by bill ingual (or multilingual) individuals. The accumulation of research from these studies revealed that communication in different languages involves some common regions and some language-specific regions, or language specific-patterns of activation in the brain (Xu et al., 2017). Giussani and colleagues (2007) reviewed seven different electrostimulation studies of the cortex in bi- and multilinguaJ patients. The patients in each of these studies were undergoing brain surgery, usually to remove lesions or tumors, and rnicroelectrodes were used to stimulate brain regions Ito assess their language function prior to surgery. The patients completed tasks such as naming objects or reading in theiir primary and secondary languages while the stimulation occurred. If the patient's performance on the task was altered or interrupted during stimulation, then a function in that language was assigned to the brain area. This process allowed the neurosurgeon to map the language functions of the brain, avoiding damage to these regions as the lesion or tumor was removed. The electrostimulation studies found both common and language-specific regions. Common and language-specific areas were found in the frontal and posterior temporal/parietal cortexes. In addition, language-specific areas were found in some subcortical structures. An example of language-specific and common language areas in a bilingual English-French speaking patient is included in Figure 14.5. Additional networks of cortical and subcortical brain regions are involved in the cognitive processes required to keep different languages separa1te, and use the correct language in certain situations (Calabria et al., 2018; Cargnelutti et al., 2019).

448 Chapter 14

Figure 14.5

Mapping Common and Language-Specific Areas of the Cortex

A 31 -year-old bilingual English-French right-handed patient was operated on for a small low-grade glioma located in the left parietal lobe. French was his native language?. He started learning English after age 11. No language problem was detected preoperatively. Direc:t cortical electrostimulation revealed one French-specific naming interference site (single flag) wheireas one site was common for English and French (overlapping flags). Source: Giussani, C., Roux, F. E., Lubrano, V., Gaini, S. M., et al. (2007). Review of language organisation in bilingual patients: What can we learn from direct brain mapping? Acta Neurochirurgica, 149(11), 1109-1111.

In other research investigating the neural basis of bilingualism, Mechelli and colleagues (2004) found that the structure of the cortex was changed by learning a second language. The researchers assessed the density of grey matter and found increased density in the left parietal cortex of bilingual compared to monolingual individuals. The change in density was greater among people who learned a second language early in life (before the age of 5) and those who were most proficient in their second language. Kuhl and her colleagues (2016) measured changes in the brains of adults who learned a second language (English) in adulthood. The researchers found that speaking experiences affected white matter in regions associated with speech comprehension, while listening experience affected white matter in regions associated with production. (See Figure 14.6.) These findings may seem counterintuitive, however, in children learning their first language, listening to speech activates regions involved in motor production, too.

Prosody LO 14.4 Identify brain structures and functions involved in prosody.

When we speak, we do not merely utter words. Speech (and other forms of communication such as signing) has

a regular rhythm and cadence. A speaker can give some words stress (for example, pronounce them louder), and vary the pitch of their voice to indicate phrasing and to

Figure 14.6

White Matter Changes in the Bilingual Brain

Diffusion tensor imaging shows differences in white matter structure associated with speaking (red) and listening (yellow) experience in a second language! among bilingual adults compared to monolingual adults.

Human Communication

distinguish between assertions and questions. In addition, a speaker shares information about their emotional state through the rhythm, emphasis, and tone of their speech. These rhythmic, emphatic, and melodic aspects of speech are referred to as prosody. The importance of these aspects of communication is illustrated by our use of punctuation symbols to indicate some elements of prosody when we write. For example, a comma indicates a short pause; a period indicates a longer one with an accompanying fall in the pitch of the voice; a question mark indicates a pause and a rise in the pitch of the voice; and an exclamation mark indicates that the words are articulated with special emphasis. The prosody of people with Wernicke's aphasias caused by lesions to posterior brain structures is normal. For example, their speech is rhythmic, with pauses after phrases and sentences, and has a melodic line. Even when the speech of a person with severe Wernicke's aphasia makes no sense, prosody is unaffected. In contrast, the anterior lesions that produce Broca's aphasia destroy grammar, and they also severely disrupt prosody. In patients with Broca's aphasia, articulation is labored and words are uttered slowly so that there is little opportunity for the patient to demonstrate any rhythmic elements. There is little variation in stress or pitch because prosodic variation usually goes along with the syntactic structure of a phrase or sentence, which is impaired in Broca's aphasia. Although prosodic disruption can occur in aphasia, studies of healthy individuals and patients with right hemisphere brain lesions have also shown that the right hemisphere of the brain plays an important role in prosody. For example, Weintraub and colleagues (1981) presented participants with two written sentences and asked a question about them. They presented the following pair of sentences: The man walked to the grocery store. The woman rode to the shoe store. The participants were instructed to answer questions by reading one of the sentences. Try this one yourself. Read the question below and then read aloud the sentence (above) that answers it. Who walked to the grocery store, the man or the woman? The question asserts that someone walked to the grocery

449

Figure 14.7 Listening to Normal Speech or Its Prosoclic Components Functional MRI scans were made while participants listened to normal speech (blue and green regions) or the prosodic elements of spee·c h w ith the meaningful components filtered out (orange and yellow regions). Source: From Meyer, M., Alter, K., Friederici, A D., Lohmann, G., and von Cramon,. 0. Y. (2002). FMRI reveals brain regions mediating slow prosodic modulations in spoken sentences. Human Brain Mapping, 17, 73-88. Reprinted with permission.

Ini a functional-imaging study by Meyer and colleagues (2002), participants heard normal sentences or semtences that contained only the prosodic elements of speech with the meaningful sounds filtered out. As you can see in Figure 14.7, the meaningful components of speech primarily activated the left hemisphere (blue and green regions), whereas the prosodic components primarily activated the right hemisphere (orange and yellow regions).

Voice Recognition LO 14.5 Identify the brain regions involved in recognizing voices. Recognizing the voice of a speaker can convey information completely independent of the meaning of the words: the identity of the speaker, possibly their gender or overall health, and hints about their age. People learn at an early age to recognize the voices of particiular individuals. Even newborn infants can recognize the voices of their parents, which they apparently learned while they were still in their mother's uterus (Beauchemin et al., 2011; Ockleford et al. 1988).

store but asks who that person was. When answering a

Some people with localized brain damage have

question like this, people normally stress the requested item of information; in this case they say, "The man walked to the grocery store." However, Weintraub and her colleagues found that although patients with right hemisphere brain damage chose the correct sentence, they either failed to stress a word or stressed the wrong one. This indicates that the right hemisphere plays a role in production of prosody.

great difficulty recognizing voices-a disorder known as phonagnosia. Most cases of phonagnosia are caused by bratin damage. Recognition of a particular voice is indeperndent of the recognition of words and their meanings: :Some people have lost the ability to understand words but can still recognize voices, while others display the opposite deficits (Belin et al., 2004) . So far, all

450 Chapter 14 cases of acquired phonagnosia (phonagnosia caused by brain damage) show damage in the right hemisphere, usually in the parietal lobe or the anterior superior temporal cortex. Functional-imaging studies have implicated the right anterior superior temporal cortex in voice recognition. For example, von Kriegstein and colleagues (2003) found that this region was activated by a task that required participants to recognize particular voices but not particular words. The first recorded case of developmental phonagnosia (that is, phonagnosia not caused by brain damage) was reported by Garrido and colleagues (2009):

K. H .. a 60-ye,ar-old management consultant, has had, all her life, great d ifficulty recognizing people by their voices. K. H. read an article in a popular scientific magazine that described prosopagnosia, the d ifficulty - or even inability- to recognize people's faces. She rea1lized that her d isorder could be an auditory form of this d isorder. Testing showed that her intelligence was above average and t11at she received normal or above normal scores on a variety of perceptual tasks, including face recognit ion, speech perception, recognition of environmental sounds, and perception of music. Structural MRI showed no evidence of brain abnormalities, but there certainly must be some subtle differences in bra1in organization to account for her disability.

Module Review: Language Production and Comprehension: Brain Mechanisms Lateralization LO 14.1

Contrast language-related functions of the left and right hemispheres.

Both hemispheres contribute to our language abilities. Language functions are lateralized in the brain with circuits for comprehension and production located in the left hemisphere for the majority of people. The right hemisphere plays a role in processing emotional content, rhythm, and stress of language.

Language Production and Comprehension in the Brain LO 14.2

Identify brain regions involved in language production and comprehension.

The occipital, temporal, and parietal lobes are involved in perceiving real or imaginary events and memories that an individual may communicate about. Broca's area, in the left frontal lobe just rostral to the region of the primary motor cortex that controls the muscles of speech, is involved with language production. Language comprehension involves recognizing a word using Wernicke's area in the left hemisphere. Language comprehension also requires understanding the meanings of words. Comprehension of the figurative aspects of language involves the right hemisphere.

Bilingualism LO 14.3

Compare common and language-specific brain regions for bilingual language processing.

Bilingual individuals likely possess some brain regions devoted to specific languages as well as areas that are common to both languages used. These brain regions can be identified using imaging techniques such as PET and

fMRI, or by direct electrostimulation. Research in bilingual patients revealed common and language-specific areas in the frontal and posterior temporal/parietal cortexes. Language-specific areas were found in some subcortical structures.

Prosody LO 14.4

lde:ntify brain structures and functions inv·olved in prosody.

Prosody involves changes in intonation, rhythm, and stress that add meaning to language. Although Broca's aphasia (caused by left hemisphere damage) produces deficits in prosody, other neural mechanisms that control prosodic ·elements appear to be located in the right hemisphere.

Voice Recognition LO 14.5

lde:ntify the brain regions involved in recognizing voices.

Voice recognition occurs early in development. Phonagnosia is a difficulty recognizing voices and is typically caused by damage to the right parietal or temporal cortex.

Thought Question In a survey of 717 people, Seidman and colleagues (2013) found that when using a cell phone most righthanded people used their right ear to converse. Similarly, most l·eft-handed people used their left ear. Although the survey only investigated correlational data, what are some plausible brain-based hypotheses for this behavior that the researchers could test next? Propose possible explanations and research strategies to better address this topic.

Human Communication 451

Disorders of Language Production and Comprehension

Figure 14.8 Assessment of Aphasia The drawing of the kitchen story is part of the Boston Diagnostic Aphasia Test.

Much of our understanding of the brain mechanisms of language has come from the study of disorders. Language disorders affect both production and comprehension, revealing different, but often overlapping, pathways and structures. The following module includes a description of Broca's and Wemicke's aphasias, as well as conduction aphasia, aphasia in people who are deaf, and stuttering.

Disorders of Language Production: Broca's Aphasia LO 14.6 Describe the symptoms and biological basis of Broca's aphasia. As you've already read, damage to the frontal lobe produces Broca's aphasia, a disorder characterized by slow, laborious, and nonfluent speech. Although they often mispronounce words, the words patients produce are usually meaningful. The posterior part of the cerebral hemispheres has something to communicate, but the damage to the frontal lobe makes it difficult for the patients to express these thoughts. People with Broca's aphasia comprehend language better than they are able to produce it. People with Broca's aphasia find it easier to say some types of words than others. They have great difficulty saying small words with grammatical meaning, such as a, the, some, in, or about. These words are called function words, because they have important grammatical functions. People with Broca's aphasia use almost entirely content words. Content words convey meaning, and include nouns, verbs, adjectives, and adverbs, such as apple, house, throw, or heavy. Here is a sample of speech from a man with Broca's aphasia, who is trying to describe the scene shown in Figure 14.8. As you w ill see, his words are meaningful, but what he says is not grammatical. The dots indicate long pauses: kid .... kk ... can ... candy ... cookie ... candy ... well I don't know but it's writ ... easy does it ... slam .. . early .. . fall ... men ... many no ... girl. Dishes .. . soap ... soap .. . water ... water ... fallingpah that's all ... dish ... that's all. Cookies ... can ... candy ... cookies cookies .. . he ... down ... That's all. Girl ... slipping water ... water ... and it hurts ... much to do ... Her ... clean up ... Dishes ... up there .. . I think that's doing it. (Obler & Gjerlow, 1999, p. 41) Lesions that produce Broca's aphasia are centered in the vicinity of Broca's area. However, damage that is

restricted to only the cortex region of Broca's area does not appear to produce Broca's aphasia. In Broca's aphasia, the damage extends to surrounding regions of the frontal lobe and to the underlying subcortical white matter, which contains bundles of myelinated axons that convey messages from one brain region to another (Damasio, 1989; Naeser et al., 1989). In addition, there is evidence that lesions of the basal ganglia-especially the head of the caudate nucleus-can also produce a Broca'slike aphasia (Damasio et al., 1984). (See Figure 14.3.) Watkins and colleagues (2002a, 2002b) studied three generations of a family, half of whose members are affected by a severe speech and language disorder caused by the mutation of a single gene found on chromosome 7. The primary deficit appears to involve the ability to perform the sequential movements necessary for speech, but the affected people also have difficulty repeating sounds they hear amd forming the past tense of verbs. The mutation causes abnormal development of the caudate nucleus and the left inferior frontal cortex, including Broca's area. W'hat do the neural circuits in and around Broca's area do? Wernicke (1874) suggested that Broca's area contains motor memories~in particular, memories of the sequences of muscular movements that are needed to articulate words.. Talking requires some very sophisticated motor control mechanisms. Talking involves rapid movements of the tongue, lips, and jaw, and these movements must be coordinated with each other and with those of the vocal cords. Circuits of neurons somewhere in the brain will, when properly activated, cause these sequences of movements to be executed. Because damage to the inferior caudal leJft frontal lobe (including Broca's area) disrupts the ability to articulate words, this region is a likely candidate for the location of these "programs." The fact that this region is directly connected to the part of the primary motor cortex that controls the muscles used for speech certainly supports this conclusion.

452 Chapter 14 But the speech functions of the left frontal lobe include more than just programming the movements used to speak. Broca's aphasia is much more than just a deficit in pronouncing words. In general, three major speech and language deficits are produced by lesions in and around Broca's area: agrammatism, anomia, and articulation difficulties. Although most patients with Broca's aphasia will have all of these deficits to some degree, their severity can vary considerably from person to person-presumably because their brain lesions differ in size and location. AGRAMMATISM Agrammatism refers to a patient's difficulty using grammatical constructions. This disorder can appear all by itself, without any difficulty in pronouncing or retrieving words (Nadeau, 1988). As we saw, people with Broca's aphasia rarely use function words. In addition, they rarely use grammatical markers such as -ed or auxiliaries such as have (as in 1 have gone). For some reason, they do often use -ing, perhaps because this ending converts a verb into a noun, or because -ing in English is the most common verb ending, and therefore might be a kind of "default" form of the verb. A study by Saffran and colleagues (1980) illustrates this difficulty. The following quotations are from people with agrammatism attempting to describe pictures:

Functional-imaging studies by Opitz and Friederici (2003, 2007) h ave shown that Broca's area is activated when people are taught an artificial grammar, which supports the conclusion that this region is involved in learning grammatical rules. Sakai and colleagues (2002) had experime~ntal participants read sentences that were correct, grammatically incorrect, or semantically incorrect (that is, did not make sense) . While the participants were judging the grammatical or semantic correctness of the sentences, the investigators applied transcranial magnetic stimulation (TMS) to Broca's area. The parameters of stimulation were chosen to activate Broca's area, not to disrupt its fwnctioning. The investigators found tha t the stimulation facilitated grammatical judgments but not semantic judgments. This provides more evidence that Broca's area is crucially involved in processing grammatical aspects of language. ANOMIA The second major language deficit seen in Broca's aphasia is anomia. Anomia refers to a wordfinding diffic1Ulty; because all people with aphasias omit words or use iinappropriate ones, anomia is actually a primary symptom of all forms of aphasia. The facia l expressions and fre,quent use of sounds such as "uh" make it clear that patiients with Broca's aphasia are searching for the correct words.

Picture of a boy being hit in the head by a baseball

ARTICULATION DIFFICULTIES The third major char·

The boy is catch ... the boy is hitch ... the boy is hit the ball. (Saffran et al., 1980, p. 229)

acteristic of Hroca's aphasia is difficulty with articulation. Patie nts mispronounc e words, often a ltering the sequence of sounds. For example, lipstick might be pronounced "liks:tip." People with Broca's aphasia recognize that their pronunciation is erroneous, and they usually try to correct iit. These thr,ee deficits are seen in various combinations in different patients, depending on the exact location of the lesion and, to a certain extent, on their stage of recovery. We can think of these deficits as constituting a hierarchy. On the lowest, most elementary level is control of the sequence of movements of the muscles of speech; damage to this ability leads to articulation difficulties. The next higher level is selection of the particular "programs" for individual words; damage to this ability leads to anomia. Finally, the highest level is selection of grammatical structure, including word order, use of function words, and word endings; damage to this ability leads to agrammatism. We might expect that the direct control of articulation would involv1e the face area of the primary motor cortex and portions of the basal ganglia, while the selection of words, word order, and grammatical markers would involve Broca's area and adjacent regions of the frontal association cortex. Some studies indicate that different categories of symptoms of Broca's aphasia do indeed involve different brain regions. Dronkers and her colleagues

Picture of a girl giving flowers to her teacher Girl ... wants to ... flowers ... flowers and wants to .. .. The woman ... wants to .... The girl wants to ... the flowers and the woman. (Saffran et al., 1980, p. 234) So far, we have described Broca's aphasia as a disorder in language production. In ordinary conversation, people with Broca's aphasia seem to understand everything that is said to them. They are distressed by their inability to express their thoughts well, and they often make gestures to supplement their missing speech. The striking disparity between their speech and their comprehension often leads people to assume that their comprehension is typical. But it is not. Schwartz and colleagues (1980) showed people with Broca's aphasia pairs of pictures in which agents and objects of the action were reversed: a truck pulling a car and a car pulling a truck. As they showed each pair of pictures, they read the participant a sentence, for example, active sentences like The truck pulls the car, or passive sentences like The car is pulled by the truck. The patients' task was to point to the appropriate picture, indicating whether they understood the grammatical construction of the sentence. They performed very poorly on passive sentences like The car is pulled by the truck, where word order does not help with interpretation.

Human Communication 453 (Baldo et al., 2011; Dronkers, 1996) identified a critical location for control of speech articulation: the left precentral gyrus of the insula. The insular cortex is located on the lateral wall of the cerebral hemisphere behind the anterior temporal lobe. Normally, this region is hidden and can be seen only when the temporal lobe is d issected away. (See Figure 14.9.) Dronkers discovered the apparent role of this region by plotting the lesions of patients with and without apraxia of speech who had strokes that damaged the same general area of the brain. (Apraxia of sp eech is an impairment in the ability to program movements of the tongue, lips, and throat that are required to produce the proper sequence of speech sounds.) At least two functional-imaging studies support Dronkers's conclusion. Kuriki and colleagues (1999) and Wise and colleagues (1999) found that pronunciation of words caused activation of the left anterior insula. However, other studies suggest that Broca's area is also involved in articulation (Hillis et al., 2004; Nestor et al., 2003). Stewart and colleagues (2001) used TMS to interfere with the activity of neurons in Broca's area or the adjacent area of primary motor cortex, which controls the muscles used for speech. The participants reported that stimulation of the motor cortex made them feel as though they had lost control of their facial muscles. In contrast, stimulation of Broca's area made them feel as if they were unable to "get the word out." Most of us have, at one time or other, had difficulty getting a word out even though the word was one that we knew well. This phenomenon has been called the "tip of the tongue phenomenon," or TOT. Shafto and colleagues (2007) found that people who often had difficulty thinking of the correct word to say but were sure that they knew it (that is, often had a TOT experience) showed loss of gray matter in the left insular cortex. In a study of older adults, fMRI was used to determine brain regions involved in TOT experiences while attempting to identify famous faces. Regions of the prefrontal cortex and insular cortex were activated in TOT (Huijbers et al., 2017). (See Figure 14.10.)

Figure 14.9 The Insular Cortex and Its Involvement in Spe,ech The cortex is normally hidden behind the rostral temporal lobe. Evidence for involvement is shown by the percentage overlap in the lesions of 25 patients. Frontal lobe pulled up

Heschl's gyrus

Temporal lobe pulled down

Disorders of Language Conrrprehension: Wernicke' s Aphasia LO 14.7 Describe the symptoms and biological b asis of Wemicke's aphasia. Speech comprehension begins in the auditory system, which detects and analyzes sounds. But recognjzing words is one thing; comprehending them-understanding their meaning- is another. Recognizing a spoken word is a complex perceptual task that relies on memories of sequences of sounds. This task appears to be accomplished by neural circuits in the superior temporal gyros of the left hemispherE~, a region that has come to be known as Wernicke's area. (Refer back to Figure 14.3.)

Figure 14.10 Brain regions involved in TOT Whole brain maps of functional MRI activity related to TOT. Brain activity is projected onto the cortical surface. On the right, a coronal slice is shown to visualize lack of activity in the hippocampal formation. Tip of the Tongue 5.0 3.5 0

454 Chapter 14 As you read, the primary characteristics of Wernick e's aphasia are poor language comprehension and production of meaningless speech. Unlike Broca's aphasia, speech in Wemicke's aphasia is fluent and unlabored. A person with Wernicke's aphasia does not strain to articulate words and does not appear to be searching for them. The patient maintains a melodic line, with the voice rising and falling normally. When you listen to the speech of a person with Wernicke's aphasia, it appears to be grammatical. That is, the person uses function words such as the and but and employs complex verb tenses and subordinate clauses. However, the person uses few content words, and the words that they string together do not make sense, illustrated by the following quotation:

Examiner: What kind of work did you do before you came into the hospital? Patient: Never, now mista oyge I wanna tell you this happened when happened when he rent. His-his kell come down here and is-he got ren something. It happened. In thesse ropiers were with him for hi-is friend-like was. And it just happened so I don't know, he did not bring around anything. And he did not pay it. And he roden all o these arranjen from the pedis on from iss pescid. In these floors now and so. He hadn't had em round here. (Kertesz, 1981, p. 73) Because of the language deficits of people with Wernicke's aphasia, when assessing their ability to comprehend language, it is important to ask them to use nonverbal responses. We cannot assume that people with Wernicke's aphasia do not understand what other people communicate to them just because they do not give a correct verbal answer. For example, you could assess a person's ability to understand questions by pointing to objects on a table in front of them. A person might be asked to "Point to the one with ink." If the person points to an object other than the pen, they have not understood the request. When tested this way, people with severe Wernicke's aphasia do indeed show poor comprehension. People with Wernicke's aphasia often seem unaware of their deficit. These individuals do not appear to recognize that their language is impaired, nor do they recognize that they cannot understand the language of others. They do not look puzzled when someone tells them something, even though they cannot understand what they hear. It is possible that the comprehension deficit prevents them from realizing that what they say and hear makes no sense. People with Wernicke's aphasia still follow social conventions, taking turns in conversation with the examiner, even though they do not understand what the examiner says and what they say in return makes little sense. They remain sensitive to the other person's facial expression and tone of voice and begin talking when the examiner asks a question and pauses

for an answer. One patient with Wernicke's aphasia made the following responses when asked to name ten common objects:

toothbrush

--+

"stoktery"

cigarette--+ "cigarette"

pen --+ "tan.kt" knife --+ "nike" fork --+ "falhk" quarter -> "minkt" pen --+ "spentee" matches - • "senktr" kei;-> "seek" comb-> "sahk" He acted confidently and gave no indication that he recognized that most of his responses were not actual words. The re:sponses that he made were not new words that he had invented; he was asked several times to name the objects and gave different responses each time (except for cigarette, which he always named correctly). Because tl11e superior temporal gyrus is a region of auditory associa1tion cortex, and because a comprehension deficit is so prominent in Wernicke's aphasia, this d isorder has been characterized as a receptive aphasia (in contrast to an expressive aphasia like Broca's aphasia, in which individuals hav·e greater difficulty expressing language, but not "receiving;" or understanding it). Wernicke suggested that the region that now bears his name is the location of memories of the sequences of sounds that constitute words. This hypothesis is reasonable. It suggests that the auditory association cortex of the superior temporal gyrus recognizes the sounds of words, just as the visual association cortex of the inferior temporal gyrus recognizes the sight of objects. But why should damage to an area that is responsible for the ability to recognize spoken words disrupt people's ability to speak? In fact, it does not; Wernicke's aphasia, like Broca's aphasia, actually appears to consist of several deficits. The albilities that are disrupted include recognition of spoken words, comprehension of the meaning of words, and the ability to convert thoughts into words. We will consider each of these abilities in turn. DEFI CITS I N SPOKEN WORD RECOG NITION As you read in the introduction to this module, recognizing a word is not the same as comprehending it. If you hear a new word several times, you will learn to recognize it; but unless someone tells you what it means, you will not comprehend it. Recognition is a perceptual task. Comprehension involves retrieval of additional (linguistic) information from memory.

Human Communication

Damage to the left temporal lobe can produce a disorder of auditory word recognition. This syndrome is called p u re word d eafness. (See Figure 14.11.) People with pure word deafness are not deaf. They can perceive and recognize speech, but they cannot understand the words. As one patient put it, "I can hear you talking, I just can't understand what you're saying." Another said, "It's as if there were a bypass somewhere, and my ears were not connected to my voice" (Saffran et al., 1976, p. 211). These patients can recognize nonspeech sounds such as the barking of a dog, the sound of a doorbell, and the honking of a horn. Often, they can recognize the emotion expressed by the intonation of speech even though they cannot understand what is being said. More significantly, their own speech is unaffected. They can often understand what other people are saying by reading their lips. They can also read and write, and they sometimes ask people to communicate with them in writing. Pure word deafness is not an inability to comprehend the meaning of words. If it were, people with this disorder would not be able to read people's lips or read words written on paper. Their speech deficit is restricted only to the recognition of spoken words. Even when specific spoken words are not recognized, individuals with pure word deafness correctly perceive the qualities of human speech and know that another person is speaking. Functional-imaging studies show that perception of speech sounds activates neurons in the auditory association cortex of the superior temporal gyrus. For example, Scott and colleagues (2000) identified a region of the

Figure 14.11 Pure Word Deafness An MRI scan shows the damage to the superior temporal lobe of a patient with pure word deafness (arrow). Source: Stefanatos, G. A., Gershkoff, A., & Madigan, S. (2005). On pure word deafness, temporal processing, and the left hemisphere. Journal of the International Neuropsychological Society, 11, 456-470. Reprinted with permission.

455

left anterior superior temporal gyrus that was specifically activated by intelligible speech, indicating that activity in this region is specific to the perception of speech sounds, but no•t particular words. (See Figure 14.12.) Sharp and colleagues (2004) found that lesions of this same region produced deficits in language comprehension. What is involved in the analysis of speech sounds? Just what tasks does the auditory system have to accomplish? And what are the differences in the functions of the auditory association cortex of the left and right hemispheres? Most researchers believe that the left hemisphere is primarily involved in judging the timing of the components of rapidly changing complex sounds, whereas the right ]hemisphere is primarily involved in judging more slowly changing components, including melody. Evidence suggests that the most crucial aspect of speech sounds is timing, not pitch. People recognize words whether they are conveyed by the lower pitch, for example of a man, or the higher pitch of a woman or child. In fact, most people can under:stand speech from which almost all tonal information has been removed, leaving only some noise modulated by the rapid stops and starts that characterize human speech sounds.

Figure 14.12 Responses to Speech Sounds Results. of PET scans indicate the regions of the superior temporal lobe that respond to speech sounds. Red: Regions that responded to phonetic information (normal speech sounds or a computerized transformation speech that preserved the complexity of the speech sounds but rendered it unintelligible). Orange: Region that responded to intelligible speech (normal speech sounds or a computerized transformation that removed most normal frequencies but preserved intelligibility). Source: Based on Scott, S. K., Blank, C. C.. Rosen, S., & Wise, R. J . (2000). Identification of a pathway for intelligible speech in the left temporal lobe. Brain, 123(12), 2400-2406.

456 Chapter 14

Two types of brain injury can cause pure word deafness: disruption of auditory input to the superior temporal cortex or damage to the superior temporal cortex itself (Poeppel, 2001; Stefanatos et al., 2005). Either type of damage disturbs the analysis of the sounds of words and prevents people from recognizing other people's speech. As we saw in Chapter 8, our brains contain circuits of mirror neurons-neurons activated when we either perform an action or see the action performed by someone else. Feedback from these neurons may help us to understand the intent of the actions of others. Although speech recognition is an auditory event, research indicates that hearing words automatically engages brain mechanisms that control speech production, too. These brain circuits appear to contain mirror neurons that are activated by the sounds of words. For example, Fridricksson and colleagues (2008) found that when people watched (but did not hear) other people making speech movements, the temporal (auditory) and frontal (motor) cortical language areas were activated. These regions were not activated when the participants watched people making nonspeech movements with their mouths. Several researchers have suggested that feedback from subvocal articulation (very slight movements of the muscles involved in speech that do not cause obvious movement) facilitate speech recognition (Pulvermiiller &

Fadiga, 2010). For example, a functional-imaging study by Pulvermiiller and colleagues (2006) had participants articulate syllables that contained the consonants p or t (for example, pa and ta), which involve movements of the lips or tongue. The participants said the syllables aloud, said them to themselves silently, and listened to the syllables spoken by someone else. As Figure 14.13 shows, in

Figure 14.13

all three conditions, regions of the brain involved with lip movements (g;reen) and tongue movements (red) were activated. Speaking, watching other people speak, thinking about speaking, and listening to speech sounds all activate brain regions involved in language, which suggests that circuits of mi1rror neurons play a role in speech and language comprehension. When we speak, or when we make subtle movements of the muscles involved in speaking, we receive somatosensory feedback from our tongue and the skin around our mouth. Ito anid colleagues (2009) found that this feedback affects our peirception of speech sounds. The investigators attached two atrms of a mechanical device to the skin of participants, just past the corners of their mouths. The device could be made to pull the skin upward or downward by the computer controlling the experiment. The participants listened to computer-generated words that varied in 10 steps between the sound of head to the sound of had. When the participants heard intermediate sounds that were neither head nor had, they were more likely to indicate that they heard head wlhen their facial skin was stretched upward and had when their facial skin was stretched downward. (Say head and had to yourself while paying attention to the movements made by the comers of your mouth. You will feel that your mouth widens and the comers rise slightly when you Sa)! head and that your mouth opens slightly, pulling the ccimers down, when you say had.) So, as the results of these studies indicate, activity of mirror neurons as well as feedback from speech movements affects speech perception. EJ posterior corpus callosum prevents information from post13rior right hemisphere from reaching left hemisphere (b)

end of the corpus callosum. The patient could still write, although he had lost the ability to read. In fact, if he was shown some of his own writing, he could not read it. The case below illustrates the unique nature of pure alexia. Although patients with pure alexia cannot read, they can recognize words that are spelled aloud to them. This indicates they have not lost their memories of the sp ellings of words. Pure alexia is a perceptual disorder. It is similar to pure word deafness, except that the patient has difficulty with visual input, not auditory input. The disorder is caused by lesions that prevent visual information from reaching the visual association cortex of the left hemisphere (Damasio & Damasio, 1983, 1986; Molko et al., 2002). Figure 14.24 explains why Dejerine's original patient could not read. The left side of the diagram

Let's trace the flow of visual information for a person with this brain damage that enables that person to read words aloud. Information from the left side of the visual field is transmitted to the tight striate cortex (primary visual cortex) and then to regions of right visual association cortex. From there the information crosses the posterior corpus callosum and is transmitted to a region of the left visual association cortex known as the visual word-form area (VWFA), where it is analyzed further. The information is then transmitted to speech mechanisms located in the left frontal lobe, and the person can read the words aloud. (Look again at Figure 14.24a.) The right side of the diagram shows Dejerine's patient. Notice how the additional lesion of the corpus callosum prevents visual information concerning written text from reaching the VWFA in the left hemisphere. Because this

shows the pathway that visual information would take

brain region is essential for the ability to recognize words,

if a person had damage only to the left primary visual cortex. In this case, the person's right visual field would be blind; they would see nothing to the right of the fixation point. But people with this disorder can read. Their only problem is that they must look to the right of each word so that they can see all of it, which means that they read somewhat more slowly than someone with full vision. (See Figure 14.24a.)

the patient cannot read. (See Figure 14.24b.) Mao-Draayer and Panitch (2004) reported the case of a man with multiple sclerosis who displayed the symptoms of pure alexia after sustaining a lesion that damaged both the subcortical white matter of the left occipital lobe and the posterior corpus callosum. As you can see in Figure 14.25, lthe lesions are in the locations that Dejerine predicted would cause this syndrome, except that the

Human Communication

Figure 14.25

Pure Alexia in a Person with Multiple Sclerosis

The lesions correspond to those shown in Figure 14.24, except that the white matter that serves the left primary visual cortex is damaged, not the cortex itself.

Figure 14.26

467

Model of the Reading Process

In this Himplified model, whole-word reading is used for most familiar words; phonetic readi ng is used for unfamiliar words and for nonwords such as glab, frisk, or chint. Sight of word

Source: Based on Mao-Draayer, Y., & Panitch, H. (2004). Alexia without

I

agraphia in multiple sclerosis: Cass report with magnetic resonance imaging localization. Multiple Sclerosis, 10, 705-707.

Letter recognition

Whole-word reading

Phonetic coding (sounds of letters)

~ --Phonetic reading

Control of speech

Saying word aloud

Damage to w hite matter that serves the left visual cortex

Damage to posterior corpus callosum

white matter that serves the left primary visual cortex is damaged, not the cortex itself. The diagrams shown in Figure 14.25 illustrate only the pathway involved in seeing a word and pronouncing it, and they ignore neural structures that would be involved in understanding its meaning. As we will see later in this chapter, evidence from patients w ith brain lesions indicates that seeing and pronouncing words can take place independently of understanding them. Although the diagrams are simplified, they are not unreasonable, given what we know about the neural components of the reading process. Writing is not the only form of visible language; people can also communicate by means of sign. Hickok and colleagues (1996) reported on a case of "sign blindness" caused by damage similar to that which causes pure alexia. The patient, a right-handed woman who was deaf, sustained a stroke that damaged her left occipital lobe and the posterior corpus callosum. The lesion did not impair her ability to sign in coherent sentences, but she could no longer understand other people's sign language, and she lost her ability to read. She had some ability to comprehend single signs (corresponding to single words), but she could not comprehend signed sentences.

Toward an Understanding of Reading LO 14.12

Describe the biological basis of acquired and developmental dyslexia.

Reading involves at least two different processes: direct recognition of the word as a whole and sounding it out letter by letter. When we see a familiar word, we normally

recognize it and pronounce it-a process known as wholeword reading. (With very long words we might instead perceive segments of several letters each.) The second metho•d, which we use for unfamiliar words, requires recognitioon of individual letters and knowledge of the sounds they make. This process is known as phonetic reading. Evidence for our ability to sound out words is easy to obt;ain. In fact, you can prove to yourself that phonetic readin1g exists by trying to read the following words: glab trisk chint These are not really words, but most readers are able to pronounce them. Readers don't recognize them, because they have probably never seen them before. Instead, readers use what they know about the sounds that are represented by particular letters (or small groups of letters, such ais ch) to figure out how to pronounce the words. Figure 14.26 illustrates some elements of the reading processes. The diagram is an oversimplification of a very complex process, but it h elps to organize some of the facts that investigators have obtained. It considers only reading and pronouncing single words, not understanding the meaning of text. When we see a familiar word, we normally recognize it as a whole and pronounce it. If we see an unfamiliar word or a pronounceable nonword, we must try to :read it phonetically. The best evidence that people can read words w ithout sounding them out, using the whole-word method, comes from studies of patients with acquired dyslexias. Dyslexia means "faulty reading." Acquired dyslexias are those caused by damage to the brains of people wh o already know how to read. In contrast, developmental dyslexias refier to reading difficulties that become apparent when

468 Chapter 14

children are learning to read. Researchers have reported several types of acquired dyslexias. Three of them will be described here: surface dyslexia, direct dyslexia, and phonological dyslexia. Developmental dyslexias, which appear to involve anomalies in brain circuitry, are discussed in a later section. SURFACE DYSLEXIA Surface dyslexia is a deficit in whole-word reading. The term surface reflects the fact that people with this disorder make errors related to the visual appearance of the words and to pronunciation rules, not to the meaning of the words, which is metaphorically "deeper" than the appearance. Because patients with surface dyslexia have difficulty recognizing words as a whole, they must sound them out. They can easily read words with regular spelling, such as hand, table, or chin. However, they have difficulty reading words with irregular spelling, such as sew, pint, and yacht. In fact, they may read these words as sue, pinnt, and yatchet. They have no difficulty reading pronounceable nonwords, such as glab, trisk, and chint. Because people with surface dyslexia cannot recognize whole words by their appearance, they must, in effect, listen to their own pronunciation to understand what they are reading. If they read the word pint and pronounce it pinnt, they will say that it is not an English word (which it is not, pronounced that way). If the word is one member of a homophone, it will be impossible for them to understand it unless it is read in the context of a sentence. For example, if you hear the single word "pair" without additional information, you cannot know whether the speaker is referring to pair, pear, or pare. (See Figure 14.27.) DIRECT DYSLEXIA As you read earlier in this chapter, recognizing a spoken word is different from understanding

Figure 14.27

Surface Dyslexia

In this hypothetical example, whole-word reading is damaged; only phonetic reading remains. Sight of word Familiar words: whole-word reading

Unfamiliar words: phonetic reading

Letter recognition

Whole-word reading is damaged

r --

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Saying word aloud

Phonetic reading

it. For examplie, patients with transcortical sensory aphasia can repeat what is said to them even though they show no signs of understanding what they hear or say. The same is true for reading. Direct dyslexia resembles transcortical sensory aphasia, except that the words in question are written, not spoken (Gerhand, 2001; Lytton & Brust, 1989; Schwartz et ail., 1979). Patients with direct dyslexia are able to read aloud even though they cannot understand the words they are saying. After sustaining a stroke that damaged his left frontal and temporal lobes, Lytton and Brust's (1989) patient lost the ability to communicate verbally; his speech was meaningless, and he was unable to comprehend what other people said to him. However, he could read words with which he was already familiar. He could not readl pronounceable nonwords; therefore, he had lost the ability to read phonetically. His comprehension deficit seemedl complete; when the investigators presented him with a word and several pictures, one of which corresponded to ithe word, he read the word correctly but had no idea what picture went with it. Gerhand's (2001) patient showed a similar pattern of deficits except that she was able to read plhonetically. She could sound out pronounceable nonwords. These findings indicate that the brain regions responsible for phonetic reading and whole-word reading are ea1ch directly connected with brain regions responsible for speech. PHO N OLO G I CAL DYSLEXIA The symptoms of phono logical d yslexia are opposite those of surface dyslexia. People with this disorder can read by the whole-word method but cannot sound words out. These individuals can read words that they are already familiar with but hav1e great difficulty figuring out how to read unfamiliar words or pronounceable nonwords (Beauvais & Derouesne, 1979; Derouesne & Beauvois, 1979). People with phonological dyslexia may be excellent readers if they had already acquired a good reading vocabulary before their braim damage occurred. Phonological dyslexia provides further evidence that whole-word reading and phonological reading involve different brain mechanisms. Phonological reading, which is the only way we can read nonwords or words we have not yet learned, emtails some sort of letter-to-sound decoding. Phonological reading of English requires more than decoding of the sounds produced by single letters, because, for example, some sounds are transcribed as two-letter sequences (such as th or sh) and the addition of the letter e to the end of ;a word lengthens an internal vowel (can becomes cane). (See Figure 14.28.) The Japanese language provides a particularly interesting distinction between phonetic and whole-word reading. The Japanese language makes use of two kinds of written symbols. Kanji symbols are pictographs, adopted from the Chinese language (although they are pronounced

Human Communication

Figure 14.28

Phonological Dyslexia

In this hypothetical example, phonetic reading is damaged; only whole-word reading remains.

Figure 14.29

469

Examples of Kanj i and Kana

Kanji: Flepresent whole words.

Sight of word Unfamiliar words: phonetic reading

Familiar words: whole-word reading

Whole-word recognition

Letter recognition

This is the Kanji symbol for a tree. The symbol strongly suggests the shape of a tree.

This is the Kanji symbol for a forest. It suggests trees close together.

Kana: nepresent sounds (not whole words). Hiragana

~

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as Japanese words). Kanji represent concepts by means of visual symbols but do not provide a guide to their pronunciation. Reading words expressed in kanji symbols is analogous, then, to whole-word reading. Kana symbols are phonetic representations of syllables and they encode acoustical information. These symbols are used primarily to represent foreign words or Japanese words that the average reader would be unlikely to recognize if they were represented by their kanji symbols. Reading words expressed in kana symbols is phonetic. (See Figure 14.29.) Studies of people with localized brain damage that read both kana and kanji, have shown that reading kana and kanji symbols involves different brain mechanisms (Iwata, 1984; Sakurai et al., 2001; Sakurai et al., 1994). Difficulty reading kanji symbols is a form of surface dyslexia, whereas difficulty reading kana symbols is a form of phonological dyslexia. What regions are involved in these two kinds of reading? Evidence from lesion and functional-imaging studies with readers of English, Chinese, and Japanese suggest that the process of whole-word reading follows the ventral stream of the visual system to a region, the fusiform gyrus, located on the base of the temporal lobe. For example, functional-imaging studies by Liu and colleagues (2008) and Thuy and colleagues (2004) found that reading kanji words or Chinese characters (whole-word reading) activated the left fusiform gyrus, a region of the cerebral cortex located at the base of the temporal lobe. This region has come to be known as the visual word-form area or VWFA (Dehaene, 2009). Part of the fusiform gyrus is also involved in the perception of faces and other shapes that require expertise to distinguish-and, recognizing whole words or kanji symbols requires expertise. The location of the neural circuitry responsible for phonological reading is less certain. Many investigators

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believ·e that it involves the region of the cerebral cortex that surrounds the junction of the inferior parietal lobe and the superior temporal lobe (the temporoparietal cortex) allld then follows a fiber bundle from this region to the in.ferior frontal cortex, which includes Broca's area Gobar·d et al., 2003; Sakurai et al., 2000; Tan et al., 2005; Thuy •e t al., 2004). However, damage restricted to the cortex of the VWFA-without damage to underlying white matter- produces pure alexia (Beversdorf et al., 1997). Although phonological reading may involve the temporoparietal cortex, the VWFA appears to play an essential role in both forms of reading. The fact that phonological reading involves Broca's area suggests that it may actually involve articulation-that we sound out words not so much by "hearing" them in our heads as by feeling ourselves pronounce them silently to ourselves. (As you read earlier in this chapter, feedback from the inferior frontal cortex plays a role in perception of spoken words.) Once words. have been identified-by either means-their meaning must be accessed, which means that the two pathways converge on regions of the brain involved in recognition of word meaning, grammatical structure, and semarntics. (See Figure 14.30 and Table 14.2.)

Table;? 14.2

Comparing Phonological and Whole-Word

Processing

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Whole· Word

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Recognition of familiar whole kanji

4 70

Chapter 14

Figure 14.30

Phonological and Whole-Word Reading

(a) Phonological read ing. (b) Whole-word reading. Inferior frontal

Phonological reading

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(a) Visual word-form area: whole-word reading

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VISUAL WORD-FORM AREA The neural circuits involved in written and auditory information must a lso eventually converge, because both must have access to the same linguistic and semantic information that identify words and their meaning. An interesting study by Marinkovic and colleagues (2003) used magnetoencephalography to trace regional brain activation as people heard or read individual words. The study showed that neural activation responsible for the analysis of a spoken word began in the auditory cortex of the temporal lobe and spread to the auditory association cortex on the superior temporal lobe (including Wernicke's area) and then to the inferior frontal cortex (including Broca's area). The neural activation responsible for the analysis of a printed word began in the visual cortex and spread to the base of the temporal lobe (including the VWFA in the fusiform gyrus) and then to the inferior frontal cortex. The temporoparietal cortex received little activation, presumably because the participants were fluent readers who did not need to sound out the common words they were asked to read. Let's consider the role of the VWFA. Some parts of the visual association cortex must be involved in perceiving written words. You will recall from Chapter 6 that visual agnosia is a perceptual deficit in which people with bilateral damage to the visual association cortex cannot

recognize objects by sight. However, people with visual agnosia can s.till read, which means that the perceptual analysis of objects and words involves at least some different brain mechanisms. This fact is both interesting and puzzling. Certainly, the ability to read cannot have shaped the evolution of the human brain, because the invention of writing is only a few thousand years old, and, until very recently, the vast majority of the world's population did not read or write. This indicates that reading and object recognition use brain mechanisms that undoubtedly existed long before the invention of writing. However, just as experience seeing faces affects the development of the fusiform face area in the right hemisphere, experience learning to read words affects tthe development of the neural circuitry in the visual word-form area-which, probably not coincidentally, is found in the fusiform cortex of the left hemisphere. A functional-imaging study by Brem and colleagues (2010) scanned the brains of young children who had not yet learned to read. Initially, the sight of printed words activated the ventral posterior occipitotemporal region bilaterally. After 3-4 hours of teaching the associations of written letters and their sounds, the sight of words activated the left hemisphere. Learning to read affects the connections of the neural system involved in recognizing letters and words. The fusiform face area has the ability to quickly recognize unique~ configurations of people's eyes, noses, lips, and other features of their faces even when the features of two people's faces are very similar. For example, relatives and close friends of identical twins can see at a glance which twin they are looking at. Similarly, our VWFA can recognize a word even if it closely resembles another one. (See Figure 14.31.) It can also quickly recognize words written in different typestyles, fonts, or CASES. This means that the VWFA can reoognize whole words with different shapes; for example, chai1r and CHAIR do not look the same. It takes an experienced reader the same amount of time to read equally familiiar three-letter words and six-letter words (Nazir et al., 1'998), which means that the whole-word reading process does not have to identify the letters one at a time, just as the face-recognition process in the right fusiform cortex does not have to identify each feature of a face individually befor•e the face is recognized. Instead, we recognize several letters and their locations relative to each other. The VWFA is critical in recognizing whole words in whole-word reading, but that may not be its only function. Vogel and colleagues (2014) suggest that the VWFA is potentially important in many dlifferent processing tasks, not just reading. Damage to the VWFA produces surface dyslexia and impaired whole-word reading. A study by Gaillard et al. (2006) combil1led fMRI and lesion evidence from a single participant and suggested that the left fusiform cortex does, indeed, contain this region. A patient with a severe seizure disorder became a candidate for surgery to remove the seizure focus. Before the surgery was performed, the patient

Human Communication

Figure 14.31

Subt le Differences in Wri tten Words

Unless you can read Arabic, Hindi, or Mandarin, you will probably have to examine these words carefully to find the small differences. However, as a reader of English, you will immediately recognize the words cars and ears. Source: Adapted from Devlin, J. T., Jamison, H. L., Gonnerman, L. M., & Matthews, P. M. (2006). The role of the posterior fusiform gyr'US in reading, Journal of Cognitive Neuroscience, 18, 911- 922.

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viewed printed words and pictures of faces, houses, and tools while his brain was being scanned. He knew that the seizure focus was located in a region that played a critical role in reading, but his symptoms were so severe that he elected to undergo the surgery. As expected, the surgery produced a deficit in whole-word reading. A combination of structural and functional imaging revealed that the lesion-a very small one-was located in the fusiform gyrus, the location of the VWFA. PLASTI CITY IN THE VIS UAL WORD FORM AREA

What did the region of the visual association cortex that we now know as the VWFA do before people invented written language? What does it do in people who do not read or write? As Dehaene and colleagues (2010) note: Cultural inventions such as reading and mathematics are too recent to have influenced the human genome. Therefore, they must be acquired through the recycling of neuronal networks evolved for other purposes, but whose initial properties are sufficiently similar to the target function and which possess enough plasticity, particularly during childhood, for their functionality to be partially converted to this novel task. (p. 1837) The ability to co-opt brain regions for new purposes allows humans across many different cultures, with many different languages and writing systems, to learn to read and write fluently. Fluency and literacy can develop very quickly in some cases, further supporting the idea that the relevant neural pathways are present prior to development of a new language. For example, consider that at least two written languages were invented by specific individuals. Hangul, the written form of the Korean language, was invented by King Sejong (and his scholars) in the fourteenth century. The characters of the Hangul alphabet are designed to look like the shapes the mouth makes when they are pronounced. In the early nineteenth century, Sequoyah, a Cherokee living in what is now the state of North Carolina, spent 12 years developing a written version of his language. He analyzed the sounds of his language

471

and selected 85 symbols-from English and Greek letters and some additional symbols that he invented. He was not familiar with the sounds that English and Greek letters re:presented, so the sounds he assigned to them bore no relationship to those of the languages they came from. Within a few months of the introduction of Sequoyah's alphabet, thousands of people learned to read and write the Cherokee language. Szwed and colleagues (2009) note that the most important cues to object recognition (which is the primary task of the visual system) are those that remain relatively constant even when we view objects from different angles. The most reliable of these cues are the ways that lines meet at vertices, forming junctions with particular shapes, such as L, T, and X. Szwed and his colleagues presented incomplete drawings of objects and letters that were missing their vertices (junctions or corners where lines meet) or they presented drawing of objects and letters that were missing portions of the midsegments (lines between these junctions). Figure 14.32a shows a drawing and a word with the vertices missing. Can you figure out what they are? What about in Figure 14.32b? Generally, people id entify these items more quickly in the second drawing that has the junctions present. Clhangizi and colleagues (2006) analyzed the configura tion:s of letters and symbols used in a large number of former aJild present writing systems from all over the world. They found that these characters seem to have been chosen by the cultures that invented them to match those found in objects in nature's scenes-and they all involve junctions of lines. Early forms of writing used actual pictures, but the pictures became simplified and eventually turned into simple lines or intersecting lines and curves. Even complex symbols such as Chinese characters consist of intersecting brush strokes. Figure 14.33 shows a few of the ways that different types of intersections of two line segments can be transformed into letters found in various writing systems. Presumably, the region of the brain that becomes the VWFA through the process of learning to read originally evolved to recognize objects by learning the configuration of lines (straight and curved) and their junctions. Our ancestors invented forms of writing that use symbols that are distinguished by these characteristics, and a portion of the fusiform gyrus became "recycled" (as Dehaene and colleagues phrased it) into the VWFA. Some children have great difficulty learning to read and never become fluent readers, even though they are intelligent. Specific language learni.Jng disorders, called developmental dyslexias, tend to occiur in families, a finding that suggests a genetic (and hence biological) component. The concordance rate of developmental dyslexia in monozygotic twins ranges from 84 percent to 100 percent, and in dizygotic twins it ranges DEVELOPMENTAL DYSLEXIAS

4 72

Chapter 14

Figure 14.32

Figure 14.3:3

Object Recognition

(a) Object and word recognition after vertices have been eliminated. (b) Object and word recognition after mid-segments of lines have been eliminated. Source: Based on Szwed, M., Cohen, L., Qiao, E., & Dehaene, S. (2009). The role of invariant line junctions in object and visual word recognition. Vision

research, 49(7), 716-725.

t

Line Intersections Transform into Letters

Segments can b'e transformed into letters found in various writing systems. Source: Adapted from Changizi, M.A., Zhang, Q., Ye, H., & Shimojo, S. (2006). The structures of leitters and symbols throughout human history are selected to match those found in objects in natural scenes. American Naturalist, 167, E117- E139.

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Indeed, researchers have found a variety of language deficits associated with dyslexia that do not directly involve reading. One common deficit is deficient phonological awareness. That is, people with developmental dyslexia have difficulty blending or rearranging the sounds of words that th1ey hear (Eden & Zeffiro, 1998). For example, they have difficulty recognizing that if we remove the first sound from "cat," we are left with the word "at." They also have diffiiculty distinguishing the order of sequences of sounds (Helenius et al., 1999). Problems such as these might be exp1ected to impair the ability to read phonetically. Childrein. with developmental dyslexia also tend to have difficulty in writing: They make spelling errors, show poor spatial arrangements of letters, and omit letters, and their writing tends to have weak grammatical development (Habib, 2000). Developmental dyslexia is a heterogeneous and complex trait, and it likely has more than one cause. However, most studies that have closely examined the nature of the impairments seen in people with developmental dyslexia have found phonological impairments to be most common. For example, a study of 16 people with developmental dyslexia by Ramus and colleagues (2003) found that all of the participants had phonological deficits. Ten of the people also had auditory deficits, four also had a motor deficit,. and two also had a visual deficit. These

age and association studies suggest that the chromosomes

deficits-espedally auditory deficits- aggravated the

3, 6, and 15 may contain genes responsible for different components of this disorder (Kang & Drayna, 2011). As we saw earlier, the fact that written language is a recent invention means that natural selection is unlikely to have given us brain mechanisms whose only role is to interpret written language. Therefore, we should not expect that developmental dyslexia involves only deficits in reading.

people's diffioculty in reading but did not appear to be primarily responsible for the difficulty. Five of the people had only phonological deficits, and these deficits were sufficient to interfere with their ability to read. Some evidence has been obtained from functionalimaging studies that suggests that the brains of people with developmental dyslexia process written information

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individual faces. A functional-imaging study by Schultz (2005) found little or no activity in the FFA in a sample of adults with autism spectrum disorder as they looked at pictures of human faces. (See Figure 15.10.) People with ASD may have difficulty recognizing facial expressions of emotion 0 1r the direction of another person's gaze or have low rates of eye contact with other people. In autism, it seems possible that the FFA responds differently to the sight of the humain face because very little time may be spent studying other people's faces and so expertise in interpersonal interactions does not develop. Grelotti and colleagues (2005) reported the case of a boy with ASD who had an extreme interest in Digimon cartoon characters. Functional imaging showed no activation of the FFA when the boy viewed photos of faces, but photos of Digimon characters evoked strong: activation of this region. This case suggests that if the sight of faces does not activate the FFA in people with autism, it could be related to a lack of experience with faces, not by abnormalities in the FFA. A study by Pelphrey and colleagues (2002) found that people with autism spectrum disorder who were asked to identify the emotions shown in photographs of faces tended not to look at other people's eyes, which are informative in making judgments of emotion. This tendency likely contributes to difficulty analyzing social information that can occur in autism. Altered development of the amygdala in people with autism may be at least partly responsible for generally low rates of eye contact with other people and difficulty in assessing other people's emotional state.

492

Chapter 15

Figure 15.10

Fusiform Face Area and Autism

Scans show activation of the fusiform face area in typically developing peers, but not in people with autism while looking at pictures of human faces. Source: Based on Schultz, R. T. (2005). Developmental deficits in social perception in autism: The role of the amygdala and fusiform face area.

International Journal of Oevelopmental Neuroscience, 23,

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Figure 15.1.1 Caudate Nucleus and Stereotyped Behavior in Autism The graph shows repetitive behavior scores of people with autism spectrum disorder as a function of the volume of the right caudate nucleus. Larger volumes are associated with higher scores. Source: Adapted from Hollander, E., Anagnostou, E., Chaplin, W., Esposito,

K., et al. (2005). Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biological Psychiatry, 58, 226-232.

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Many investigators have noted that the presence of repetitive, stereotyped behavior and obsessive preoccupations with particular subjects in autism spectrum disorder resemble the symptoms of obsessive-compulsive disorder. As described in Chapter 18, the symptoms of OCD appear to be related to increased activity of the caudate nucleus. Research suggests that the same may be true

saw a video o•f other people yawning. A group of people without ASD showed an increased rate of yawning during or immediately after seeing videos that depicted yawning but not those that depicted other kinds of mouth movements. Presumably, the mirror neuron system is involved in this type of imitation. Baron-Cohen (2002) noted that the behavioral charac-

for the behavioral symptoms of autism. Several studies

teristics of people with autism spectrum disorder appear

have observed increased volume of the caudate nucleus in autism (Langen et al., 2007; Sears et al., 1999). In fact, Hollander and colleagues (2005) found that the volume of the right caudate nucleus was positively correlated with ratings of repetitive behavior in patients with ASD. (See Figure 15.11.) Chapters 8 and 11 describe the role of a circuit of mirror neurons in the perception of emotions and behavioral intentions. This circuit is typically activated when individuals see another person produce an expression of emotion or perform a goal-directed action, and feedback from this activity helps individuals understand what the person feels or is trying to accomplish. In other words, the mirror neuron system may be involved in people's ability to understand what others are trying to do and to empathize with their emotions. Iacoboni and Dapretto (2006) suggested that the social characteristics of autism may be a result of altered development of the mirror neuron system. A functional-

to amplify traits that tend to be associated with males. As we saw, the overall incidence of ASD is four times more prevalent in males. Baron-Cohen hypothesized that ASD may be a reflection of an "extreme male brain." According to Baron-Cohen, people with ASD show an exaggerated pattern of masculine interests and behaviors. For example, a lack of interest in other people and an obsession with counting and lining up objects in a row that is seen in mainy people with autism are seen as extreme examples of masculine traits. However, this theory has received criticism on the grounds that it does not address all aspects of gender identity and the "masculine traits" or lack of empathy are not universal in autism. We saw in Chapter 10 that sexual differentiation of the brain is largely controlled by exposure to prenatal androgens. Auy1eung and colleagues (2009) used two tests that measure symptoms of autism spectrum disorder to assess the behavior of typically developing children whose mothers had undergone amniocentesis (removal

imaging study by Dapretto and colleagues (2006) ob-

of a small amount of amniotic fluid during pregnancy).

served reduced activation in the mirror motor neuron system of children with ASD, and a structural MRI study by Hadjikhani and colleagues (2006) found that the cerebral cortex in the mirror neuron system was thinner in people with ASD. A study by Senju and colleagues (2007) found that children with autism did not yawn when they

Auyeung and colleagues found a significant positive correlation in both boys and girls between fetal testosterone levels and scores on these tests. In addition, Knickmeyer and colleagues (2006) found that females with congenital adrenal hyperplasia, who were exposed to abnormally high levels of androgens during fetal development,

The Developing Nervous System

had a greater number of traits associated with autism. Even if Baron-Cohen's hypothesis is correct, we cannot conclude that autism is caused by prenatal exposure to excessive amounts of testosterone. An "extreme masculine brain" could be caused by genetic abnormalities that increase the sensitivity of a developing brain to androgens, and there could be (and probably are) other causes of autism that have nothing to do with masculinization of the brain. Recent studies have produced contradictory results and suggested that previous conclusions were based on small, under powered studies. For example, Nadler and colleagues (2019) assessed a causal role of testosterone in cognitive empathy. The authors reported no effect of testosterone administration on measures of cognitive empathy (a measure used in many prior studies) in two large samples of men. In addition to changes in steroid hormones, changes in neuropeptide signaling may be involved in the symptoms of autism. As we saw in Chapter 10, oxytocin, a peptide that serves as a hormone and neuromodulator, facilitates pair bonding and increases trust and closeness to others. Modahl and colleagues (1998) reported

493

that children with ASD had lower levels of this peptide. Studies suggest that oxytocin can increase sociability of people with ASD. Guastella and colleagues (2010a) found that administering oxytocin increased the performance of adolescent boys with ASD on a test of emotional recognihon. Andari and colleagues (2010) found that oxytocin increased the performance of adults with ASD on a computerized ball-toss game that required social interactions with fictitious partners. In contrast, a large randomized controlled trial found little effect of oxytocin on social symptoms, but improvement on repetitive behaviors in ASD (Yamasue et al., 2019). Other researchers have ~mggested that changes in the genetic code for the oxytocin receptor may underlie social differences in ASD (Campbell et al., 2011). New treatment approaches to autism have begun to focus on these brain-based changes. Several research groups are pursuing oxytocin-based interventions (Gordon et al., 2013; Preti et al., 2014) or deep brain stimulation of the prdrontal cortex (Enticott et al., 2014) as new avenues of treatment for symptoms of autism.

Module Review: Autism Spectrum [)isorder Symptoms

Genetic studies have shown that autism is highly heritable but that many different genes are involved. ASD can also be caused by events that interfere with prenatal development, such as prenatal thalidomide exposure or maternal rubella infection.

follows a similar pattern of development. Regions of the brain involved in higher-order processes, such as communicative functions and interpretation of social stimuli, develop more quickly in people with ASD but then development slows. People with ASD may tend not to pay attention to other people's faces, as reflected in the lack of activation of the fusiform face area when they do so, and their ability to perceive emotional expressions on other people's faces is altered. The volume and connectivity of white matter in the brain is changed in ASD. Activation of the STS and prefrontal cortex in tasks requiring theory of mind is different in ASD. Reduced activation of the mirror neuron system may be involved in ASD. Increased activity in the caudate nucleus may be involved in some of the behavioral symptoms of ASD. Reduced levels of the neuropeptide oxytocin or changes in the oxytocin receptor may also be involved in symptoms of ASD.

Brain Changes

Thought Question

LO 15.7

List the symptoms of ASD.

Symptoms of ASD include altered social interaction and communication, as well as restricted, repetitive interests, activities, or patterns of behavior. Symptoms are present early in life.

Genetic and Environmental Factors LO 15.8

LO 15.9

Describe the rol es of genetic and envi ronmental factors in ASD.

Describe differences in the brain associated with ASD.

MRI studies indicate that the brains of babies who are later diagnosed with ASD show more rapid growth until 2 to 3 years of age and then grow more slowly than the brains of typically-developing children. The amygdala

Many people have heard about research that suggests childhood immunizations are associated with autism, despite the fact that the publication that initially reported this research and its principal author were discredited. Why do you think many parents are still fearful about having their children immunized?

494 Chapter 15

Attention-Deficit/ Hyperactivity Disorder Some children have significant difficulty concentrating, remaining still, and working on a task. At one time or another,

most children exhibit these characteristics. But children with atten tion-deficit/hyperactivity d isorder (ADHD) display these symptoms so often that they interfere with the children's ability to learn. Symptoms of ADHD can affect individuals in both childhood and adulthood.

Symptoms LO 15.10 List the symptoms of ADHD.

ADHD is the most common behavior disorder that shows itself in childhood. It is often first discovered in the classroom, where children are expected to sit quietly and pay attention to the teacher or to work steadily on a project. Some children's inability to meet these expectations then becomes evident. They have difficulty withholding a response, act without reflecting, often show reckless and impetuous behavior, and let interfering activities intrude into ongoing tasks. According to the DSM-5, the diagnosis of ADHD requires the presence of six or more of nine symptoms of inattention and/ or six or more of nine symptoms of hyperactivity and impulsivity that have persisted for at least 6 months. (See Table 15.3.) Descriptions of inattention symptoms include such things as "often had difficulty sustaining attention in tasks or play activities" or "is often easily distracted by extraneous stimuli." Symptoms of hyperactivity and impulsivity include such things as "often runs about or climbs excessively in situations in which it is inappropriate" or "often interrupts or intrudes on others (e.g., butts into conversations or games)" (American Psychiatric Association, 2013, pp. 59-60.) The prevalence of ADHD is approximately 5 percent of children in most cultures (American Psychiatric Association, 2013). Boys are about 10 times more likely than girls to receive a diagnosis of ADHD, but in adulthood

Table 15.3

the ratio is approximately 2 to 1, which suggests that many girls with this disorder are not diagnosed. Because the symptoms can vary-some children's symptoms are primarily those of inattention, some are those of hyperactivity, and some show mixed symptoms-most investigators believe that this disorder has more than one cause. Di.agnosis is often difficult because the symptoms are not well defined. ADHD is often associated with aggression, conduct disorder, learning disabilities, depression, anxiety, and low self-esteem. Approximately 60 percent of children with ADHD continue to display symptoms of this disorder into adulthood, at which time a disproportionately large number develop antisocial personality disorder and may be diagnosed with a substance abuse disorder (Ernst et al., 1998). Adults with ADHD are also more likely to show cognitive impairments and lower occupational attainment than would be predicted by their education (Seiidman et al., 1998). According to Sagvolden and his colleagues (Sagvolden & Sergeant, 1998; Sagvolden et al., 2005), the impulsive and hyperactive behaviors that are seen in children with ADHD are the result of a delay of reinforcement gradient that is steeper than normal. As we saw in Chapter 13, the occurrence of a1n appetitive stimulus can reinforce the behavior that just preceded it. For example, a piece of food can reinforce the lever press that a rat just made, and a smile can reinforce a person's attempts at conversation. Reinforcing stimuli are most effective if they immediately follow a behavior: The longer the delay, the less effective the reinforcement. Sagvolden and Sergeant suggest that deficiencies irn dopaminergic transmission in the brains of people with ADHD increase the steepness of their delay of reinforcement gradient, which means that immediate reinforcement is even more effective in these children, but even slightly delayed reinforcement loses its potency. (See Figure 15.12.) Why would a steeper delay of reinforcement gradient produoe the symptoms of ADHD? According to Sag.volden anid his colleagues, for people with a steep gradient, reinforcement with a short delay will be even more effective, thus producing overactivity. On the other

Symptoms of Attention-Deficit/Hyperactivity Disorder

A persistent pattern of inattention and/or hyperactivity-irnpulsivity that interferes with functioning or development

Inattention: Decreased attention to details: makes careless mistakes or fails to follow directions or complete activities: has difficulty in organization: avoids activities that require sustained attention; easily distracted, forgetful; often loses things Hyperactivity and impulsivity: Fldgets or squirms, leaves seat when sitting is expected, runs or climbs when inappropriate, talks excessively, interrupts or responds before question is finished, has d ifficulty waiting Symptoms are present in childhood Source: Based on American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (DSM-5®). Washington, DC: American Psychiatric Association.

The Developing Nervous System

Figure 15.12

Hypothetical Delay of Reinforcement Gradient in ADHD The graph illustrates different delay of reinforcement gradients as a function of time. Sagvolden and Sergeant (1998) hypothesize that a steeper gradient is responsible for the impulsive behavior of children withADHD.

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495

dopamine in the human prefrontal cortex have effects on behavior comes from studies of people with two different varian1ts of the gene for an enzyme that affects dopamine levels in the brain. COMT (catechol-0-methyltransferase) is an enzyme that breaks down catecholamines (including dopamine and norepinephrine) in the extracellular fluid. Although reuptake is the primary means of removing catecholamines from the synapse, COMT also plays a role im deactivating these neurotransmitters after they are released. Mattay and colleagues (2003) noted that the clinical effects of amphetamine (which are similar to those of methylphenidate) are variable. In some people, amphetamine increases positive mood and facilitates performance on cognitive tasks, but in other people it has the opposite effect. Mattay and colleagues tested the effect of amphetamine on tasks that made demands on working memory in peopll~ with two different variants of the COMT gene. They found that people with the val-val variant, who have lower brain levels of catecholamines, performed better when they were given low doses of amphetamine. In contrast, administration of amphetamine to people with the met-met varian1t, who have higher brain levels of catecholamines, actually impaired their performance. Presumably, the first group was pushed up the U-shaped curve, and the second group,, already around the top of the curve, was pushed down the other side. (See Figures 15.13 and 15.14.)

our behaviors (especially classroom activities) are. In support of this hypothesis, Sagvolden and colleagues (1998) trained typically developing boys and boys with ADHD on an operant conditioning task. When a signal was present, responses would be reinforced every 30 seconds with coins or small prizes. When the signal was not present, responses were never reinforced. The typically developing boys learned to respond only when the signal was present. When the signal was off, they waited patiently until it came on again. In contrast, the boys with ADHD showed impulsive behavior- intermittent bursts of rapid responses whether the signal was present or not. According to the investigators, this pattern of responding was what would be expected by a steep delay of reinforcement gradient.

Figure 15.13 Interactions Between Amphetamine and COMT Alleles in Working Memory The graph shows the differential effects of amphetamine on the performance on a working-memory task of people with two diftferent vari ants of the gene for the COMT enzyme. The performance of people with the val-val variant was enhanced by amphettamine, and the performance of people with the met-met variant was reduced. Source: Based on data from Mattay, V. $.,Goldberg, T. E., Fera, F., Hariri, A. R., et al. (2003). Catechol 0-methyltransferase val159-met genotype and individual variation in the brain response to amphetamine. Proceedings of the National Academy of Sciences, USA, 100, 6 186-6191.

18 16

Genetic and Environmental Factors LO 15.11 Describe the roles of genetic and

environmental factors in ADHD. There is strong evidence from both family studies and twin studies that hereditary factors play an important role in determining a person's likelihood of developing ADHD. The estimated heritability of ADHD is high, ranging from 75 percent to 91 percent (Thapar et al., 2005). Genetic differences in enzymes involved in catecholamine transmission may help us understand factors associated with ADHD. Good evidence that the levels of

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Chapter 15

Figure 15.14

An Inverted U Curve

The graph illustrates an inverted U-curve function, in which low and high values of the variable on the horizontal axis are associated with low values of the variable on the vertical axis and moderate values are associated with high values. Presumably, the relationship between brain dopamine levels and the symptoms of ADHD follow a

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sleep were positively correlated with decreases in ratings of depressive symptoms. It is possible that the beneficial results of SWS deprivation were actually produced by suppression of REM sleep. However, REM sleep deprivation usually produces a therapeutic effect over the course of several weeks, and the benefits in this study occurred after just one night of SWS deprivation. This promising approach app1ears to deserve further study. Total sleep deprivation also has an antidepressant effect. Unlike specific deprivation of REM sleep, which takes several weeks to reduce depression, total sleep deprivation produces immediate effects (Wu & Bunney, 1990). Typically, the depression is lifted by the sleep deprivation but returns the next day, after a normal night's sleep. In fact, ketamine treatment and total sleep deprivation are the only treatments that produce an immediate (but transient) effect. Wu and Bunney suggest that, during sleep, the brain produces a chemical that has a depressogenic effect in susceptible people. During waking, this substance is gradually metabolized and hence inactivated. Some of the evidence for this hypothesis is presented in Figure 17.24. The data are taken from eight different studies cited by Wu and Bunney (1990) and show self-ratings of depression of people who did and did not respond to sleep deprivation. Total sleep deprivation improves the mood of patients with major depressiion approximately two-thirds of the time. Why do only some people benefit from sleep deprivation? This question has not yet been answered, but several studies have sl110wn that it is possible to predict who will respond and who will not (Haug, 1992; Riemann et al., 1991; Wirz-Justice &: Van den Hoofdakker, 1999). In general, patients with depression whose mood remains stable will TOTAL SLEEP' D EPRIVATION

Figure 17 .2'.4

Antidepressant Effects of Sleep

Deprivation The graph show:> the mean mood rating of responding and nonresponding patients deprived of one night's sleep as a function of the time of day. Source: Based on data from Wu, J.C., & Bunney, W. E. (1990). The biological basis of an antideprnssant response to sleep deprivation and relapse: Review and hypothesis. American Journal of Psychiatry, 147, 14-21.

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Schizophrenia and the Affective Disorders probably not benefit from sleep deprivation, whereas those whose mood fluctuates probably will. The patients who are most likely to respond are those who feel depressed in the morning but then gradually feel better as the day progresses. In these people, sleep deprivation appears to prevent the depressogenic effects of sleep from taking place and simply permits the trend to continue. If you examine Figure 17.24, you can see that the responders were already feeling better by the end of the day. This improvement continued through the sleepless night and during the following day. The next night they were permitted to sleep normally, and their depression was back the following morning. As Wu and Bunney note, these data are consistent with the hypothesis that sleep produces a substance with a depressogenic effect. Although total sleep deprivation is not a practical method for treating depression (it is impossible to keep people awake indefinitely), several studies suggest that partial sleep deprivation can hasten the beneficial effects of antidepressant drugs. For example, Leibenluft and colleagues (1993) found that depriving treatment-resistant patients of sleep either early or late in the night facilitated treatment with antidepressant medication. Some investigators have found that intermittent total sleep deprivation (for example, twice a week for 4 weeks) can have beneficial results (Papadimitriou et al., 1993). ROLE OF ZEITGEBERS Yet another phenomenon relates

depression to sleep and waking-or, more specifically, to the mechanisms that are responsible for circadian rhythms. Some people become depressed during the winter season, when days are short and nights are long (Rosenthal et al., 1984). The symptoms of this form of depression, called seasonal affective d isorder (SAD), are somewhat different from those of major depression; both forms include lethargy and sleep disturbances, but seasonal depression includes a craving for carbohydrates and an accompanying weight gain. (As you will recall, many people with major depression tend to lose their appetite.) SAD, like MDD and bipolar disorder, appears to have a genetic basis. In a study of 6,439 adult twins, Madden and colleagues (1996) found that SAD ran in families, and they estimated that at least 29 percent of the variance in seasonal mood disorders could be attributed to genetic factors. One of the genetic factors that contribute to susceptibility to SAD is a particular allele of the gene responsible for the production of melanopsin, the retinal photopigment that detects the presence of light and synchronizes circadian rhythms (Wulff et al., 2010). Gonzalez and Aston-Jones (2006, 2008) found that rats that spent 6 weeks in total darkness exhibited behavioral symptoms of depression in an animal model of this disorder. In addition, the investigators found increased apoptosis (programmed cell death) in noradrenergic neurons of the locus coeruleus, dopaminergic neurons of the ventral tegmental area, and serotonergic neurons of the

563

raphe nuclei. In addition, they observed fewer NE, DA, and 5·-HT terminals in the prefrontal cortex. (You will recall from Chapter 9 that these monoaminergic regions play an important role in sleep and waking.) Administration of desipramine, an antidepressant drug, decreased both the behavioral and anatomical signs of depression. Perhaps, the authors note, the anatomical changes they observed are responsible for the depressant effects of prolonged exposure to limited amounts of light. (See Figure 17.25.) SAD can be treated by phototherapy: exposing people to brig;ht light for several hours a day (Rosenthal et al., 1984; Stinson & Thompson, 1990). As you will recall, circadian rhythms of sleep and wakefulness are controlled by the activity of the suprachiasmatic nucleus of the hypothalamus. Light :serves as a zeitgeber; that is, it synchronizes the activity of the biological clock to the day /night cycle. One possibility is that people with SAD require a stronger-than-normal zeitgeber to reset their biological clock. According to Lewy and colleagues (2006), SAD is caused by a mismatch betweien cycles of sleep and cycles of melatonin secretion. Normally, secretion of melatonin begins in the evening, before p1eople go to sleep. In fact, the time between the onset of melatonin secretion and the midpoint of sleep (halfway betweien falling asleep and waking up in the morning) is approximately 6 hours. People with SAD most often show a phase delay between cycles of melatonin and sleep; that is, the time interval between the onset of melatonin secretion and the midpoint of sleep is more than 6 hours. Exposure

Figure 17 .25 Effects of Living in Total Darkness on Monoaminergic Systems Rats that spent 6 weeks in total darkness showed apoptosis (cell death) in the NE neurons of the locus coeruleus, DA neurons of the ventral tegmental area, and 5-HT neurons of the raphe nuclei. The graph shows the number of terminal buttons in the prefrontal cortex from nEiurons in each of these areas after the 6-week period. Source: Based on data from Gonzalez, M. M., & Aston-Jones, G. (2008). Light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats. Proceedings of the National Academy of Sciences, USA, 105, 4898-4903; and Gonzalez. M. M., & Aston,Jones, G. (2006.). Circadian regulation of arousal: Role of the noradrenergic locus coeruleus system and light exposure. Sleep, 29, 1327-1336.

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564 Chapter 17

to bright light in the morning or administration of melatonin late in the afternoon (or, preferably, both treatments) advances the circadian cycle controlled by the biological clock in the suprachiasmatic nucleus. (These cycles were discussed in Chapter 9.) Those people with SAD who show a phase advance in their cycles can best be treated with exposure to bright light in the evening and administration of melatonin in the morning. (See Figure 17.26.) By the way, phototherapy has been found to help patients with major depressive disorder, especially in conjunction with administration of antidepressant drugs (Terman, 2007). Phototherapy is a safe and effective treatment for SAD. According to a study by Wirz-Justice and colleagues (1996), a special apparatus is not even needed. The authors found that a 1-hour walk outside each morning reduced the symptoms of SAD. They noted that even on an overcast winter day, the early morning sky provides considerably more illumination than normal indoor artificial lighting, so a walk outside increases a person's exposure to light. The exercise helps, too. Many studies (for example, Dunn et al., 2005) have shown that a program of exercise improves the symptoms of depression.

Figure 17 .2'.6

Cycles of Sleep and Melatonin Secretion

Normally, melatonin secretion begins in the evening, approximately 6 hours before tt1e midpoint of sleep. Most people with seasonal affective disorder begin secreting melatonin earlier, showing a phase delay between cycles of melatonin and sleep. A few people with this disorder show a phase advance, with melatonin secretion beginning

at a later time. Source: Based on data from Lewy, A. K., Lefler, B. J., Emens, J. S., & Bauer, V. K. (2006). The ci1rcadian basis of winter depression. Proceedings of the National Academy of Sciences, USA, 103, 7414-7419.

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Module Review: Affective Disorders Description LO 17.7

Contrast the symptoms of major depressive disorder and bipolar disorder.

The symptoms of major depressive disorder include chronic or episodic depression without mania. People with major depressive disorder feel sad, unworthy, and guilty and have an increased incidence of suicide. The symptoms of bipolar disorder include alternating periods of mania and depression. Symptoms of mania include feeling euphoric, exhibiting increased speech and motor activity, and grandiosity.

Biological Treatments LO 17.9

Identify biological treatments for affective d isorders.

Biological treatments for affective disorders include monoamine o:xidase (MAO) inhibitors, drugs that inhibit the reuptake of norepinephrine or serotonin, enhance GABA activity, or interfere with NMDA receptors; electroconvulsive therapy; transcranial magnetic stimulation; deep brain stimulation; vagus nerve stimulation; phototherapy; sleep deprivation; and lithium.

Role of the Frontal Cortex Genetic Factors LO 17.8

Describe the role of genetic factors in affective disorders.

Heritability studies suggest that genetic anomalies are at least partly responsible for these disorders. Close relatives of people with affective disorders are 10 times more likely to develop these disorders than are people without diagnosed relatives. The concordance rate for affective disorders is 69 percent in monozygotic twins, versus 13 percent in dizygotic twins.

LO 17.10 Describe the role of the frontal cortex in

d epression. A consistent finding in neuroimaging studies of depressed patients is hyperactivity of subgenual ACC along with decreased activity in other regions of the frontal cortex, including the dorsolateral PFC, the ventrolateral PFC, the vent1romedial PFC, and the orbitofrontal cortex. A variety of successful antidepressant treatments reliably decrease the activity of the subgenual ACC and, usually, increase the activity of other regions of the frontal cortex.

Schizophrenia and the Affective Disorders

565

The Monoamine H ypothesis

Role of Neurogenesis

LO 17.11 Explain the monoamine theory of affective disorders.

LO 17'.13 Describe the role of neurogenesis in affective disorders and their treatment.

The therapeutic effect of noradrenergic and serotoner-

Stress and depression are associated with reduced hippo-

gic agonists and the depressant effect of reserpine, a

campal neurogenesis. Antidepressant treatment increases

monoaminergic antagonist, suggested the monoamine h ypothesis of depression: that depression is caused by insufficient activity of monoaminergic neurons. Depletion of tryptophan (the precursor of 5-HT) in the brain causes a recurrence of depressive symptoms in depressed patients who are in remission, which lends further support to th e conclusion that 5-HT plays a role in mood. However, although SSRis have an immediate effect on serotonergic transmission in the brain, they do not relieve the symptoms of depression for several weeks, posing a challenge to the monoam ine h ypothesis.

hippocampal neurogenesis. The time period of onset of therapeutic effect coincides with the time period of increased neurogenesis.

Role of Circadian Rhythms LO 17'.14 Summarize the role of circadian rhythms in affective disorders.

Role of the 5-HT Transporter

Sleep disturbances are characteristic of affective disorders. In fact:, total sleep deprivation rapidly (but temporarily) reduces depression in many people, and selective deprivation oJf REM sleep does so slowly (but more lastingly). In addition, almost all effective antidepressant treatments suppress REM sleep. A specific form of depression, seasonal affective disorder, can be treated by exposure to bright light.

LO 17.12 Critique the role of serotonin transporter allele polymorphisms in affective disorders.

Thought Question

Stressful life experiences increase the likelihood of dep ression in people with one or two short alleles of the

In this chapter, you read about a variety of biological factors related to affective disorders. Many experts also

5-HT transporter promoter gene, and a better response

believe that environmental factors such as trauma or

to antidepressant treatment is seen in depressed people with two long alleles. However, the results of existing meta-analyses do not support a significant role for th e 5-HT transporter promoter in depression.

chang•es in sleep, day length, or hormones also play a role in the~;e d isorders. Choose one affective disorder and describe an example of how biological and environmental factom might interact as risk or protective factors .

Chapter Review Questions 1. Describe the symptoms of schizophrenia, and discuss

2.

3. 4.

5.

the evidence that schizophrenia is heritable. Discuss drugs that alleviate or produce the positive symptoms of schizophrenia, and discuss research into the nature of a possible dopamine abnormality in the brains of people with schizophrenia. Discuss direct evidence that schizophrenia is associated with brain damage. Describe the role of the prefrontal cortex in symptoms of schizophrenia. Describe the two major affective disorders (major depressive disorder and bipolar d isorder), the

heritability of these diseases, and their physiological tn~atments.

6. Summarize the monoarnine hypothesis of depression, changes in neurogenesis, evidence for brain abnormalities, and evidence concerning the role of the subgenual ACC in depression. 7. Explain the role of circadian and seasonal rhythms in affective disorders: the effects of REM sleep deprivation, slow-wave sleep deprivation, total sleep depri-

vation, and seasonal affective disorder.

Chapter 18

Stress and Anxiety I)isorders

Cross-section of the adrenal medulla, a part of the sympathetic adrenal-medullary system. The adrenal medulla releases epinephrine and norepinephrine, which help coordinate responses to stressors.

Chapter Outline Stress Physiology of the Stress Response

Health Effects of Long-Term Stress Effects of Stress on the Brain Psychoneuroimmunology Posttraumatic Stress Disorder

Anxiety Dis orders Symptoms Genetic and Environmental Factors

Brain Chan ges Treatment Obsessive-Compulsive Disorder

Symptoms Genetic and Environmental Factors

Symptoms Genetic and Environmental Factors

Brain Changes Treatment

Brain Changes Treatment

566

Stress and Anxiety Disorders

II LO 18.1

Learning Objectives Compare the SAM system and HPA axis in coordinating a stress response.

LO 1Sl.8

Summarize treatments for PTSD.

LO 1Sl.9

List the symptoms of anxiety disorders.

LO 18.2

Describe the negative health outcomes associated with chronic stress.

LO 1Sl.10

LO 18.3

Compare the effects of long-term glucocorticoid exposure and early nurturing experiences on the brain in response to stress.

Describe the roles of genetic and environmental factors in anxiety disorders.

LO 1Sl.11

Describe changes in the brain associated with anxiety disorders.

LO 1Sl.12

Summarize treatments for anxiety disorders.

LO 1Sl.13

List the symptoms of OCD.

LO 18.4

Summarize the relationship between the immune and nervous systems in response to stress.

LO 18.5

List the symptoms of PTSD.

LO 1Sl.14

LO 18.6

Describe the roles of genetic and environmen tal factors in PTSD.

Describe the roles of genetic and environmental factors in OCD.

LO 1Sl.15

Describe changes in the brain associated with PTSD.

Describe changes in the brain associated with OCD.

LO 1Sl.16

Summarize treatments for OCD.

LO 18.7

567

Graciela is a busy college student, 6 weeks away from graduation. She is involved in intramural sports and works as an undergraduate researcher in a neuroscience lab on campus. Her hockey team is playing in the championship next week, and she is completing a study of serotonin cells that her advisor believes could be published in a prestigious journal. Graciela's week is filled with classes, time in the lab, hockey practices, and homework. She has also applied to six graduate programs and four full-time laboratory technician positions in hopes of beginning a career after graduation. She has three exams next week and has been staying up very late to study, but is having trouble remembering facts that used to come easily to her. On top of everything else, she has had a sinus infection for nearly a week, which is further draining her energy. Hurrying across campus so she wouldn't be late to class one day, she suddenly felt herself filled with an intense fear. Her mind began racing. Did she complete all of her assignments?

Graciela's experience illustrates that both physiological symptoms, such as shortness of breath and increased heart rate, and emotional symptoms, such as the experience of fear, can accompany anxiety disorders such as panic disorder. As you read this chapter, consider how elements of Graciela's experience reveal the role of the nervous system in stress and immune responses, and the experience of anxiety. The chapter begins with a description of stress, a physiological reaction that many people experience as part of their daily lives. Next, we will explore some of the disorders that

Had she shut down the equipment in the lab? Did she send in her final job application? She began having d ifficulty breathing. She was able to take only short, shallow breaths, and her hands anal arms were tingling. She could feel her heart pounding and her body shaking. Terrified, Graciela suddenly fell to the ground. ShEl wondered if she were having a heart attack. A friend saw Graciela fall, rushed to her side, and called an ambulance. At the hospital doctors ran an EKG test to record the activity of Graciela's heart. They also ran a number of other stress tests. Fortunately, the tests indicated that Graciela's heart was healthy and she had not had a heart attack. The consensus was that Graciela experienced a panic attack, a period of symptoms that can include shortness of breath, irregularities in heartbeat, anal other autonomic symptoms accompanied by intense fear. Recurrent panic attacks are one of the criteria for a diagnosis of paniic disorder.

can indude elements of a chronic or pathological stress response; posttraumatic stress disorder, anxiety disorders, and obsessive-compulsive disorder.

Stress Aversive stimuli can harm people's health. Man y harmful effects. are produced not by the stimuli themselves but by our reactions to them. Walter Cannon, the physiologist who

568 Chapter 18

criticized the James-Lange theory described in Chapter 11, introduced the term stress to refer to the physiological reaction caused by the perception of aversive or threatening situations. The word stress was borrowed from engineering, in which it refers to the action of physical forces on mechanical structures. The word can be a noun or a verb, and the noun can refer to situations or the individual's response to them. When we say that someone was subjected to stress, we really mean that someone was exposed to a situation that elicited a particular reaction in that person: a stress response. The physiological responses that accompany the negative emotions prepare us to threaten rivals or fight them, or to run away from dangerous situations. Cannon introduced the phrase fight-or-flight response to refer to the physiological reactions that prepare us for the strenuous efforts required by fighting or running away. Usually, once we have fought with an adversary or run away from a dangerous situation, the threat is over, and our physiological condition can return to normal. The fact that the physiological responses may have adverse long-term effects on our health is unimportant as long as the responses are brief. But sometimes, the threatening situations are continuous rather than episodic, producing a more or less continuous stress response. And as we will see in the following module on posttraumatic stress disorder, sometimes threatening situations are so severe that they trigger responses that can last for months or years.

Physiology of the Stress Response LO 18.1 Compare the SAM system and HPA axis in

the sympathet:ic adrenal-medullary system (SAM system). In response to a stressful stimulus or environment, the hypothalamus and the sympathetic nervous system stimulate the adrenal medulla to release epinephrine and norepinephrine. Together, these catecholamine hormones initiate a rapid activation of the sympathetic nervous system. (See Figure 18.1.) Epinephriine affects glucose metabolism, causing the nutrients stored in muscles to become available to provide energy for strenuous exercise. Along with norepinephrine, the hormone .also increases blood flow to the muscles by increasing the output of the heart. In doing so, it increases blood pressure, which, over the long term, contributes to cardiovascula:r disease. Besides serving as a stress hormone, norepinephrine is (as you know) secreted in the brain as a neurotransmitter. Some of the behavioral and physiological responses produced by aversive stimuli appear to be mediated by noradrenergic neurons (McCall et al., 2015). For example, micro-dialysis studies have found that stressful situations increase the release of norepinephrine in the hypothalamus, frontal cortex, and lateral basal forebrain (Cenci et al., 1992; Yokoo et al., 1990). Montero and colleagues (1990) found that destroying the noradrenergic axons that ascend from the brain stem to the forebrain prevented the rise in blood pressure that is normally produced by social isolation stress. The stressinduced release of norepinephrine in the brain is controlled by a pathway from the central nucleus of the amygdala to the locus coeruleus, the nucleus of the brain stem that contains norepinephrirn~-secreting neurons (Van Bockstaele et al., 2001). HYPOTHALAMIC PITUITARY ADRENAL AXIS The other stress-related hormone is cortisol, a steroid secreted

coordinating a stress response. As we saw in Chapter 11, emotions consist of behavioral, autonomic, and endocrine responses. The latter two components, the autonomic and endocrine responses, are the ones that can have adverse effects on health. (The behavioral components can, too, if, say, a person rashly gets into a fight with someone who is much bigger and stronger.) Because threatening situations generally call for vigorous activity, the autonomic and endocrine responses that accompany them are catabolic and help to mobilize the body's energy resources. The sympathetic branch of the autonomic nervous system is active, and the adrenal glands secrete epinephrine, norepinephrine, and steroid stress hormones. Because the effects of sympathetic activity are similar to those of the adrenal hormones, we will limit our discussion to the hormonal responses. The release of catecholamine stress hormones (epinephrine and norepinephrine) is controlled by the sympathetic adrenal-medullary system, while release of the glucocorticoid hormones is controlled by the hypothalamic pituitary adrenal axis. SYMPATHETIC ADRENAL-MEDULLARY SYSTEM The release of catecholamine stress hormones is controlled by

Figure 18.1.

Control of Secretion of Stress Hormones

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Stress and Anxiety Disorders

by the adrenal cortex. Cortisol is called a glucocorticoid because it has profound effects on glucose metabolism. In addition, glucocorticoids help to break down protein and convert it to glucose, help to make fats available for energy, increase blood flow, and stimulate behavioral responsiveness, presumably by affecting the brain. They decrease the sensitivity of the gonads to luteinizing hormone (LH), which suppresses the secretion of the sex steroid hormones. For example, Singer and Zumoff (1992) found that the blood level of testosterone in male hospital residents (doctors, not patients) was severely depressed, presumably because of the stressful work schedule they were obliged to follow. In women, daily self-report ratings of stress were inversely related to estradiol concentrations (Roney et al., 2015). Glucocorticoids have other physiological effects, too, some of which are only poorly understood. Almost every cell in the body contains glucocorticoid receptors, which means that few of them are unaffected by these hormones. Glucocorticoid release is controlled by the activity of the h ypothalamic pituitary adrenal axis (HPA axis). Glucocorticoid secretion is controlled by neurons in the paraventricular nucleus of the hypothalamus (PVN), whose axons terminate in the median eminence, where the hypothalamic capillaries of the portal blood supply to the anterior pituitary gland are located. (The pituitary portal blood supply was described in Chapter 3.) The neurons of the PVN secrete a peptide called corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH enters the general circulation and stimulates the adrenal cortex to secrete glucocorticoids. (See Figure 18.1.) CRH (also called CRF, or corticotropin-releasing factor) is also secreted within the brain, where it serves as a neuromodulator/neurotransmitter, especially in regions of the limbic system that are involved in emotional responses, such as the periaqueductal gray matter, the locus coeruleus, and the central nucleus of the amygdala. The behavioral effects produced by an injection of CRH into the brain are similar to those produced by aversive situations. This indicates that some elements of the stress response appear to be produced by the release of CRH by neurons in the brain. For example, intracerebroventricular injection of CRH decreases the amount of time a rat spends in the center of a large open chamber, which is considered an anxiety-like behavior (Britton et al., 1982), enhances the acquisition of a classically conditioned fear response (Cole & Koob, 1988), and increases the startle response elicited by a sudden loud noise (Swerdlow et al., 1986). On the other hand, intracerebroventricular injection of a CRH antagonist reduces the anxiety-like behavior in animal models caused by a variety of stressful situations (Gafford et al., 2012; Heinrichs et al., 1994; Kalin et al., 1988; Skutella et al., 1994). The effects of CRH on stress response in the brain appear to be mediated through feedback to the locus coeruleus (McCall et al., 2015).

569

The secretion of glucocorticoids does more than help an animal react to a stressful situation: It helps the animal to survive. If a rat's adrenal glands are removed, the rat becomes much more susceptible to the effects of stress. In fact, a stressful situation that a normal rat would take in its stride might be fatal to one whose adrenal glands have been removed. And physicians know that if an adrenalectomized person is subjected to stressors, he or she must be given additional amounts of glucocorticoid (Tyrell & Baxter, 1981).

Health Effects of Long-Term Stress LO 18.2 Describe the negative health outcomes associated with chronic stress. Many studies of people who have experienced chronic or repeated stressful situations have found evidence of ill health. For example, survivors of concentration camps, who were subjected to long-term stress, have had generally poorer health later in life than other people of the same age (Cohen, 1953). A review of research involving hundreds of thousands of people reported a significant relationship between workrelated stress and increased risk of heart disease and stroke (Kivimaki & Kawachi, 2015). Drivers of subway trains that injure or kill people are more likely to experience illnesses several months later (Theorell et al., 1992). Air traffic controllers, especially those who work at busy airports where the danger of collisions is greatest, show a greater incidence of high blood pressure, which gets worse as they grow older (Cobb & Rose, 1973). (See Figure 18.2.) They also are more likely to develop ulcers or diabetes.

Figure 18.2

Stress and Hypertension

The gra1ph shows the incidence of hypertension in various age groups of air traffic controllers at high-stress and low-stress airports. Source: Based on data from Cobb, S., & Rose, R. M. (1973). Hypertension, peptic u leer, and diabetes in air traffic controllers. Journal of the American Medical Association, 224, 489-492.

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570 Chapter 18

A key researcher in this area, Hans Selye, suggested that most of the harmful effects of stress were produced by the prolonged secretion of glucocorticoids (Selye, 1976). Although the short-term effects of glucocorticoids are essential and often beneficial, the long-term effects of sustained glucocorticoid exposure are damaging. These effects include increased blood pressure, damage to muscle tissue, steroid diabetes, infertility, inhibition of growth, inhibition of the inflammatory responses, and suppression of the immune system. High blood pressure can lead to heart attacks and stroke. Inhibition of growth in children who are subjected to prolonged stress prevents them from attaining their full height. Inhibition of the inflammatory response makes it more difficult for the body to heal itself after an injury, and suppression of the immune system makes an individual vulnerable to infections. Long-term administration of steroids to treat inflammatory diseases often produces cognitive deficits and can even lead to steroid psychosis, whose symptoms include profound distractibility, anxiety, insomnia, depression, hallucinations, and delusions (de Kloet et al., 2005; Lewis & Smith, 1983). A growing collection of research suggests that impaired regulation of the HPA axis is involved in many of the harmful effects of long-term stress (McEwen, 2006). Allostasis is a term to describe the process of responding to stimuli and regaining and maintaining homeostasis. Allostasis may include a change in the set point of a system to respond to stimuli that are outside the range of typical homeostatic functioning (McEwen & Wingfield, 2010; Sterling & Eyer, 1988). A related concept, allostatic load refers to the cumulative and collective wear and tear on body systems when there is too much stress response or when the stress response is not turned off. Allostatic load has been implicated in the negative health effects of prolonged or exaggerated stress response in stress and anxiety disorders. Fortunately, interventions such as physical activity and social integration can help restore healthy homeostatic HPA axis regulation (McEwen & Gianaros, 2010). The adverse effects of stress on healing were demonstrated in a study by Kiecolt-Glaser and colleagues (1995), who performed punch biopsy wounds in the participants' forearms, a harmless procedure that is used often in medical research. The participants were people who were providing long-term care for relatives with Alzheimer's disease-a situation that is known to cause stress-and control participants of the same approximate age and family income. The investigators found that wound healing took significantly longer in the caregivers (48.7 days versus 39.3 days). (See Figure 18.3.) A subsequent study (Kiecolt-Glaser et al., 2005) found that the wounds of couples who displayed high levels of hostile behavior healed more slowly than those of couples with more friendly interactions. Another study found impaired wound healing among students during an exam period, compared to summer vacation (Marucha et al., 1998).

Figure 18.3:

Stress and Wound Healing

The graph shows the percentage of caregivers and control participants w ho·se wounds had healed as a function of time after the biopsy was performed. Source: Based on data from Kiecolt-Glaser, J . K., Marucha, P. T., Malarkey, W. B., Mercado, A. M., & Glaser, R. (1995). Slowing of wound healing by

psychological stre~;s, Lancet, 345, 1194-1196. 1OO - •

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dopamiinergic terminals. Source: Based on Mccann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., et al. (1 9198). Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: Evidence from positron emission tomography studies with [11C)WIN-35,428. Journal of Neuroscience, 18, 8417-8422.

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cocaine, they can self-inject so much cocaine that they die. As a result, researchers who study this drug must limit animals' access to the drug. As we have seen, the mesolimbic dopamine system plays an essential role in all forms of reinforcement, except perhaps for the reinforcement that is mediated by direct stimulation of opiate receptors. Many studies have shown that intravenous injections of cocaine and amphetamine increase the concentration of dopamine in the NAC, as measured by microdialysis. For example, Figure 19.15 shows data collected by Di Ciano and colleagues (1995) in a study with rats that learned to press a leve:r that delivered intravenous injections of cocaine or amph1etamine. The colored bars at the base of the graphs indicate the animals' responses, and the line graphs indicate the level of dopamine in the NAC.

Nicotine LO 19.8 Describe the roles of reinforcem ent and physical dependence in nicotine abuse. Although its use is common, nicotine is a drug of abuse, and it accounts for more deaths than the other drugs described so far in this chapter. DESCRIPTION The combination of nicotine and other substances in tobacco smoke is carcinogenic and leads to cance1r of the lungs, mouth, throat, and esophagus. Approximately one-third of the adult population of the world smokes, and smoking is one of the few causes of death that is rising in developing countries. The World Health Organization estimates that 50 percent of the people who begin to smoke as adolescents and continue smoking throughout their lives will die from smoking-related diseases.

608

Chapter 19

Figure 19.15

Release of Dopamine in the Nucleus Accumbens

The graphs show dopamine concentration in the nucleus accumbens, measured by microdialysis, during self-administration of intravenous cocaine or amphetamine by rats. Source: Based on data from Di Ciano, P., Coury, A., Depoortere, R. Y. , Egilmez, Y., et al. (1995). Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous selfadministration of cocaine or d-amphetamine. Behavioural Pharmacology, 6,

311-322.

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to vaporize nicotine (vaping) presents new challenges to understanding nicotine abuse (Chapman et al., 2014). While these mutes of administration reduce exposure to the harmful substances in combustible cigarettes, their use is also associated with negative effects to the respiratory, digestive, and nervous systems (Chen, 2013; Hua et al., 2013). The abuse potential of nicotine should not be underestimated; many people continue to smoke even when doing so causes serious health problems. For example, Sigmund Freud, whose theory of psychoanalysis stressed the importance of insight in changing one's behavior, was unable to stop smoking even after most of his jaw had been removed because of the cancer that this habit had caused (Brecher, 1972). He suffered severe pain and, as a physician, realized that he should have stopped smoking. He did not, and cancer finally kil!ted him.

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Tobacco use is the leading cause of preventable death in developed countries (Dani & Harris, 2005). In the United States alone, tobacco abuse kills more than 430,000 people each year (Chou & Narasimhan, 2005). Worldwide, stroke is the second leading cause of death and lung cancer is the fifth (Lozano et al., 2013). Both of these causes of death are negatively influenced by smoking. Smoking by pregnant women also has negative effects on the health of their fetuses- potentially worse than those of cocaine (Slotkin, 1998). Increased use of electronic cigarettes and devices

REI NFORC EM ENT Nicotine has a very high abuse potential. In a review of the literature, Stolerman and Jarvis (1995) note that smokers tend to smoke regularly or not at all; few can smoke just a little. Nineteen out of 20 smokers smoke every day, and only 60 out of 3,500 smokers ques-

tioned smoke fewer than five cigarettes per day. Forty percent of people continue to smoke after having their larynx removed (whiich is usually performed to treat throat cancer). More than 50 percent of heart attack survivors continue to smoke, and about 50 percent of people continue to smoke after surgery for lung cancer. Of those who attempt to quit smoking by enrolling in a special program, 20 percent manage to abstain for 1 year. The record is much poorer for those who try to quit on their own: One-third manage to stop for 1 day, one-fourth abstain for 1 week, but only 4 per·cent manage to abstain for 6 months. Ours is not the only species willing to self-administer nicotine; so will laboratory animals (Donny et al., 1995). Nicotine stimulates nicotinic acetylcholine receptors. It also increases the activity of dopaminergic neurons of the mesolimbic system (Mereu et al., 1987) and causes dopamine to be rE!leased in the NAC (Damsma et al., 1989). Figure 19.16 demonstrates the effects of two injections of nicotine or saline on the extracellular dopamine level of the NAC, measuned by microdialysis. Injection of a nicotinic agonist directly into the VTA will reinforce a conditioned place preference (Museo & Wise, 1994). Conversely, injection of a nicotinic antagonist into the VTA will block the ability of nicotine to cause the release of dopamine in the nucleus accumbens and reduce the reinforcing effect of intravenous injections of nicotine (Corrigall et al., 1994; Gotti et al., 2010). But although nicotinic recepto1rs are found in both the VTA and the NAC, Corrigall and .colleagues found that injections of a nicotinic antagonist in the NAC have no effect on reinforcement. Consistent with these findings, Nisell and colleagues (1994)

Substance Abu se

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Figure 19.16 Nicotine and Dopamine Release in the

Figure 19.17 Effect of Knockout of the a5 ACh

Nucleus Accumbens

Recepitor Gene in Mice

The graph shows changes in dopamine concentration in the nucleus accumbens, measured by microdialysis, in response to injections of nicotine or saline. The arrows indicate the time of the injections.

The gra1ph shows that mice with a targeted mutation against as ACh receptors in the medial habenula self-administer inc reasing doses of nicotirni, whereas control mice limit their intake.

Source: Based on data from Damsma, G., Day, J., & Fibiger, H. C. (1989). Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. £uropean Journal of Pharmacology, 168, 363-368.

Source: Based on data from Fowler, C., Lu, Q., Johnson, P. M., Marks, M. J. , et al. (2011 ). Habenular aS nicotinic receptor subunit signaling controls nicotine intake. Nature, 471, 597-601 .

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found that infusion of a nicotinic antagonist into the VTA will preven t an intravenous injection of nicotine from triggering the release of dopamine in the NAC. Infusion of the antagonist into the NAC will not have this effect. The reinforcing effect of nicotine appears to be caused by activation of nicotinic receptors in the VTA. Researchers have discovered a pathway in the brain that inhibits the reinforcing effects of nicotine. Neurons in the medial habenula, a region of the midbrain, contain a special type of nicotinic ACh receptor that includes an a5 subunH. The neurons that contain these receptors send their axons to the interpeduncular nucleus, located in the midline of the midbrain, caudal to the medial habenula. This pathway appears to be part of a system that inhibits the reinforcing effects of nicotine. Fowler and colleagues (2011) prepared a targeted mutation against the gene responsible for synthesis of a5 ACh receptors in the medial habenula of mice. They found that the knockout increased self-administration of high doses of nicotine. They also found that the procedure decreased the ability of nicotine to activate the interpeduncular nucleus, and that d isruption of activity in this nucleus increased nicotine self-administration. The medial habenula-interpeduncular nucleus circuit appears to protect the animals (and presumably, our own species) against intake of large quantities of nicotine. A control mouse will increase its response rate when the amount of nicotine contained in each injection increases- up to a point, that is. Eventually, larger injections will suppress the animal's response rate so that it will not receive too much nicotine. But if a5 ACh receptors in the habenula are deactivated, this inhibitory effect does not occur. (See Figure 19.17.)

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Role o f Cannabino id Receptors Studies have found that the endogenous cannabinoids play a role in the reinforcing effects of nicoti ne. Rimonabant, a drug that block~; cannabinoid CBl receptors, reduces nicotine self-administration and nicotine-seeking behavior in rats (Cohen et al., 2005), apparently by reducing the release of dopamine in the NAC (De Vries & Schoffelme•er, 2005). By blocking CBl receptors, rimonabant decreases the reinforcing effects of nicotine. As we saw in Chapter 12, rimonabant was used for antiobesity therapy for a short time but was withdrawn from the market because of dangerous side effects. Clinical trials have found that rimonabant appears to help prevent relapse in people who are trying to quit smoking, but it is not approved for this purpose, either. However, the effects of the drug in humans and laboratory animals suggest that craving for nicotine, like the craving for food, is enhanced by the release of endocannabinoids in the brain. The nicotinic ACh receptor exiists in three states. When a burst of ACh is released by an acetylcholinergic terminal button, the receptors open briefly, permitting the entry of calcium. (Most nicotinic receptors serve as heteroreceptors on terminal buttons that release another neurotransmitter. The entry of calcium stimulates the release of that neurotransmitter.) Within a few milliseconds, the enzyme AChE has destroyed the acetylcholine, and the receptors either close again or enter a desensitized state, during which they bind with, but do not react to, ACh. Normally, few PHYSICAL DEPENDENCE

610 Chapter 19

nicotinic receptors enter the desensitized state. However, when a person smokes, the level of nicotine in the brain rises slowly and stays steady for a prolonged period because nicotine, unlike ACh, is not destroyed by AChE. At first, nicotinic receptors are activated, but the sustained low levels of the drug convert many nicotinic receptors to the desensi tized state. Nicotine has dual effects on nicotinic receptors: activation and then desensitization. In addition, probably in response to desensitization, with repeated use of the drug the number of nicotinic receptors increases (Dani & De Biasi, 2001). Many smokers report that their first cigarette in the morning brings the most pleasure, presumably because the period of abstinence during the night has allowed many of their nicotinic receptors to enter the closed state and become sensitized again. The first dose of nicotine in the morning activates these receptors and has a reinforcing effect. After that, a large proportion of the smoker's nicotinic receptors become desensitized again; as a consequence, most smokers say that they smoke less for pleasure than to relax and gain relief from nervousness and craving. If smokers abstain for a few weeks, the number of nicotinic receptors in their brains returns to normal. However, as the high rate of relapse indicates, craving continues, which means that other changes in the brain must have occurred. Cessation of smoking after long-term use causes withdrawal symptoms, including anxiety, restlessness, insomnia, and inability to concentrate (Hughes et al., 1989). Like the withdrawal symptoms of other drugs, these symptoms may increase the likelihood of relapse, but they do not explain why people become dependent to the drug in the first place. The case of patient N. demonstrates an unusual exception to this phenomenon.

Patient N. is a (38-year-old man who) started smoking at the age of 14. At the time of his stroke, he was smoking more than 40 unfiltered cigarettes per day and was enjoying smoking very much . . .. [H)e used to experience frequent urges to smoke, especially upon waking, after eating, when he drank coffee or alcohol, and when he was around other people who were smoking. He often found it difficult to refrain from smoking in situations where it was inappropriate, e.g., at work or when he was sick. He was aware of the health risks of smoking before his stroke but was not particularly concerned about those risks. Before his stroke, he had never tried to stop smoking, and he had had no intention of doing so. N. smoked his last cigarette on the evening before his stroke. When asked about his reason for quitting smoking, he stated simply, "I forgot that I was a smoker." When asked to elaborate, he said that he did not forget the fact that he was a smoker but rather that "my body forgot the urge to smoke." He felt no urge to smoke during his hospital stay,

As Naqvi and colleagues (2007) report, patient N. sustained a stroke that damaged his insula. In fact, several other patients with insular damage had the same experience. Naqvi and colleagues identified 19 cigarette smokers with damage to the insula and 50 smokers with brain damage that spared this region. Of the 19 patients who had damage to the insula, 12 "quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke" (Naqvi et al., 2007, p. 531). One patient with insula damage g1uit smoking but still reported feeling an urge to smoke. Figure 19.18 shows computer-generated images

Figure 19.1.8 Damage to the lnsula and Smoking Cessation The diagram shows the regions of the brain (shown in red) where damage was most highly correlated with cessation of smoking. Source: From Naqvi, N. H., Rudrauf, D., Damasio, H., & Bechara, A. (2007). Damage to the insula disrupts addiction to cigarette smoking. Science, 315, 531 - 534.

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even though he had the opportunity to go outside to smoke. His wife was surprised by the fact that he did not want to smoke in the hospital, given the degree of his prior craving. N. recalled how his roommate in the hospital would frequently go outside to smoke and that he was so disgusted by the smell upon his roommate's return that he asked to change rooms. He volunteered that smoking in his dreams, which used to be pleasurable before his stroke, was now disgusting. N. stated that, although he ultimately came to believe that his stroke was caused in some way by smoking, suffering a stroke was not the reason why he quit. In fatct, he did not recall ever making any effort to stop smoking. Instead, it seemed to him that he had spontaneously lost all interest in smoking. When asked whether his stroke might have destroved some part of his brain .. . that made him want to smoke, h(9 agreed that this was likely to have been the case (Naqvi et al., 2007, p. 534).

Substance Abuse

of brain damage that showed a statistically significant correlation with disruption of smoking. As you can see, the insula, which is colored red, showed the highest association with cessation of smoking. Other studies have corroborated the report by Naqvi and colleagues (Hefzy et al., 2011). In addition, Forget and colleagues (2010) found that infusion of an inhibitory drug into the insula of rats reduced the reinforcing effects of nicotine. (See Figure 19.19.) Zhang and colleagues (2011) found decreased gray matter in the frontal cortex of smokers, which may be at least partly responsible for the difficulty that smokers have in breaking their habit. These investigators also found that the insula was larger in smokers, which is consistent with the apparent role of the insula in nicotine addiction. One of the several deterrents to cessation of smoking is the fact that overeating and weight gain frequently occur when people stop smoking. As mentioned earlier in this chapter and in Chapter 12, eating and a reduction in metabolic rate are stimulated by the release of MCH and orexin in the brain. Jo and colleagues (2005) found that nicotine inhibits MCH neurons, suppressing appetite. When people try to quit smoking, they are often discouraged by the fact that the absence of nicotine in their brains releases their MCH neurons from this inhibition, increasing their appetite. Nicotine also stimulates the release of orexin, which, as we saw earlier in this chapter, is involved in drug-seeking behavior (Huang et al., 2011).

Figure 19.19

Effects of Inactivation of the lnsula on Reinstatement of Drug-Seeking Behavior in Rats

Rats were trained to work for injections of nicotine, and then the behavior was extinguished. The graph shows that inactivation of the insula substantially reduced drug-seeking behavior elicited by nicotine or cues previously associated with nicotine. Source: Based on data from Forget, 8., Pushparaj, A., & Le Foll, 8. (2010). Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction. Biological Psychiatry, 68, 265-271.

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Orexin is released in many parts of the brain, but one region may play an especially important role in smoking: the insula. Hollander and colleagues (2008) found that infusion of a drug into the insula that blocks orexin receptors decreased the responding of rats for injections of nicotine.

Alcohol LO 19.9 Describe the roles of reinforcement and

physical dependence in alcohol abuse. Alcohol has enormous costs to society. A large percentage of deaths and injuries caused by motor vehicle accidents are rellated to alcohol use, and alcohol contributes to violence and aggression. People who abuse alcohol may lose their jobs, their homes, and their families; many die of cirrhosis of the liver, exposure, or diseases caused by poor living conditions and injury or neglect of their bodies. Understanding the physiological and behavioral effects of this drug is an important issue. DESCRIPTION At low doses, alcohol produces mild euphoria and has an anxiolytic effect-that is, it reduces the discomfort of anxiety. At higher doses, it produces incoordinatiion and sedation. In studies with laboratory animals, the anxiolytic effects manifest themselves as a release from the punishing effects of aversive stimuli. For example, if an animal is given electric shocks whenever it makes a particular response (say, one that obtains food or water), it will stop doing so. However, if it is then given some alcohol, it will b1egin making the response again (Koob et al., 1984). This phenomenon explains why people often do things they rnormally would not when they have had too much to drink; the alcohol removes the inhibitory effect of social contwls on their behavior. Alcohol has two major sites of action in the nervous system, acting as an indirect antagonist at NMDA receptors and as an indirect agonist at GABAA receptors (Chandler et al., 1998). That is, alcohol enhances the action of GABA at GABAA receptors and interferes with the transmission of glu1tamate at NMDAreceptors. (See Figure 19.20.) A:s we saw in Chapter 13, NMDA receptors are involved in long-term potentiation, a phenomenon that plays an important role in learning. Alcohol, which antagonizes t:he action of glutamate at NMDA receptors, d isrupts long-berm potentiation and interferes with the spatial receptive fields of place cells in the hippocampus (Givens & McMahon, 1995; Matthews et al., 1996). Presumably, this effect at least partly accounts for the deleterious effects of alcohol on memory and other cognitive functions. The second site of action of alcohol is the GABAA receptor. Alcohol binds with one of the many binding sites on this receptor and increases the effectiveness of GABA in opening the chloride channel and producing

612

Chapter 19

Figure 19.20 Alcohol Binds to NMDA and GABAA Receptors NMDA Receptor

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inhibitory postsynaptic potentials. Proctor and colleagues (1992) recorded the activity of single neurons in the cerebral cortex of slices of rat brains. They found that the presence of alcohol significantly increased the postsynaptic response produced by the action of GABA at the GABAA receptor. As we saw in Chapter 4, the anxiolytic effect of the benzodiazepines is caused by their action as indirect agonists at the GABAA receptor. Because alcohol has this effect also, we can surmise that the anxiolytic effect of alcohol is a result of this action of the drug. The sedative effect of alcohol also appears to be exerted at the GABAA receptor. Suzdak and colleagues (1986) discovered a drug (RolS-4513) that reverses alcohol intoxication by blocking the alcohol binding site on this receptor. Although the behavioral effects of alcohol are mediated by their action on GABAA receptors and NMDA receptors, high doses of alcohol have other, potentially fata l effects on all cells of the body, including destabilization of cell membranes. As you have read previously, prenatal exposure to alcohol can have effects on the developing nervous system. Ikonomidou and colleagues (2000) found that exposure of the immature rat brain to alcohol triggered widespread cell death through apoptosis. The investigators exposed immature rats to alcohol at different times during the period of brain growth and found that different regions were vulnerable to the effects of the alcohol at different times. Apparently, both of alcohol's actions at GABA and glutamate receptors trigger apoptosis. To confirm this mechanism, Ikonomidou and colleagues found that administration of a GABAA agonist (phenobarbital, a barbiturate) or an NMDA antagonist (MK-801) to 7-dayold rats caused brain damage by means of apoptosis. (See Figure 19.21.)

Figure 19.2'.1 Early Exposure to Alcohol and Apoptosis The photomicrog1raphs of sections of rat brain show degenerating neurons (black spots). Exposure to alcohol (ethanol) during the period of rapid b1rain growth causes cell death by inducing apoptosis. These effects are? mediated by the actions of alcohol as an NMDA antagonist and a GABAA agonist. MK-801, an NMDA antagonist, and

phenobarbital, a GABAA agonist, also induce apoptosis. Source: From lkonomidou, C., Bittigau, P., lshimaru, M. J., et al. (2000). Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science, 287, 105Ei-1060. By permission.

SALINE

REI NFORCEMENT Alcohol produces both positive and

negative reinforcement. The positive reinforcement manifests itself as mild euphoria. As we saw earlier, negative reinforcement: is caused by the termination of an aversive stimulus. If a person feels anxious and uncomfortable, then an anxiolytic drug that relieves this discomfort provides at least a temporary escape from an unpleasant situation. The negative reinforcement provided by the anxiolytic effect of alcohol is probably not enough to explain the drug's abuse potential. Other drugs, such as the benzodiazepines (for example, Valium or Ativan), are even more potent anxiolytics than alcohol, yet such drugs are abused less often. It is probably the unique combination

Substance Abuse

of stimulating and anxiolytic effects-of positive and negative reinforcement-that makes alcohol so difficult for some people to resist. Alcohol, like other drugs of abuse, increases the activity of the dopaminergic neurons of the mesolimbic system and increases the release of dopamine in the NAC as measured by microdialysis (Gessa et al., 1985; Imperato & Di Chiara, 1986). The release of dopamine appears to be related to the positive reinforcement that alcohol can produce. An injection of a dopamine antagonist directly into the NAC decreases alcohol intake in rats (Samson et al., 1993), as does the injection of a drug into the VTA that decreases the activity of the dopaminergic neurons there (Hodge et al., 1993). In a double-blind study, Enggasser and de Wit (2001) found that haloperidol, an antipsychotic drug that blocks DA receptors, decreased the amount of alcohol that participants subsequently drank. Presumably, the drug reduced the reinforcing effect of the alcohol. In addition, individuals who normally feel stimulated and euphoric after having a drink reported a reduction in these effects after taking haloperidol. Opiate receptors appear to be involved in a reinforcement mechanism that does not directly involve dopaminergic neurons. The reinforcing effect of alcohol is at least partly caused by its ability to trigger the release of the endogenous opioids. Several studies have shown that the opiate receptor blockers such as naloxone block the reinforcing effects of alcohol in a variety of species, including rats, monkeys, and humans (Altschuler et al., 1980; Davidson et al., 1996; Reid, 1996). In addition, endogenous opioids may play a role in alcohol craving. Heinz and colleagues (2005) found that 1 to 3 weeks of abstinence increased the number ofµ opiate receptors in the NAC. The greater the number of receptors, the more intense the craving was. Presumably, the increased number of µ receptors increased the effects of endogenous opiates on the brain and served as a contributing factor to the craving for alcohol. (See Figure 19.22.) PHYSICAL DEPEN DENCE Withdrawal from long-term

alcohol intake (like that of heroin, cocaine, amphetamine, and nicotine) decreases the activity of mesolimbic neurons and their release of dopamine in the NAC (Diana et al., 1993). If an indirect antagonist for NMDA receptors is then administered, dopamine secretion in the NAC recovers. The evidence suggests the following sequence of events: Some of the acute effects of a single dose of alcohol are caused by the antagonistic effect of the drug on NMDA receptors. Long-term suppression of NMDA receptors causes upregulation-a compensatory increase in the sensitivity of the receptors. Then, when alcohol intake suddenly ceases, the increased activity of NMDA receptors inhibits the activity of ventral tegmental neurons and the release of dopamine in the NAC.

Figure 19.22

613

Cravings for Alcohol andµ Opiate

Recepitors The dra1wings of the results of PET scans show the presence of µ opiate receptors in the dorsal striatum of detoxified patients diagnosed with alcohol abuse and healthy control participants. The graiph shows the relative alcohol craving score as a function of relative numbers ofµ opiate receptors. Source: Based on data from Heinz, A., Reimold , M., Wrase, J., Hermann, D., et al. (2005). Correlation of stable elevations in striatal µ-opioid receptor availabiliity in detoxified alcoholic patients with alcohol craving. Archives of General Psychiatry, 62, 57~.

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Although the effects of opiate withdrawal are often exaggerated, those produced by barbiturate or alcohol withdrawal are serious and can even be fatal. The increase!d sensitivity of NMDA receptors as they rebound from the suppressive effect of alcohol can trigger seizures that are considered to be a medical emergency and are usually treated with benzodiazepines. Confirming the cause of these reactions, Liljequist (1991) found that seizures caused by alcohol withdrawal could be prevented by giving mice a drug that blocks NMDA receptors.

614

Chapter 19

Cannabis LO 19.10 Describe the role of reinforcement in cannabis abuse.

Another drug that people regularly self-administer is 89-tetrahydrocannabinol, or THC, the psychoactive compound found in marijuana. THC is produced by the marijuana plant, or it can be created synthetically. Synthetic cannabinoids such as K2 or Spice were implicated in nearly 30,000 emergency room visits in 20IO, doubling the number from 200I (Substance Abuse and Mental Health Services Administration, 20I8.). Synthetic cannabinoids were made illegal in the United States in 20I2. The percentage of Americans responding to a national survey of marijuana use in their lifetime (45 percent), past year (I6 percent), and past month (IO percent) all increased from 20I7 to 20I8, with marijuana use making up the large majority of all illicit drug use in the United States (Substance Abuse and Mental Health Services Administration, 20I8).

Figure 19.2'.3 THC and Dopamine Secretion in the Nucleus Accumbens The graph shows changes in dopamine concentration in the nucleus accumbens, measured by microdialysis, in response to injections of THC or an inert placebo. Source: Based on c:lata from Chen, J., Paredes, W., Li, J., Smith, D., et al. (1990). 69-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freel\t-moving rats as measured by intracerebral microd ialysis. Psychopharmacolo•gy, 102, 156-162.

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REI NFORCEMENT THC, like other drugs that are abused, has a stimulating effect on dopaminergic neurons. Chen and colleagues (I990) injected rats with low doses of THC and measured the release of dopamine in the NAC by means of microdialysis. Sure enough, they found that the injections caused the release of dopamine. (See Figure I9.23.) Chen and colleagues (I993) found that local injections of small amounts of THC into the VTA had no effect on the release of dopamine in the NAC. However,

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D ESCRIPTION As you learned in Chapter 4, the site of action of the endogenous cannabinoids in the brain is the CBI receptor. The endogenous ligands for the CBI receptor, anandamide and 2-AG, are lipids. Administration of a drug that blocks CBI receptors abolishes the "high" produced by smoking marijuana (Huestis et al., 200I). As we saw in Chapter 4, the hippocampus contains a large concentration of CBI receptors. Marijuana produces memory impairment. Evidence indicates that the drug does so by disrupting the normal functions of the hippocampus, which plays such an important role in memory. Pyramidal cells in the CAI region of the hippocampus release endogenous cannabinoids, which provide a retrograde signal that inhibits GABAergic neurons that normally inhibit them. In this way the release of endogenous cannabinoids facilitates the activity of CAI pyramidal cells and facilitates longterm potentiation (Kunos & Batkai, 200I). We might expect that facilitating long-term potentiation in the hippocampus would enhance its memory functions. However, the reverse is true; Hampson and Deadwyler (2000) found that the effects of cannabinoids on a spatial memory task were similar to those produced by hippocampal lesions. Thus, excessive activation of CBI receptors in field CAI appears to interfere with normal functioning of the hippocampal formation.

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injection of THC into the NAC did cause dopamine release there. THC appears to act directly on dopaminergic terminal buttons-jpresumably on presynaptic heteroreceptors, where it increases the release of dopamine. A variety of laboratory animals, including mice, rats, and monkeys, will self-administer drugs that stimulate CBI receptors:, including THC (Maldonado & Rodriguez de Fonseca, 2002). A targeted mutation that blocks the production of CBI receptors abolishes the reinforcing effect not only of cannabinoids but also of morphine and heroin (Cossut et al., 200I). This mutation also decreases the reinforcing effects of alcohol and the acquisition of selfadministration of cocaine (Houchi et al., 2005; Soria et al., 2005). In addition, rimonabant, the CBI receptor antagonist, decreases the :reinforcing effects of nicotine. The primary reinforcing component of marijuana, THC, is one of approximately 70 different chemicals produced only by the cannabis plant. Another chemical, cannabitliol (CBD), plays an entirely different role. Unlike THC, which produces anxiety and psychotic-like behavior in large doses, CBD has antianxiety and antipsychotic effects. THC is a partial agonist of cannabinoid receptors, whereas CBD is an antagonist. Also unlike THC, CBD does not produce psychotropic effects: It is not reinforcing, and it does not produce a "high." In recent years, levels of THC in marijuana have increased greatl)r, while levels of CBD have decreased. During the past decade, the numbers of people who seek treatment for cannabis abuse has also increased (Morgan et al., 20IO). Morgan and her colleagues (2010) recruited 94 people who used ma1cijuana regularly for a study on the effects of THC and CBD. The investigators measured the concentration of THC and CBD in a sample of their marijuana and

Substance Abuse

in a sample of their urine. They found that people smoking their customary marijuana with low levels of CBD and high levels of THC paid more attention to photographs of cannabis-related stimuli and said that they liked them better than those smoking their customary marijuana with higher levels of CBD. Both groups gave high ratings to food-related photographs, so CBD had no effect on their interest in food. (See Figure 19.24.) A study by Ren and colleagues (2009) found that an injection of CBD reduced heroin-seeking behavior in rats, even up to 2 weeks later, which indicates that the effects of this drug are not limited to marijuana. CBD did not affect the animals' intake of heroin, but it did decrease the reinforcing effect of stimuli that had previously been associated with heroin.

615

Figure 19.24 Effects of Varying Ratios of CBD and THC in Marij uana The gra1ph shows that smoking marijuana with high levels of CBD decreases the pleasantness of photographs associated with marijuana smoking. Source: Based on data from Morgan, C. J. A., Freeman, T. P. , Schafer, G. L., & Curran, H. V. (2010). Cannabidiol attenuates the appetitive effects of 69-tet:rahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology, 35, 1879- 1885.

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Module Review: Brain Mechanisms Associated with Commonly Abused Drugs Opiates LO 19.6

Describe roles of reinforcement and physical dependence in opiate abuse.

Opiates produce their effects as agonists at opiate receptors. Opiate receptors in the periaqueductal gray matter are responsible for the analgesia, those in the preoptic area for the hypothermia, those in the mesencephalic reticular formation for the sedation, and those in the VTA and NAC at least partly for the reinforcement. A targeted mutation in mice indicates thatµ opiate receptors are responsible for analgesia, reinforcement, and withdrawal symptoms. The release of the endogenous opioids may play a role in the reinforcing effects of natural stimuli or even other drugs such as alcohol. The symptoms that are produced by antagonist-precipitated withdrawal from opiates can be elicited by injecting naloxone into the periaqueductal gray matter and the locus coeruleus, which implicates these structures in these symptoms.

Stimulants LO 19.7

Describe the role of reinforcement in stimulant abuse.

Cocaine inhibits the reuptake of dopamine by terminal buttons, and amphetamine causes the dopamine transporters in terminal buttons to run in reverse, releasing dopamine from terminal buttons. Besides producing

alertness, activation, and positive reinforcement, cocaine and amphetamine can produce psychotic symptoms that resemble positive symptoms of schizophrenia. The reinforcing effects of cocaine and amphetamine are mediated by an increase in dopamine in the NAC. Chronic methamphcetamine abuse is associated with reduced numbers of dopaminergic axons and terminals in the striatum (revealed as a decrease in the numbers of dopamine transporters located there).

Nicotine LO 191.8

Describe the roles of reinforcement and physical dependence in n icotine abuse.

Nicotine does not cause intoxication and is readily available and legal. The craving for nicotine is extremely motivating. Nicotine stimulates the release of DA from mesolimbic dopaminergic neurons, and injection of nicotine into the VTA is reinforcing. CBl receptors a1re involved in the reinforcing effect of nicotine as well. Nicotine excites nicotinic acetykholine receptors but also desensitizes them, which leads to withdrawal effects. The activation of nicotinic receptors on presynaptic !terminal buttons in the VTA also produces longterm potentiation. Damage to the insula is associated with cessation of smoking, which suggests that this region plays a role in the maintenance of smoking. Suppression of its activity with inhibitory drugs reduces

616 Chapter 19

nicotine in take in laboratory animals. N icotine stimula· tion of the release of GABA in the lateral hyp othalamus d ecreases the activity of MCH neurons a nd reduces food intake, wh ich exp lains wh y cessatio n o f smoking o ften leads to weigh t gain . Infusion o f an orcxin a ntagonist in th e insula suppresses nicotine intake. Activity o f a circuit from the medial habenu la to the in terpeduncula r nucleus does Uie same. This e ffect depends o n th e prese nce of neurons w ith ~s ACh receptors in the habcnula.

Alcohol LO 19.9

Describe the roles of reinforcement and physical dependence in alcohol abuse.

Alcohol has positively reinfo rcing effects a nd, Uirough its a nxioly tic action, has negatively reinforcing effects as well. It serves as an indirect antagonist at N~ifDA receptors a nd as an indirect agonist at GABAA recep· tors. It stimulates th e release of dopamine in th e NAC. Withdrawa l from lo ng -term alcoh ol abuse can lead to seizures, an effect that seems to be caused by compensa· tory upregula tion o f NMDA receptors. Release o f endoge nous op ioid s also plays a rofo in the reinfo rcing effects o f alcohol. Increases in the numbers o f µ opiate receptors d uring abstinence from akohol may in ten sify craving.

Treatment for Substance Abuse There are many reasons for engaging in research on the neu· roscience o f substance abuse, including an acad emic in terest in the na ture of reinforceme nt and the pharmacology o f psychoactive drugs. But most researchers hope that the results of their research will contribute to the development of ways to treat and- better yet- prevent substance abuse. The in· cidence of substan ce abuse is hig h and research has not yet solved Uie problem. However, progress is being made. A variety of therapeutic interventions have been developed. When selecting a therapeutic in ten,ention, importan t considerations are to dete rmine whethe r the inten,e ntion is supported by research d emonstrating effi· cacy and to assess the quality and q uantity of the research supporting Uie treatment. Strategies, such as contingency management (a form of beh avioral inten,e ntion using vouchers or rewards for reduced substan ce use), cogni· tive therapies, family therapies, agonist rcpJaceme nt fo r opiates and nicotin e, an d opiate an tagonists for alcohol paired with behavioral interventions, arc supported by research as effective treatments for substan ce a buse (Carroll & Onke n, 2014; Carroll & Rounsaville, 2014).

Cannabis LO 19.10 Describe the role of reinforcement in cannabis abuse. The active ingredient in cannabis, THC, stimulates receptors whose natural ligand is anandamid e. THC, like o ther d rugs o f a buse, stimulates the release of dopamine in the NAC. Th e CBl receptor is resp onsible for the ph ysiological and beh avioral effects of THC and th e end ogeno us cannabinoids. A targeted mutation against the CBl receptor reduces th e rein forcin g e ffect o f alcohol, cocain e, and the opia tes as well as th at of th e cannabinoids. Blocking CBI recep tors also d ecreases the rein forcin g effects o f nic· otine. Cannabin oids produce me mory deficits by acting on inhibitory GABAergic neurons in the CAl field of the hippocampus.

Thought Question Although executives o f tobacco comp anies used to in· sist tha t cigarettes were not addictive and asserted tha t people smoked simply because of th e pleasure th e act gave them, research indica tcs th at nicotine is indeed a poten t d rug of a buse. Why d o you think it took so long to recogn ize this fact?

Despite developmen t of a wid e range of interventions, successful treatment of substance abuse is chaUcnging . Approximately 40-«l percent o f individ uals are abstinent one year after a substance abuse intervention (McLcllan ct al , 2(XX)). It is important to also keep in mind that people have different goals for treatment, ranging from complete abstinence to reduced use of a drug. The remainder of this module will includ e summaries of some of the empirically supported interventions for substance abuse that are knmvn to in teract with brain mechanisms responsible for substance abuse. This is no t an exhaustive list, and research is undenvay to develop new and poten tially more effective treatments.

Opiates LO 19.11 Summarize effective treatments for opiate abuse. One treatment for opiate abuse is methadone maintenance. Methadone is a potent opiate, just like morphine o r heroin. If it were available in a fonn suitable for injection, it would be abused. (MeUiad one clinics control their stock of methadone carefully to prevent it from being stolen and sold.) Methadone maintenance programs administer the drug to their patients in an oral fonn, which they must consume in

Substance Abuse

the presence of the personnel supervising this procedure. Because the oral route of administration increases the opiate level in the brain slowly, the drug does not produce a high, the way an injection of opiates will. In addition, because methadone is long lasting, the patient's opiate receptors remain occupied for a long time, which means that an injection of heroin has little effect. However, a very large dose of heroin will still produce a "rush," so the method is not foolproof. A newer drug, buprenorphine, shows promise of being an even better therapeutic agent for opiate abuse treatment than methadone (Vocci et al., 2005). Buprenorphine is a partial agonist for the µ opiate receptor. A partial agonist is a drug that has a high affinity for a particular receptor but activates that receptor less than the normal ligand does. This action reduces the effects of a receptor ligand in regions of high concentration and increases it in regions of low concentration, as shown in Figure 17.13. Buprenorphine blocks the effects of opiates and itself produces only a weak opiate effect. Unlike methadone, it has little value on the illicit drug market. A randomized placebo-controlled trial compared the effectiveness of buprenorphine and buprenorphine plus naloxone in people recovering from opiate abuse (Fudala et al., 2003). People in the two drug-treatment groups reported less craving than those in the control group. The proportion of people who continued to be abstinent was 17.8 percent for people treated with buprenorphine, 20.7 percent for people treated with the combination of the two drugs, and only 5.8 percent for people receiving a placebo. (See Figure 19.25.) After 1 month, all participants were given buprenorphine plus naloxone for 11 months. The percentage of people who abstained (indicated by the absence of opiates in urine samples) ranged from 35.2 to 67.4 percent at various times during the 11-month period. A major advantage of buprenorphine, besides its efficacy, is the fact that it can be used in office-based treatment. The addition of a small dose of naloxone ensures that the combination drug has no abuse potential- and will, in fact, cause withdrawal symptoms if it is used by a person who is currently abusing an opiate. The combination ofbuprenorphine and naloxone is sold as Suboxone or Zubsolv.

Table 19.4

Figure 19.25

617

Buprenorphine as a Treatment

for Opiate Abuse The gra1ph shows the effects of treatment w ith buprenorphine, bupren•orphine + naloxone, and a placebo on opiate craving in people being treated for opiate abuse. Source: Based on data from Fudala, P. J., Bridge, T. P., Herbert, S., Williford, W. 0., et al. (2003). Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. New England Journal of Medicine, 349, 949-958.

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Medications To Treat Symptoms of Opioid Withdrawal

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Eleven studies with human participants have targeted the NAC or the STN with DBS. So far, the authors report, the NAC appears to be the most promising target. For example, Mantione and colleagues (2010) used DBS to stimulate the NAC of a 47-year-old man who smoked. The investigators reported that the man effortlessly stopped smoking and lost weigh t (he was obese). Subsequent DBS studies with human participants have reported reduced use or craving for alcohol, nicotine, cocaine, and opioids (Coles et al., 2018). Deep brain stimulation is not a procedure to take lightly. It involves brain surgery, which runs a risk of complications such as hemorrhage and infection. Of course, substance abutse itself presents significant health risks, including death from infections or lung cancer, so each case

Substance Abuse

requires an analysis of the potential risks and benefits. In any event, the use of DBS is currently experimental, and we must consider the strong possibility that such a dramatic procedure will produce placebo effects. (Yes, surgical procedures are susceptible to placebo effects.) A less invasive procedure, transcranial magnetic stimulation (TMS), is also being investigated as a treatment for substance abuse.

621

For example, Amiaz and colleagues (2009) applied TMS over the left dorsolateral PFC of people who smoked. The treatment reduced tobacco use (verified by urinalysis), but the th1;?rapeutic effects eventually diminished over time. A later review of TMS studies revealed beneficial effects of TMS on reducing use or craving of alcohol, nicotine, cocaine, methamphetamine, and heroin (Coles et al., 2018).

Module Review: Treatment for Substance Abuse Opiates LO 19.11 Summarize effective treatments for opiate abuse. Methadone maintenance treats physical dependence on opiates with an opiate that does not produce euphoric effects when administered orally, but reduces withdrawal symptoms. Buprenorphine, a partial agonist for the µ opiate receptor, reduces craving for opiates.

Stimulants LO 19.12 Summarize effective treatments for stimulant abuse. The development of antibodies to cocaine and nicotine in humans and to several other drugs in rats creates the possibility that people may someday be immunized against drugs of abuse, preventing the entry of the drugs into the brain.

Nicotine LO 19.13 Summarize effective treatments for nicotine abuse. Nicotine-containing gum and transdermal patches help smokers to reduce withdrawal symptoms of nicotine. However, sensations from the airways produced by the presence of cigarette smoke play an important role in nicotine abuse, and oral and transdermal nicotine administration do not provide these sensations. Rimonabant, a CBl receptor antagonist, aids in smoking cessation and reduces the likelihood of weight gain, but it may produce

adverse emotional effects. Bupropion, an antidepressant drug, has also been shown to help smokers stop their habit. Varenicline, a partial agonist for the nicotinic receptor~ may be even more effective.

Alcolhol LO 191.14 Sum marize effective treatments for alcohol abuse. The most effective pharmacological adjuncts to treatment for alcohol abuse appear to be opiate antagonists that reduce the drug's reinforcing effects. Acamprosate, an NMDA-receptor antagonist, appears to facilitate treatment of alcohol abuse as well.

Brain Stimulation LO 191.15 Describe the implications for brain stimulation treatments in substance abuse. Deep brain stimulation of the NAC and STN and TMS of the prefrontal cortex shows promise as a treatment for substance abuse.

Thought Question A friend has recently asked you for advice about helping a family member who is interested in treatment for alcohol abuse. Your friend is curious about how some of the pharmacological treatments for alcohol abuse work. In an email to your friend, explain how one or more pharmacological treatments for alcohol abuse work.

Chapter Review Questions 1. Describe two common features of substance abuse: positive and negative reinforcement. 2. Describe the neural mechanisms responsible for craving and relapse. 3. Review the neural basis of the reinforcing effects and withdrawal effects of opiates. 4. Describe the behavioral and physical effects of the stimulants cocaine, amphetamine, and nicotine.

5. Describe the behavioral and physical effects of alcohol and cannabis. 6. Describe research on the role that genetic factors plays in substance abuse. 7. Discuss different treatment strategies for substance abuse.

Glossary 2-deoxyglucose (2-DG) (dee ox ee g l oo kohss) A suga r that enters cells along w ith g lucose but is not metabolized. a-melanocyte-stimulating hormone (a -MSH) A neuropeptide that acts as an agorust at MC4 receptors and inhibits eating. abse nce seizure A type of seizure disorder often seen in child ren; cha racterized by periods of inattention, which are not subsequently remembered; also called petit ma/ seizure. absorptive phase The p hase of metabolism during which nu trients are absorbed from the digestive system; glucose and amino acids constitute the principal source of energy for cells during this phase, and excess nutrients are stored in adipose tissue in the form of triglycerides. accessory olfactory bulb A neural structu re located in the main o lfactory bulb that receives information from the vomeronasal o rgan. accommodation Changes in the thickness of the lens of the eye, accomp lished by the ciliary muscles, that focus images of near or distant objects on the retina. acetylcholine (ACh) (n see tu/ kol1 leen) A neurotransmitter found in the brain, spinal cord, and parts of the peripheral nervous system; responsible for muscular contraction. acetylcholinesterase (AChE) (a see tu/ koh /in ess fer nee) The enzyme that destroys acetylcholine soon after it is liberated by the terminal buttons, thus terminating the postsynaptic poten tial. actin One of the proteins (with myosin) that provide the physical basis for muscular contraction. action potential The brief electrical impulse that prov ides the basis for conduction of information along an axon. activational effect (of hormone) The effect of a hormone that occurs in the fully developed orgarusm; may depend on the orgarusm's prior exposure to the organizational effects of hormones. acute anterior poliomyelitis (poh lee oh my a lye tis) A viral disease that destroys motor neurons of the brain and spinal cord . adenosine A neuromodulator that is released by neurons engaging in high levels of metabolic activity; may play a primary role in the initiation of sleep. adenosine triphosphate (ATP) (nh den o seen) A molecule of prime importance to cellular energy metabolism; its breakdown liberates energy. adrenocorticotropic hormone (ACTH) A hormone released by the anterior pituitary gland in response to CRH; stimulates the adrenal cortex to produce glucocorticoids. advanced sleep phase syndrome A 4-hour advance in rhythms of sleep and temperature cycles, apparently caused by a mutation of a gene (per2) involved in the rhythmicity of neurons of the SCN. affective blindsight The ability of a person who cannot see objects in his or her blind field to accurately identify facial expressions of emotion while remaining unconscious of perceiving them; caused by damage to the visual cortex. afferent axon An axon directed toward the central nervous system, conveying sensory information. affinity The read iness with which two molecules join together. agonist A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell. agoraphobia A fear of being away from home or other protected places. agouti-related protein (AGRP) A neuropeptide that acts as an antagonist at MC4 receptors and increases eating. agrammatism One of the usual symptoms of Broca's aphasia; a difficulty in comprehending or properly employing grammatical devices, such as verb endings and word order. akinetopsia Inability to perceive movement, caused by damage to area VS (also called MST) of the visual association cortex. all-or-none law The principle that once an action potential is triggered in an axon, it is propagated, without decrement, to the end of the fiber.

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allele The natur·e of the pa rticula r sequence of base pairs o f DNA that constitutes a gene; for example, the genes that code for blue or brown iris pigment are different alleles of a particular gene. allostasis The process of responding to stimuli to regain and maintain homeostasis, including a change in the set point of a system to respond to stimuli that are outside the range of typical homeostatic functioning. allostatic load lhe cumulative and collective wear and tear on body systems when the re· is excessive stress response or when the stress response is not turned off. alpha activity Smooth electrical activity of 8-12 Hz recorded from the brain; generally associated with a state of relaxation. alpha motor neu1ron A neuron whose axon forms synapses with extrafusal muscle fib1?rs of a skeletal muscle; activation contracts the muscle fibers. alprazolam An iindirect agonist for the GA BAA receptor; part of the benzodiazepine class of drugs. Alzheimer's disease A degenerative brain disorder of unknown origin; causes progressive memory loss, motor deficits, and eventual death. amacrine cell (amm n krine) A neuron in the retina that interconnects adjacent gangl ion cells and the inner p rocesses of the bipolar cells. AMPA receptor An ionotropic glutamate receptor that controls a sodium channel; when open, it produces excitatory postsynaptic potentials. amphetamine An an tagonis t at dopamine and norepinephrine transporters that causes them to run in reverse, releasing these neurotransmitters into the synapse.. AMPT A drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of the catecholamines. ampulla (nm pull uh) An enlargemen t in a semicircular canal; con tains the cupula. amusia (n mew zia) Loss or impairment of musical abi lities, produced by hereditary factors or brain damage. amygdala (a mig da In) A structure in the interior of the rostral temporal lobe, containing a set of nuclei; part of the limbic system. amyloid plaque (mnm i loyd) An extracellular deposit con taining a dense core of 13-amyloiid protein surrounded by degenerating axons and dendrites and activated microglia and reactive astrocytes. amyotrophic Jate1ral sclerosis (ALS) A degenerative disorder that attacks the spinal cord and cranial nerve motor neurons. anandamide (n 11t111 dn mide) The fi rst cannabinoid to be discovered and probably the most important one. androgen (an dro jen) A ma le sex steroid hormone. Testosterone is the principal mammalian androgen. angiotensin (m111 _gee oh ten sin) A peptide hormone that constricts blood vessels, causes the retention of sodium and water, and produces thirst and a salt appetite. anomia Difficulty in finding (remembering) the appropriate word to describe an object, action, or attribute; one of the symptoms of aphasia. anorexia nervosa A disorder that most frequently affects young women; exaggerated concern with being overweight that leads to excessive dieting and often compulsive exercising; can lead to starvation. antagonist A driug that opposes o r inhibits the effects o f a particular neurotransmitter on the postsynaptic cell. antagonist-precip;itated withdrawal Sudden withdrawal from long-term administration of a drug caused by cessation of the drug and administration of an antagonistic drug. anterior With re:spect to the central nervous system, located near or toward the head. anterior cingulate cortex A region of the cerebral cortex associated with the perception olf unpleasant stimuli, including pain and thirst. anterior pituitary gland The anterior part of the pituitary gland; an endocrine gland whose secretions are con trolled by the hypothalamic hormones.

Glossary

anterograde In a direction along an axon from the cell body toward the term inal buttons. anterograde amnesia Amnesia for events that occur after some disturbance to the brain, such as head inj ury or certain degenerative brain diseases. anterograde labeling method (arm ter olz grade) A histological method that labels the axons and terminal buttons of neurons whose cell bodies are located in a particular region. anti-Miillerian hormone A peptide secreted by the fetal testes that inhibits the development of the Miillerian system, wh ich wou ld otherwise become the female internal sex organs. antibody A protein produced by a cell of the immune system that recognizes antigens present on invading microorganisms. anticipatory anxiety A fear of having a panic attack; may lead to the development of agoraphobia. antigen A protein present on a microorganism that permits the immune system to recognize the microorganism as an invader. antisense oligonucleotide (oh Ii go new klee oh tide) Modified strand of RNA or DNA that binds with a specific molecule of mRNA and prevents it from producing its protein. anxiety disorder A psychological disorder characterized by tension, overactivity of the autonomic nervous system, expectation of an impending disaster, and continuous vigilance for danger. anxiolytic (angz ee 0/1 lit ik) An anxiety-reducing effect. APS (2-amino-5-phosphonopentanoate) A drug that blocks the glutamate binding si te on NMDA receptors. aphasia Difficulty in producing or comprehending speech not produced by deafness or a simple motor deficit; caused by brain damage. apolipoprotein E (ApoE) (ay po lye po prol1 teen) A glycoprotein tha t transports cholesterol in the blood and plays a role in cellular repair; presence of the E4 allele of the ApoE gene increases the risk of late-onset Alzheimer's d isease. apomorphine (ap o more feen) A drug that blocks dopamine autoreceptors at low doses; at higher doses, blocks postsynaptic receptors as well. apoptosis (ay po toe sis) Death of a cell caused by a chemical signal that activates a genetic mechanism inside the cell. apraxia Difficulty in carrying out purposeful movements, in the absence of paralysis or muscular wea kness. apraxia of speech Impairment in the ability to program movements of the tongue, lips, and throat required to produce the proper sequence of speech sounds. arachnoid granulation Small projections of the arachnoid membrane through the dura mater into the superior sagitta l sinus; CSF flows through them to be reabsorbed into the blood supply. arachnoid membrane (a rak 11oyd) The middle layer of the meninges, located between the outer dura mater and inner pia mater. arcuate fasciculus A bundle of axons that connects Wernicke's area with Broca's area; damage causes conduction aphasia. arcuate nucleus A nucleus in the base of the hypothalamus that controls secretions of the anterior pituitary gland; contains NPY-secreti.ng neurons involved in feeding and control of metabolism. area postrema (poss tree ma) A region of the medulla where the bloodbrain barrier is weak; poisons can be detected there and can initia te vomiting. astrocyte A glial cell that provides support for neurons of the central nervous system, provides nutrients and other substances, and regulates the chemical composition of the extracellular fluid. asymmetrical division Division of a progenitor cell that gives rise to another p rogenitor cell and a neuron, which migrates away from the ventricular zone toward its final resting place in the brain. atropine (a tro peen) A drug that blocks muscarinic acetylcholine receptors. attention-deficit/hyperactivity djsorder (ADHD) A disorder characterized by uninhlbited responses, lack of sustained attention, and hyperactivity; presents in childhood. aura A sensation that precedes a seizu re; its exact nature depends on the location of the seizure focus. autism spectrum disorder (ASD) A disorder whose symptoms can affect social relations with other people, development of communicative ability, imaginative ability, and include repetitive, stereotyped movements.

623

autonomic nervous system (ANS) The portion of the peripheral nervous systernt that controls the body's vegetative functions. autoradiography A procedure that locates radioactive substances in a slice of tissue; the radiation exposes a photographic emulsion or a piece of film that covers the tissue. autorec1eptor A recep tor molecule located on a presynaptic neuron that responds to the neurotransmitter released by that neuron. axon 1rhe long, thin, cylindrical structure that conveys information from the soma of a neuron to its terminal buttons. axoplasmic transport An active process by which substances are propelled along microtubules that run the length of the axon. 13-amyloid (Al3) A protein found in excessive amounts in the brains of patienlts with Alzheimer's disease. 13-amyloid precursor protein (APP) A protein produced and secreted by cells thtat serves as the precursor for 13-amyloid protein. B-lymp.hocyte A white blood cell that originates in the bone marrow; part of the immune system. basal ganglia A group of subcortical nuclei i11 the telencephalon, the caudate nucleus, the globus pallidus, and the putamen; important parts of the motor system. basal m~cleus A nucleus of the amygdala that receives information from the la tieral nucleus and sends projections to the ventromedial prefrontal cortex and the central nucleus. basilar membrane (bazz i /er) A membrane in the cochlea of the inner ear; contains the organ of Corti. behavioral neuroscientist A scientist who studies the physiology of behavior, primarily by performing physiological and behavioral experiments. belt reg;ion The first level of auditory association cortex; surrounds the primary auditory cortex. benign tumor (bee 11i11e) A noncancerous (li terally, "harmless") tumor; has a dlistinct border and can.not metastasize. benzod iazepine (ben zoe dy azz a peen) A category of anxiolytic drugs; an indirect agonist for the GABA A receptor. beta activity Irregu lar electrical activ ity of 13-30 Hz recorded from the brain; :generally associa ted with a sta te of arousal. bicuculline (by kew kew leen) A direct antagonist for the GABA binding site on the GABAA receptor. bilingu.al The ability to communicate fluently in two languages. binding site The location on a receptor protein to w hich a ligand binds. binge eating disorder A disorder that includes bouts of excessive eating. bipolar cell A bipolar neuron located in the middle layer of the retina, conveying information from the photoreceptors to the ganglion cells. bipolar disorder A mood disorder characterized by cyclical periods of mania and depression. black widow spider venom A poison produced by the black widow spider that triggers the release of acetylcholine. bisexual Having emotional, roman tic, or sexual attractions to men and women. blindsight The ability of a person who can.not see objects in their visual field to accurately reach for them while remaining unconscious of perceiving them; caused by damage to cortical regions involved in conscious perception of visual stimuli. blood- brain barrier A semipermeable ba rrier between the blood and the brain produced by the cells in the wa lls of the brain's capillaries. botulin um toxi n (bot you Lin 11111) An acetylcholine antagonist; prevents release· by termina l buttons. brain stem The "stem" of the brain, from the medulla to the midbrain, excluding the cerebelJum. bregma The junction of the sagittal and coronal sutures of the skull; often used as a reference point for stereotaxic brain su rgery. brightness One of the perceptual dimensions of color; intensity. Bruce effect Termination of pregnancy caused by the odor of a pheromone iin the urine of a male other than the one that impregnated the fema le; first identified in mice. bulimia1 nervosa Bouts of excessive hunger and eating, often followed by forced vomiting or purging with laxatives; sometimes seen in people with amorexia nervosa. buspiroine (BuSpar) A 5-HT1 A partial agon ist.

624

Glossary

calcarine fissure (kal ka rine) A fissure located in the occipital lobe on the medial surface of the brain; most of the primary visual cortex is located along its upper and lower banks. CaM-KII Type 11 calcium-calmodulin kinase, an enzyme that must be activated by calci um; may play a role in the establishment of long-term potentiation. CART Cocaine- and amphetamine-regulated transcript; a peptide neurotransmitter found in a system of neurons of the arcuate nucleus that inhibit feeding. caspase A "killer enzyme" that plays a role in apoptosis, or programmed cell death. cataplexy (kat a plex ee) A symptom of narcolepsy; complete paralysis that occurs during waking. catecholamine (cat a kolrl a 111een) A class of amines that includes the neurotransmitters dopamine, norepinephrine, and epinephrine. cauda equina (ee kwye na) A bundle of spinal roots located caudal to the end of the spinal cord. caudal "Toward the tail"; with respect to the central nervous system, in a direction along the neuraxis away from the front of the face. caudal block The anesthesia and paralysis of the lower part of the body produced by injection of a local anesthetic into the cerebrospinal fluid surrounding the cauda equina. caudate nucleus A telencephalic nucleus, one of the input nuclei of basal ganglia; involved with control of voluntary movement. central nervous system (CNS) The brain and spinal cord. central nucleus The region of the amygdala that receives information from the basal, lateral, and accessory basal nuclei and sends projections to a wide variety of regions in the brain; involved in emotional responses. central sukus The sukus that separates the frontal lobe from the parietal lobe. cerebellar cortex The cortex that covers the surface of the cerebellum. cerebellar peduncle (pee d1111 k11l) One of three bundles of axons that attach each cerebellar hemisphere to the dorsal pons. cerebellum (sair a bell um) A major part of the brain located dorsal to the pons, contain ing the two cerebellar hemispheres, covered with the cerebellar cortex; an important component of the motor system. cerebral achromatopsia (ay kro/1m a top see a) Inability to discriminate among different hues; caused by damage to area VS of the visual association cortex. cerebral aqueduct (sa ree bru/) A narrow tube interconnecting the third and fourth ventricles of the brain, located in the center of the mesencephalon. cerebral cortex The outermost layer of gray matter of the cerebral hemispheres. cerebral hemisphere One of the two major portions of the forebrain, covered by the cerebra I cortex. cerebrum Consists of the two cerebral hemispheres. chlorpromazine (klor prolr ma z.eeu) A drug that reduces the symptoms of schizophrenia by blocking dopamine 02 receptors. cholecystokinin (CCK) (coal i sis toe ky nin) A hormone secreted by the duodenum that regulates gastric motility and causes the gallbladder (cholecyst) to contract; appears to provide a satiety signal transmitted to the brain through the vagus nerve. choline acetyltransferase (ChAT) (kolr leen a see 111/ trans fer ace) The enzyme that transfers the acetate ion from acetyl coenzyme A to choline, producing the neurotransmitter acetylcholine. chorda tympani A branch of the facial nerve that passes beneath the ear· drum; conveys taste information from the anterior part of the tongue and controls the secretion of some salivary glands. choroid plexus The highly vascular tissue that protrudes into the ventricles and produces cerebrospinal fluid. chromosome A strand of DNA, with associated proteins, found in the nucleus; carries genetic information. cilium A hairlike appendage of a cell involved in movement or in transducing sensory information; found on the receptors in the auditory and vestibular system. cingulate gyrus (sing yew fell) A strip of limbic cortex lying along the lateral walls of the groove separating the cerebral hemispheres, just above the corpus callosum. circadian rhythm (s11r kay dee 1111 or sur ka dee 1111) A daily rhythmical change in behavior or physiological process.

circumlocution A strategy by which people with anomia find alternative ways to say something when they are unable to think of the most appropriate word. clasp-knife refle>C A reflex that occu rs when force is applied to flex or extend the limb of an animal showing decerebra te rigidity; resistance is replaced by sudden relaxation. classical conditioning A learning procedure; when a stimulus that initially produces mo particular response is followed several times by an unconditioned stimulus (US) that produces a defensive or appetitive response (the unco1nditioned response-UR), the first stimulus (now called a conditioned stimulus- CS) itself evokes the response (now called a conditioned response- CR). clonic phase Thie phase of a grand mal seizu re in which the patien t shows rhythmic jerking movements. clozapine An atypical antipsychotic drug. cocaine A drug that inhibits the reuptake of dopamine. cochlea (cock lee uh) The snail-shaped structure of the inner ear that contains the auditory transducing mechanisms. cochlear implant An electronic device surgically implanted in the inner ear that can enable a person with cochlear deficits to hear. cochlear nerve The branch of the audi tory nerve that transmits audi tory information from the cochlea to the brain. cochlear nucleus One of a group of nuclei in the medulla that receive auditory information from the cochlea. cognitive symptom A symptom of schizophrenia that involves cognitive defici ts, such as d ifficulty in sustaining attention, deficits in learning and memory, poor abstract thinking, and poor problem solving. color constancy The relatively constant appearance of the colors of objects viewed undler varying lighting conditions. complementary c:olors Colors that make white or gray when mixed together. complex partial s.eizure A partial seizure, starting from a focus and remaining localized, that produces loss of consciousness. compulsion The feeling that one is obliged to perform a behavior, even if one prefers not to0 do so. computerized tomography (CT) The use of a device that employs a computer to analyze data obtained by a scanning beam of X-rays to produce a two-dimensional picture of a "slice" through the body. conditioned emoltional response A classically conditioned response that occurs when a noeutral stimulus is followed by an aversive stimulus; usually includes autonomic, behavioral, and endocrine components such as changes in heart rate, freezing, and secretion of stress-related hormones. cond uction aphasia An aphasia characterized by inabili ty to repeat words that are heard but the ability to speak spontaneously and comprehend the speech of others. conditioned resp·o nse (CR) A learned, reflexive response to a conditioned stimulus; established after repeated pairing of unconditioned and conditioned stimiuli. conditioned stimulus (CS) A stimulus that elicits a learned reflexive response following pairing with an unconditioned stimulus. cone One of the receptor cells of the retina; maximally sensitive to one of three different wavelengths of light and hence encodes color vision. confocal laser scanning microscope A microscope that provides highresolution images of va rious depths of thick tissue that contains fluorescen t molecules by scanning the tissue with light from a laser beam. congenital adrenal hyperplasia (CAH) (hy per play zha) A condition characterized by hypersecretion of androgens by the adrenal cortex; in females, causes rnasculinization of the external genitalia. construc tional ap•raxia Difficulty in drawing pictures or diagrams or in making geometrical constructions of elements such as building blocks or sticks; caused by damage to the right parietal lobe. consolidation The process by which short-term memories are converted into long-term memories. content word A noun, verb, adjective, or adverb that conveys meaning. contralateral Located on the opposite side of the body. convulsion A viiolent sequence of uncontrollable muscular movements caused by a seizure. core region The primary auditory cortex, located on a gyrus on the dorsal surface of the temporal lobe. corpus callosum 1(ka lolr sum) A large bundle of axons that interconnects corresponding regions of the association cortex on each side of the brain.

Glossary

corpus luteum (/ew tee um) A cluster of cells that develops from the ovarian follicle after ovulation; secretes estradiol and progesterone. correctional mechanism In a regulatory process, the mechanism that is capable of changing the val ue of the system variable. corticobulbru: tract A bundle of axons from the motor cortex to the fifth, seventh, ninth, tenth, eleventh, and twelfth cranial nerves; controls movements of the face, neck, tongue, and parts of the extraocular eye muscles. corticorubral tract The system of axons that travels from the motor cortex to the red nucleus. corticospinal tract The system of axons that originates in the motor cortex and terminates in the ventral gray matter of the spinal cord. corticotropin-releasing hormone (CRH) A hypothalamic hormone that stimulates the anterior pituitary gland to secrete ACTH (adrenocorticotropic hormone). cranial nerve A peripheral nerve attached di rectly to the brain. CRISPR-Cas A technique that inactivates or alters the production of proteins by inserting new genetic sequences into DNA. cross section With respect to the central nervous system, a slice taken at right angles to the neuraxis. cryostat An instrun1ent that produces very thin slices of tissue inside a freezer chamber. cupula (kew pew lull) A gelatinous mass found in the ampulla of the semicircular canals; moves in response to the flow of the fluid in the canals. curru:e (kew raltr ee) A drug that blocks nicotinic acetylcholine receptors. cutaneous sense (kew ta11e ee us) One of the somatosenses; includes sensitivity to stimuli that involve the skin. cytochrome oxidase (CO) blob The central region of a module of the primary visual cortex, revealed by a stain for cytochrome oxidase; contains wavelength-sensitive neurons; part of the parvocell ular system. cytokine A category of chemicals released by certain white blood cells when they detect the presence of an invading microorganism; causes other white blood cells to proliferate and mount an attack against the invader. cytoplasm The viscous, semiliqu id substance con tained in the interior of

a cell. cytoskeleton Formed of microtubules and other protein fibers, linked to each other and forming a cohesive mass that gives a cell its shape. decerebrate Describes an animal whose brain stem has been transected. decerebrate rigidity Simultaneous contraction of agonistic and antagonistic muscles; caused by decerebration or damage to the reticular formation. decerebrati on A surgical procedure that severs the brain stem, disconnecting the hindbrain from the forebrain. deep brain stimulation (OBS) A surgical procedure that involves implanting electrodes in a particular region of the brain and attaching a device that permits the electrical stimulation of that region through the electrodes. deep cerebellru: nuclei Nuclei located within the cerebellar hemispheres; receive projections from the cerebellar cortex and send projections out of the cerebellum to other parts of the brain. defeminizing effect An effect of a hormone present early in development that reduces or prevents the later development of anatomical or behavioral characteristics typica l of females. defensive behavior A species-typical behavior by which an animal defends itself aga inst the threa t of another an ima l. Deiters's cell (dye terz) A supporting cell found in the organ of Corti; sustains the auditory hair cells. delayed matching-to-sample task A task that requires the subject to indicate which of several stimuli has just been perceived. delayed sleep phase syndrome A 4-hour delay in rhythms of sleep and temperature cycles, possibly caused by a mutation of a gene (per3) involved in the rhythmicity of neurons of the SCN. delta activity Regular, synchronous electrical activity of less than 4 Hz recorded from the brain; occurs during the deepest stages of slowwave sleep. delusion A belief that is clearly in contradiction to reality. dementia (da me11 slin) A loss of cognitive abilities such as memory, perception, verbal ability, and judgment; common causes are multiple strokes and Alzheimer's disease. dendrite A branched, treelike structure attached to the soma of a neuron; receives information from the terminal buttons of other neurons.

625

dendritic spike An action potential that occurs in the dendrite of some types of pyramidal cells. dendritic spine A small bud on the surface of a dendrite, with wh ich a terminal button of another neuron forms a synapse. dentate nucleus A deep cerebellar nucleus; involved in the control of rapid, skilled movements by the corticospinal and rubrospinal systems. depolarization Red uction (toward zero) of the membrane potential of a cell from its normal resting potential; membrane potential becomes more positiV'e. deprenyl (depp rn nil) A drug that blocks the activ ity of MAO-B; acts as a dopamine agonist. detecto1r In a regulatory process, a mechanism that signals when the system variable deviates from its set point. deuteranopia (dew ter an owe pee a) An inherited form of defective color vision in which red and green hues are confused; "green" cones are filled with "ired" cone opsin. developmental dyslexia A reading difficulty in a person of typical intelligence and perceptual ability; of genetic origin or ca used by prenatal or perinatal factors. diazepa1m An indirect agonist for the GABA A receptor; part of the benzodiazep ine class of drugs. diencepihalon (dy e11 self a ln!m) A region of the forebrain surrounding the thi rd ventricle; includes the tha lam us and the hypothalamus. diffusion Movement of molecules from regions of high concentration to regions of low concentration. diffusion tensor imaging (OTO An imaging method that uses a modified MRI scanner to reveal bundles of myelinated axons in the living brain. dihydro•testosterone (dy liy dro less tahss ter own) An androgen, produced from tE!Stosterone through the action of the enzyme Sa red uctase. diphenlil.ydramine An antihistamine drug; antagonist at histamine receptors. direct a:gonist A drug that binds with and activates a receptor. direct a:ntagonist A synonym for receptor blocker. direct dlyslexia A language disorder caused by brain damage in which the pe1:son can read words aloud without understanding them. direct pathway (in basal ganglia) The pathway that includes the caudate nucleus and putamen, the internal division of the globus pallidus, and the ventral anterior /ventrolateral thalamic nuclei; has an excitatory effect on movement. doctrino~ of specific nerve energies Muller's conclusion that, because all nerve fibers carry the same type of message, sensory information must be specifi.ed by the particular nerve fibers that are active. dopamine (DA) (dope 11 111ee11) A neurotransmitter; one of the catecholamines. dopamine transporter Proteins that remove dopamine from the synapse. dorsal "Toward the back"; with respect to the central nervous system, in a direction perpendicular to the neuraxis toward the top of the head or the lback. dorsal lateral geniculate nucleus (LGN) A group of cell bodies wi thin the lalt!ral geniculate body of the thalamus; receives inputs from the retina and projects to the primary visual cortex. dorsal r·oot ganglion A nodule on a dorsal root that contains cell bodies of affe1rent spinal nerve neurons. dorsal rnot The spinal root that contains incoming (afferent) sensory fibers. dorsal stream A system of interconnected regions of visual cortex involved! in the perception of spatial location, beginning with the striate cortex and ending with the posterior parietal cortex. dose-re:sponse curve A graph of the magnitude of an effect of a drug as a function of the amount of drug administered. Down s:yndrome A disorder caused by the presence of an extra twentyfirst chromosome, characterized by moderate to severe intellectual disability and often by atypical physical features. dr onabiinol Cannabinoid receptor agonist. drug An exogenous chemical not necessary for normal cellular functioning tha1t significantly alters the functions of certain cells of the body when taken in relatively low doses. drug effects Observable changes in an ind ividua l's physiology and/or behavior. dualism The belief that the body is physical but the mind (or soul) is not.

626

Glossary

dura mater The outermost of the meninges; tough and flexible. dyspraxia A difficul ty in planning, coordinating, or perform ing skilled motor behaviors. efferent axon (elf ur ent) An axon directed away from the central nervous system, conveying motor commands to muscles and glands. electro-oculogram (EOG) (ah kew /oh gram) An electrical potential from the eyes, recorded by means of electrodes placed on the skin around them; detects eye movements. electroconvulsive therapy (ECT) A brief electrical shock, applied to the head, that results in a seizure; used therapeutically to allevia te severe depression. electroencephalogram (EEG) An electrical brain potential recorded by placing electrodes on the scalp. electrolyte An aqueous solution of a material that ionizes-namely, a soluble acid, base, or sal t. electromyogram (EMG) (my oll gram) An electrical potential recorded from an electrode placed on or in a muscle. electrostatic pressure The attractive force between atomic particles charged with opposite signs or the repulsive force between atomic particles charged with the same sign. embolus (emm bo /11s) A piece of matter (such as a blood clot, fat, or bacterial debris) that dislodges from its site of origin and occludes an artery; in the brain an embolus can lead to a stroke. emotional facial paresis Lack of movement of facial muscles in response to emotions in people w ho have no difficulty moving these muscles voluntarily; caused by damage to the insular prefrontal cortex, subcortical white matter of the frontal lobe, or parts of the thalamus. encephalitis (en self a lye tis) An inflammation of the brain; caused by bacteria, viruses, or toxic chemicals. endocannabinoid (e11 do cnn ab in oyd) A lipid; an endogenous ligand for cannabinoid receptors, which also bind with THC, the active ingredient of marijuana. endocrine gland A gland that liberates its secretions into the extracellular fluid around capillaries and hence into the bloodstream. endogenous opioid (e11 dodge e11 11s 011 pee oyd) A class of peptides secreted by the brain that act as opiates. endplate potential The postsynaptic potential that occurs in the motor endplate in response to release of acetylcholine by the terminal button. enkephalin (en kelf a /in) One of the endogenous opioids. enzymatic deactivation The destruction of a neurotransmitter by an enzyme after its release-for example, the destruction of acetylcholine by acetylcholinesterase. enzyme A molecule that controls a chemical reaction, combining two substances or breaking a substance into two parts. epidemiology The study of the distribution and causes of diseases in populations. epigenetics Changes to gene expression induced by environmental factors. episodic memory Memory of a collection of perceptions of events organized in time and identified by a particular context. estradiol (ess tra dye nhl) The principal estrogen of many mammals, including humans. estrogen (ess trow jen) A class of sex hormones that cause maturation of the female genitalia, growth of breast tissue, and development of other physical features characteristic of females. estrous cycle The female reproductive cycle of mammals other than primates. estrus A period of sexual receptivity in many female mammals (excluding humans). eszopiclone An indirect agonist for the GABAA receptor; used to treat insomnia. evolution A gradual change in the structure and physiology of a species-generally producing more comp lex organisms-as a result of natural selection. excitatory amino acid transporters Proteins that remove glutamate (and other excitatory amino acids) from the synapse. excitatory postsynaptic potential (EPSP) An excitatory depolarization of the postsynaptic membrane of a synapse caused by the Liberation of a neurotransmitter by the termi nal button. excitotoxic lesion (ek sigh tow tok sik) A brain lesion produced by intracerebral injection of an excitatory amino acid, such as kainic acid.

exocytosis (ex o sy toe sis) The secretion of a substance by a cell through means of vesicles; the process by which neurotransmitters are secreted. experimental abla1tion The removal or destruction of a portion of the brain of a laboratory animal; presumably, the functions that can no longer be performed are the ones the region was previously involved in. extension A movement of a limb that tends to straighten its joints; the opposite of flexion. extracellular fluid All body fluids outside cells: includes interstitial fluid, blood p lasma, and cerebrospinal fluid. extrafusal muscle: fiber One of the muscle fibers that are responsible for the force exerted by contraction of a skeletal muscle. extrastriate body area (EBA) A region of the visual association cortex loca ted in the lateral occipitotemporal cortex; involved in perception of the human body and body parts other than faces. extrastriate cortex: (visual association cortex, or V2) The second cortical area for vision p1rocessing; receives fibers from the striate cortex and from the superior colliculi and projects to the inferior temporal cortex. fastigial nucleus A deep cerebellar nucleus; involved in the control of movement by the reticulospinal and vestibulospinal tracts. fasting phase The phase of metabolism during which nutrients are not available from the digestive system; glucose, amino acids, and fatty acids are derived from glycogen, protein, and adipose tissue during this phase. fatal familial instJmnia A fatal inherited disorder characterized by progressive insomni1a. fatty acid A sulbstance derived from the breakdown of triglycerides, along with glyce·rol; can be metabolized by most cells of the body except for the brain. fenfluramine (fen fluor i meen) A drug that stimulates the release of serotonin (5-HT). fetal alcohol syndlrome A birth defect caused by ingestion of alcohol by a pregnan t woman; includes characteristic facial anomalies and fau lty brain development. fight-or-flight res:ponse A species-typical preparatory response to fighting or fleeing; tho::>ught to be responsible for some of the deleterious effects of stressful situaltions on health. fissure A major :groove in the surface of the brain, larger than a sulcus. fixative A chemical such as formalin; used to prepare and preserve body tissue. flexion A movement of a limb that tends to bend its joints; the opposite of extension. flocculonodular lobe A region of the cerebellum; involved in control of postural reflexes. fluorogold (flew rolz gold) A dye that serves as a retrograde label; taken up by terminal buttons and carried back to the cell bodies. fluoxetine (floo ox i teen) A drug that inhibits the reuptake of serotonin (5-HT).

follicle-stimulatimg hormone (FSH) The hormone of the anterior pituitary gland that causes development of an ovarian follicle and the maturation of an ovum. formalin (for ma i'in) The aqueous solution of formaldehyde gas; a commonly used tissue fixative. fornix A fiber bundle that connects the hippocampus with other parts of the brain, including the mammillary bodies of the hypothalamus; part of the limbic system. Fos (falls) A prortein produced in the nucleus of a neuron in response to synaptic stimulation. fourth ventricle The ventricle located between the cerebellum and the dorsal pons, in the center of the metencephalon. fovea (foe vee n) The region of the retina that media tes the most acute vision of birds and higher mammals. Color-sensitive cones constitute the only type of photoreceptor found in the fovea. free radical A molecule with unpaired electrons; acts as a powerful oxidizing agent; tox:ic to cells. frontal lobe The anterior portion of the cerebral cortex, rostral to the parietal lobe and doorsal to the temporal lobe. frontal section A slice through the brain parallel to the forehead. frontotemporal d·ementia A mutation of the gene for tau protein ca uses degeneration of the frontal and temporal cortex, and subsequent dementia. function word A preposition, article, or other word that conveys little of the meaning of a sentence but is important in specifying its grammatical structure.

Glossary

functional imaging A computerized method of detecting metabolic or chemical changes in particular regions of the brain. functional MRI (fMRJ) A functional imaging method; a modification of the MRI procedure that permits the measurement of regiona l metabolism in the brain, usually by detecting changes in blood oxygen level. functionalism The principle that the best way to understand a biological phenomenon (a behavior or a physiological structure) is to try to understand its useful fw1ctions for the organism. fundamental &equency The lowest, and usually most intense, frequency of a complex sound; most often perceived as the sound's basic pitch. fusaric acid (few sahr ik) A drug that inhibits the activity of the enzyme dopamine ~-hydroxylase and thus blocks the production of norepinephrine. fusiform face area (FFA) A region of the visual association cortex located in the inferior temporal; involved in perception of faces and other comp lex objects that require expertise to recognize. G protein A protein coupled to a metabotropic receptor; conveys messages to other molecules when a ligand binds with and activates the receptor. GABA An amino acid; the most important inhibitory neurotransmitter in the brain. GABA transporter Proteins that remove GABA from the synapse. galactosemia (gn lak tow see mee u/z) An inherited metabolic disorder in which galactose (milk sugar) cannot easily be metabolized. gamete (ga111111 eel) A mature reproductive cell; a sperm or ovum. gamma motor neuron A neuron whose axons form synapses with intrafusal muscle fibers. ganglion cell A neuron located in the retina that receives visual information from bipolar cells; its axons give rise to the optic nerve. gap junction A special junction between cells that permits direct communication by means of electrical coupling. gender Refers to the socially influenced identity, roles, and/or behavior of an individual as they pertain to male and female identities. generalization A type of scientific explanation; a general conclusion l::>servations of similar phenomena. generalized anxiety disorder A disorder characterized by excessive anxiety and worry serious enough to cause disruption of a person's life. generalized seizure A seizure that involves most of the brain, as contrasted with a partial seizure, which remains localized. genetic sex Determined by presence of XX (female) or XY (male) chromosomes in humans. genome The complete set of genes that compose the DNA of a particular species. ghrelin (grell i11) A peptide hormone released by the stomach that increases eating; also produced by neurons in the brain. glabrous skin (glab russ) Skin that does not contain ha ir; found on the palms and the soles of the feet. glia (glee 11/z) The supporting cells of the central nervous system. glioma (glee oh malz) A cancerous brain tumor composed of one of several types of glial cells. globus pallidus A telencephalic nucleus; the primary output nucleus of the basal ganglia; involved with control of voluntary movement. glucagon (gloo kn g11lm) A pancreatic hormone that promotes the conversion of liver glycogen into glucose. glucocorticoid One of a group of hormones of the adrenal cortex that are important in protein and carbohydrate metabolism, secreted especially in times of stress. glucoprivation A dramatic fall in the level of glucose available to cells; can be caused by a fall in the blood level of glucose or by drugs that inhibit glucose metabolism. glutamate excitotoxicity Toxic overstimulation of the postsynaptic cell by excess glutamate. glutamine synthase Enzyme that converts glutamate into its precu rsor glutamine. glycerol (gliss er 111/) A substance (also called glycerine) derived from the breakdown of triglycerides, along with fatty acids; can be converted by the liver into glucose. glycogen (gly ko jen) A polysaccharide often referred to as animal starch; stored in liver and muscle; constitutes the short-term store of nutrients. Golgi tendon organ The receptor organ at the junction of the tendon and muscle that is sensitive to stretch.

627

gonad (rhymes with moan ad) An ovary or testis. gonadotropic hormone A hormone of the anterior pituitary gland that has a stimulating effect on cells of the gonads. gonadotropin-releasing hormone (GnRH) (go nad olz trow pin) A hypothalamic hormone that stimulates the anterior pituitary gland to secrete gonadotropic hormone. grand mal seizure A generalized, tonic-clonic seizure, which results in a convulsion. gyrus (plural: gyri) (jye mss, jye rye) A convolu tion of the cortex of the cerebral hemispheres, separated by sulci or fissures. hair cell The receptive cell of the auditory apparatus. hallucination Perception of a nonexistent object or event. Hebb riule The hypothesis proposed by Donald Hebb that the cellular basis of learning involves strengthening of a synapse that is repeatedly active w hen the postsynaptic neuron fires. hemich,o linium-3 An antagonist at the choline transporter. hemorrlhagic stroke A cerebrovascular accident caused by the rupture of a cerebral blood vessel. heroin Agonist for opiate receptor. herpes simplex virus A form of herpes virus used for anterograde transneuronal tracing, which labels a series of neurons that are interconnected synaptically. hertz (Hz) Cycles per second. hindbrnin The most caudal of the three major div isions of the brain; includes the metencephalon and myelencephalon. heterosiexual Having emotional, romantic, or sexual attractions to members of another sex. hippocampal formation A set of forebrain structures of the temporal lobe, constituting an important part of the limbic system; includes the hippocampus proper (Ammon's horn), dentate gyrus, and subiculum. hippornmpus A forebrain structure of the temporal lobe, constituting an important part of the limbic system. histamine A neurotransmitter synthesized from the amino acid histidine; plays can important role in maintenance of wakefulness and arousal. homeos,tasis (home ee oh stay sis) The process by which the body's substances and characteristics (such as temperature and glucose level) are maintati.ned at their optimal level. horizontal cell A neuron in the retina that interconnects adjacent photorecepto rs and the outer processes of the bipola r cells. horizon.tal section A slice through the brain parallel to the ground. hormorne A chemical substance that is released by an endocrine gland that hats effects on target cells in other organs. hue One of the perceptual dimensions of color; the dominant wavelength.. huntin~;tin (Htt) A protein tha t may serve to facilitate the production and transport of brain-derived neurotrophic factor. Abnormal huntingtin is the c:ause of Huntington's disease. H untinigton's disease An inherited disorder that causes degeneration of the basal ganglia; characterized by progressively more severe uncontrollable jerking movements, w ri thing movements, dementia, and finally death. hyperdiirect pathway An excitatory pathway from the pre-SMA to the subthalamic nucleus that increases the activity of the GPi and appears to play a role in preventing or quickly stopping movements that are being initiated by the direct pathway. hypnagogic hallucination (hip 11a gah jik) A symptom of narcolepsy; vivid dreams that occur just before a person falls asleep; accompanied by sleep paralysis. hypofrontality Decreased activity of the prefron tal cortex; believed to be responsible for the negative symptoms of schizophrenia. hypothalamic pituitary adrenal axis (HPA axis) A circuit that is activated as part of the stress response; results in the release of glucocorticoids. hypothalamus The group of nuclei of the diencephalon situated beneath the thalamus; involved in regulation of the autonomic nervous system, control of the anterior and posterior pituitary glands, and integration of speciei;-typical behaviors. hypovolemia (hy po/1 voh lee 111ee a) Reduction in the volume of the intravascul:ar fluid. idazoxan A drug that blocks presynaptic noradrenergic CI2 receptors and hence acts as an agonist, facilitating the synthesis and release of norepinephrine.

628 Glossary immunocytochemical method A histological method that uses radioactive antibodies or antibodies bound with a dye molecule to indicate the presence of particular proteins of peptides. immunoglobulin An antibody released by B-lymphocytes that binds with antigens and helps to destroy invading microorganisms. incus The "anvil"; the second of the three ossicles. indirect agonist A drug that attaches to a binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding si te for the principal ligand. indirect antagonist A drug that attaches to a binding site on a receptor and interferes with the action of the receptor; does not interfere with the binding site for the principal ligand. indirect pathway (in basal ganglia) The pathway that includes the caudate nucleus and putamen, the external division of the globus pall idus, the subthalamic nucleus, the internal d ivision of the globus pallidus, and the ventral anterior/ventrolateral thalamk nuclei; has an inhibitory effect on movement. inferior colliculi Protrusions on top of the rnidbrain; part of the auditory system. inferior temporal cortex The highest level of the ventral stream of the visual association cortex; involved in perception of objects, including people's bodies and faces. informed consent The process in which researchers must inform any potential participant about the nature of the research, how any data will be collected and stored, and what the anticipated benefits and costs of participating will be ingestive behavior (in jess /iv) Eating or drinking. inhalation Administration of a vaporous substance into the lungs. inhibitory postsynaptic potential (IPSP) An inhibitory hyperpolarization of the postsynaptic membrane of a synapse caused by the liberation of a neurotransmitter by the terminal button. insertional plaque The point of attachment of a tip link to a cilium. insufflation Administration of a substance by sniffing or snorting; drug is absorbed through the mucous membranes of the nose. insular cortex (in sue fur) A sunken region of the cerebral cortex that is normally covered by the rostral superior temporal lobe and caudal inferior frontal lobe. insulin A pancreatic hormone that facilitates entry of glucose and amino acids into the cell, conversion of glucose into glycogen, and transport of fats into adipose tissue. internal division of the globus pallidus (GPi) A division of the globus pallidus that provides inhibitory input to the motor cortex via the thalamus; sometimes stereotaxically lesioned to treat the symptoms of Parkinson's disease. interneuron A neuron located entirely within the central nervous system. interposed nuclei A set of deep cerebellar nuclei; involved in the control of the rubrospinal system. intersex A variety of combinations of biologically male and female characteristics, such as external female genitalia and internal male sex organs. interstitial fluid The fluid that bathes the cells, filling the space between the cells of the body (the "interstices"). intracellular fluid The fluid contained within cells. intracerebral administration Administration of a substance directly into the brain. intracerebroventricular (ICV) administration Administration of a substance into one of the cerebral ventricles. intrafusal muscle fiber A muscle fiber that functions as a stretch receptor, arranged parallel to the extrafusal muscle fibers, thus detecting changes in muscle length. intramuscular (IM) injection Injection of a substance into a muscle. intraparietal sukus OPS) The end of the dorsal stream of the visual association cortex; involved in percep tion of location, visual attention, and control of eye and hand movements. intraperitoneal (IP) injection (i11 Ira pair i toe nee 11/) Injection of a substance into the perito11eal cavity-the space that surrounds the stomach, intestines, liver, and other abdominal organs. intravascular fluid The fluid found within the blood vessels. intravenous (IV) injection Injection of a substance di rectly into a vein. ion A charged molecule. Cations are positively charged, and anions are negatively charged.

ion channel A specialized protein molecule that permits specific ions to enter or leave cellls. ionotropic receptoor (eye 011 oh trow pik) A receptor that contains a binding site for a neurotr:ansmitter and an ion channel that opens when a molecule of the neurotransmitter attaches to the binding si te. ipsilateral Localted on the same side of the body. ischemic stroke A cerebrovascular accident ca used by occlusion of a blood vessel and interruption of the blood supply to a region of the brain. James-Lange theory A theory of emotion that suggests that behaviors and physiological responses are directly elicited by situations and that feelings of emotions are produced by feedback from these behaviors and responses. kainate receptor 1:k11y in ate) An ionotropic glutamate receptor that controls a sodium channel; sti mulated by kainic acid. ketamine A dmg that binds with a noncompetitive binding site of the NMDA receptor and serves as an indirect antagonist. kinesthesia Perception of the body's own movements. kisspeptin A peptide produced by neurons in the arcuate nucleus of the hypothalamus uinder the control of leptin receptors; essential for initiation of puberty and maintenance of reproductive ability. koniocellular sublayer (koh nee 0/1 sell yew lur) One of the sublayers of neurons in the dorsal lateral geniculate nucleus found ventral to each of the magnocellular and parvocellular layers; transmits information from shortwavelength (''blue") cones to the primary visual cortex. Korsakoff's syndrome Permanent anterograde amnesia caused by brain damage resulting from chronic alcohol abuse or malnutrition. I-DOPA (ell dope ,a) The levorotatory form of DOPA; the precursor of the catecholamines; often used to treat Parkinson's disease because of its effect as a doparnime agonist. Jamella A layer of membrane containing photopigments; found in rods and cones of the retina. lateral Toward the side of the body, away from the middle. lateral corticospinal tract The system of axons that originates in the motor cortex and terminates in the contralateral ventral gray matter of the spinal cord; controls movements of the distal limbs. lateral fissure The fissure that separates the temporal lobe from the overlying frontal and. parietal lobes. lateral geniculate nucleus A group of cell bodies within the lateral geniculate body of the thalamus that receives fibers from the retina and projects fibers to the primary visual cortex. lateral g.r oup TI1e corticospinal tract, the corticobuJbar tract, and the rubrospinal tract. lateral lemniscus A band of fibers running rostrally through the medulla and pons; carries fibers of the auditory system. lateral nucleus A nucleus of the amygdala that receives sensory information from1 the neocortex, thalamus, and hippocampus and sends projections to tine basal, accessory basal, and central nucleus of the amygdala. lateral occipital c:omplex (LOC) A region of the extrastriate cortex, involved in perception of objects other than people's bodies and faces. lateral ventricle One of the two ventricles located in the center of the telencephalon. Lee-Boot effect The slowing and eventual cessation of estrous cycles in groups of femaloe anin1als that are housed together; caused by a pheromone in the animals' urine; first observed in mice. leptin A hormome secreted by adipose tissue; decreases food intake and increases metabolic rate, primarily by inhibiting NPY-secreting neurons in the arcuate nu.deus. lesion study A synonym for experimental ablation. Lewy body Abrnormal circular structures wi th a dense core consisting of a-synuclein protein; found in the cytoplasm of nigrostriatal neurons in people with Parkinson's disease. ligand (lye gand or ligg and) A chemical that binds with the binding site of a receptor. light microscope A microscope that passes light through a tissue sample to make details of the sample visible through magnifying lenses. limbic cortex Plhylogenetically old cortex, located at the medial edge ("limbus") of the cerebral hemispheres; part of the limbic system. limbic system A group of brain regions including the anterior thalamic nuclei, amygdala, hippocampus, limbic cortex, and parts of the hypothalamus, as well as their interconnecting fiber bundles.

Glossary

lithium A chemical element; lithium carbonate is used to treat bipolar disorder. locus coeruleus (LC) (sa roo lee us) A dark-colored group of no radrenergic cell bodies located in the pons near the rostra l end of the floor of the fourth ventricle; involved in arousal and vigi lance. long-term potentiation (LTP) A long-term increase in the excitability of a neuron to a particular synaptic input caused by repeated high-frequency activity of that input. lordosis A spinal sexual reflex seen in many four-legged female mammals; arching of the back in response to approach of a male or to touching the flanks, wh ich elevates the hindquarters. loss of function Said of a genetic disorder caused by a recessive gene that fails to produce a protein that is necessa ry for good health. loudness A perceptual dimension of sound; corresponds to intensity. LSD A drug that stimulates 5-HT2A receptors. luteinizing hormone (LH) (lew lee a nize ing) A hormone of the anterior pituitary gland that causes ov ulation and development of the ovarian follicle into a corpus luteum. macroelectrode An electrode used to record the electrical activity of large numbers of neurons in a pa rticula r region of the brain; much larger than a microelectrode. magnetic resonance imaging (MRI) A technique whereby the interior of the body can be accurately imaged; involves the interaction between radio waves and a strong magnetic field. magnetoencephalography A procedure that detects groups of synch ronously activa ted neurons by means of the magnetic field induced by their electrical activity; uses an array of superconducting quan tum in terference devices, or SQUIDs. magnocellular layer One of the inner two layers of neurons in the dorsal lateral geniculate nucleus; transmits information necessary for the perception of form, movement, depth, and small differences in brightness to the primary visual cortex. major depressive disorder (MDD) A serious mood disorder that consists of unremitting depression or periods of depression that do not alternate with periods of mania. malignant tumor A cancerous (literally, "harm-prod ucing") tumor; lacks a distinct border and may metastasize. malleus The "hammer"; the first of the three ossicles. mammillary bodies (11111111 i lair ee) A protrusion of the bottom of the brain at the posterior end of the hypothalamus, containing some hypothalamic nuclei; part of the limbic system. masculinizing effect An effect of a hormone present ea rly in development tha t p romotes the later development of ana tomical or behavioral characteristics typical of males. MOMA A drug that serves as a noradrenergic and serotonergic agonist, also known as "ecstasy"; has excitatory and hallucinogenic effects. mechanoreceptor A sensory neuron that responds to mechanical stimuli for example, those that produce pressure, stretch, or vibration of the skin or stretch of muscles or tendons. medial Toward the middle of the body, away from the side. medial forebrain bundle A fiber bundle that runs in a rostral-ca udal direction through the basal forebrain and lateral hypothalamus; electrical stimulation of these axons is reinforcing. medial geniculate nucleus A group of cell bodies within the medial geniculate body of the thalamus; receives fibers from the auditory system and projects fibers to the primary auditory cortex. medial nucleus of the amygdala (a mig da la) A nucleus that receives olfactory information from the olfactory bulb and accessory olfactory bulb; involved in the effects of odors and pheromones on reproductive behavior. median preoptic nucleus A small nucleus situated around the decussation of the anterior commissure; plays a role in thirst stimulated by angiotensin. medulla oblongata (me doo la) The most caudal portion of the brain; located in the myelencephalon, immediately rostral to the spinal cord. Meissner's corpuscle A touch-sensi tive cutaneous receptor, important in detecting edge contours or Braille-like stimuli, especially by fingertips. melanin-concentrating hormone (MCH) A peptide neurotransmitter found in a system of la teral hypothalamic neurons that stimulate appetite and reduce metabolic ra te. melanocortin 4 receptor (MC4R) A receptor foun d in the brain tha t binds with a -MSH and agouti-related protein; plays a role in control of appetite.

629

melanopsin (me/I a 11op sin) A photopigment present in ganglion cells in the retina whose axons transmit information to the SCN, the thalamus, and the olivary pretectal nuclei. melatonin (me/I a tone in) A hormone secreted during the night by the pineal body; p lays a role in ci rcadian and seasonal rhythms. membrane A structure consisting principally of lipid molecules that defines the outer boundaries of a cell and also constitutes many of the cell organe:lles, such as the Golgi apparatus. meninges (singular meninx) (men i11 jees) The three layers of tissue that encase the central nervous system: the dura mater, arachnoid membrane, and pi.a mater. meningioma (111en in jee oil 11111) A benign brain tu mor composed of the cells thtat constitute the meninges. meningitis (men in jy tis) An inflammation of the meninges; can be caused! by viruses or bacteria. menstmal cycle (men strew al) The female reproductive cycle of most prima tes, including humans; characterized by growth of the lining of the uterus.. ovulation, development of a corpus luteum, and (if pregnancy does not occur), menstruation. Merkel·'s disk A touch-sensitive cutaneous receptor, important for detection of form and roughness, especially by fingertips. mesenc·ephalic locomotor region A region of the reticular formation of the mi.dbrain whose stim ulation ca uses alternating movements of the limbs n ormally seen during locomotion. mesenc.ephalon (mezz en self a la/111) The midbrain; a region of the brain that surrounds the cerebral aqueduct; includes the tectum and the tegmentum. mesocortical system (mee zo kor Ii kul) A system of dopa minergic neurons 01:igi nating in the ven tral tegmenta l area and terminating in the prefrontal cortex. mesolimbic system (mee zo lim bik) A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus. messen.ger ribonucleic acid (mRNA) A macromolecule that delivers genetic in formation concerning the synthesis of a protein from a portion of

a chromosome to a ribosome. metabotropic glutamate receptor (meh tnb n troli pik) A category of metabotropic receptors that are sensitive to glutama te. metabotropic receptor A receptor that contains a binding site for a neurotransmitter; activates an enzyme that begins a series of events that opens an ion channel elsewhere in the membran e of the cell when a molecule of the neurotransmitter attaches to the binding site. metastasis (meh tass ta sis) The process by which cells break off of a tumor, travel through the vascular system, and grow elsewhere in the body. metenco~phalon A region of the hindbrain; includes the cerebellum and pons. methamphetamine An antagonist at dopamine and norepinephrine transpmters that causes them to run in reverse, releasing these neurotransmitters into th e synapse. methylphenidate (metl1 11/ f e11 i date) A drug tha t inhibits the reuptake of dopa mine. microdi.a lysis A procedu re for analyzing chemicals present in the interstitial fluid by extracting them through a small piece of tubing made of a semipermeable membrane that is implanted in the brain. microelectrode A very small electrode, generally used to record activity of individual neurons. microglia The smallest of glial cells; they act as phagocytes an d protect the bra1in from invading microorganisms. microtome (my krow tome) An instrument that produces very thin slices of body tissues. microtu bule (my kro too byool) A long strand of bunclles of protein filaments arranged around a hollow core; part of the cytoskeleton and involved in transporting substances from place to place within the cell. midbraiin The mesencephalon; the central of the three major divisions of the bra1in. midsagiittal plane The plane through the neuraxis perpendicula r to the ground; div ides the brain into two symmetrical halves. mirror neurons Neurons located in the ventral premotor cortex and inferior pa1rietal lobule that respond when the individual makes a particular movement or sees another individual making that movement. mitochondrion (plural: mitochondria) An organelle tha t is responsible for extracting energy from nutrients.

630

Glossary

mitral cell A neuron located in the olfactory bulb that receives information from olfactory receptors; axons of mitral cells bring information to the rest of the brain. moclobemide (111ok low bem ide) A drug that blocks the activity of MAOA; acts as a noradrenergic agonist. monism (maim ism) The belief that the world consists only of matter and energy and that the mind is a phenomenon produced by the workings of the nervous system. monoamine (ma Imo a meen) A class of amines that includes indolamines, such as serotonin, and catecholamines, such as dopamine, norepinephrine, and epinephrine. monoamine hypothesis A hypothesis that states that depression is caused by a low level of activity of one or more monoamine systems. monoamine oxidase (MAO) (mahn o a 111een) A class of enzymes that destroy the monoamines dopamine, norepinephrine, and serotonin. monosynaptic stretch reflex A reflex in which a muscle contracts in response to its being quickly stretched; involves a sensory neuron and a motor neuron, with one synapse between them. morphine Agonist for opiate receptor. motor association cortex The region of the frontal lobe rostral to the primary motor cortex; also known as the premotor cortex. motor endplate The postsynaptic membrane of a neuromuscular junction. motor learning Learning to make a new response. motor neuron A neuron located within the central nervous system that controls the contraction of a muscle or the secretion of a gland. motor unit A motor neuron and its associated muscle fibers. multiple sclerosis An autoimmune demyelinating disease. muscarine An agonist for the metabotropic acetylcholine receptor muscarinic receptor (m11ss ka rin ic) A metabotropic acetylcholine receptor that is stimulated by muscarine and blocked by atropine. muscimol (11111sk i maw/) A direct agonist for the GABA binding site on the GABAA receptor. myelencephalon A region of the hindbrain; includes the medulla oblongata. myelin sheath (my a /in) A sheath that surrounds axons and insulates them, preventing messages from spreading between adjacent axons. myofibril An element of muscle fibers that consists of overlapping strands of actin and myosin; responsible for muscular contractions. myosin One of the proteins (with actin) that provide the physical basis for muscular contraction. mutation A change in the genetic information contained in the chromosomes of sperm or eggs, which can be passed on to an organism's offspring; p rovides genetic variability. Miillerian system The embryonic precursors of the female internal sex organs. naloxone (na lox own) A drug that blocks opiate receptors. narcolepsy (nalir ko lep see) A sleep disorder characterized by periods of irresistible sleep, attacks of ca tap lexy, sleep pa ralysis, and hypnagogic hallucinations. natural selection The process by which inherited traits that confer a selective advantage (increase an animal's likelihood to live and reproduce) become more prevalent in a population. negative afterimage The image seen after a portion of the retina is exposed to an intense visual stimulus; consists of colors complementary to those of the physical stimulus. negative feedback A process whereby the effect produced by an action serves to diminish or terminate that action; a characteristic of regulatory systems. negative reinforcement The removal or reduction of an aversive stimulus that is contingent on a particular response, with an attendant increase in the frequency of that response. negative symptom A symptom of schizophrenia characterized by the absence of behaviors that are normally present social withdrawal, lack of affect, and reduced motivation. neostigmine (nee o stig meen) A drug that inhibits the activity of acetylcholinesterase. neoteny A slowing of the process of maturation, allowing more time for growth; an important factor in the development of large brains. neural adhesion protein A protein that plays a role in brain development; helps to guide the growth of neurons.

neural integratiom The process by which inhibitory and excitatory postsynaptic potentials surnmate and control the rate of firing of a neuron. neural tube A h ollow tube, closed at the rostral end, that forms from ectodermal tissue •early in embryonic development; serves as the origin of the central nervous system. neuraxis An imaginary line drawn through the center of the length of the central nervous system, from the bottom of the spinal cord to the front of the foreb rain. neuroethics An interdisciplinary field devoted to understanding implications of and developing best practices in ethics for neuroscience research. neurofibrillary tangle (new row fib ri lair y) A dying neuron containing intracellular accumulations of abnormally phosphorylated tauprotein filaments that formerly served as the cell's internal skeleton. neurogenesis Production of new neurons through the division of neural stem cells; occurs in the adult hippocampus and olfactory bulb and appea rs to play a role in learning. neuromodulator A naturally secreted substance that acts Uke a neurotransmitter exc:ept that it is not restricted to the synaptic cleft but diffuses through the extracellular fluid. neuromuscular jmnction The synapse between the terminal buttons of an axon and a musde fiber. neurosecretory cell A neuron that secretes a hormone or hormonelike substance. neurons Nerve cells; the informa tion-processing and informationtransmitting cell:s of the nervous system. neuropeptide Y (NPY) A peptide neurotransmitter found in a system of neurons of the rurcuate nucleus that stimulate feeding, insulin and glucocorticoid secretion, decrease the breakdown of triglycerides, and decrease body temperatw·e. neurotransmitter··dependent ion channel An ion channel that opens when a molecule·of a neurotransmitter binds with a postsynaptic receptor. nicotine An ago•nist for the ionotropic acetylcholine receptor. nicotinic recepto1· An ionotropic acetylcholine receptor that is stimulated by nicotine and blocked by curare. nigmstriatal sysh!m (nigh grow stry ay tu/) A system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen). nitric oxide synthase An enzyme responsible for the production of nitric oxide (NO). NMDA receptor A specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; involved in long-term pot•entia ti on. node of Ranvier i(raw vee ay) A naked portion of a myelinated axon between adjacent oligodendroglia or Schwann cells. noncompetitive binding Binding of a drug to a site on a receptor; does not interfere with the binding si te for the principal ligand. norepinephrine ONE) (nor epp i neff ri11) One of the catecholamines; a neurotransmitter found in the brain and in the sympathetic division of the autonomic nervous system. norepinephrine transporter Proteins that remove norepinephrine from the synapse. nucleus (plural: rnuclei) An identifiable group of neural cell bodies in the central nervous system, or a structure in the central region of a cell, containing the nucle·olus and chromosomes. nucleus accumbens (NAC) A nucleus of the basal forebrain near the septum; receives dc•pamine-secreting termina l buttons from neurons of the ventral tegmenta1l area and is thought to be involved in reinforcement and attention. nucleus of the sollitary tract A nucleus of the medulla that receives information from visceral organs and from the gustatory system. nucleus paragigantocellularis (nPGi) A nucleus of the medulla that receives input from the medial preoptic area and contains neurons whose axons form synapses with motor neurons in the spinal cord that participate in sexual reJflexes in males. nucleus raphe m.agnus A nucleus of the raphe that contains serotoninsecreting neurons that project to the dorsal gray matter of the spinal cord and is involved in analgesia produced by opiates. ob mouse A strain of mice whose obesity and low metabolic rate are ca used by a mut.ation that prevents the prod uction of leptin. obsession An unwanted thought or idea with which a person is preoccupied.

Glossary

obsessive-compulsive disorder (OCD) A mental disorder characterized by obsessions and compulsions. obstructive hydrocephalus A condi tion in which all or some of the brain's ventricles are enla rged; caused by an obstruction that impedes the normal flow of CSF. occipital lobe (ok sip i 111/) The region of the cerebral cortex caudal to the parietal and temporal lobes. olfactory bulb The protrusion at the end of the olfactory nerve; receives input from the olfactory receptors. olfactory epithelium The epithelial tissue of the nasal sinus that covers the cribriform pla te; contains the cilia of the olfactory receptors. olfactory glomerulus (.glow mare yo11 l11ss) A bundle of dendrites of mitral cells and the associated terminal buttons of the axons of olfactory receptors. oligodendrocyte (oh Ii go de11 droll site) A type of glial cell in the central nervous system tha t forms myelin sheaths. olivocochlear bundle A bundle of efferent axons that travel from the olivary complex of the medulla to the auditory hair cells on the cochlea. ondansetron 5-HT3 receptor antagonist. operant conditioning A learning procedure whereby the effects of a particular behavior in a particular situation increase (reinforce) or decrease (punish) the probability of the behavior; also called instrumental conditioning. opium Agonist for opiate receptor. opsin (opp sin) A class of protein that, together with retinal, constitutes the photopigments. optic chiasm (kye a:z:'m) An X-shaped connection between the optic nerves, located below the base of the brain, just anterior to the pituitary gla nd. optic disk The location of the exit point from the retina of the fibers of the ganglion cells that form the optic nerve; responsible for the blind spot. optic flow The complex motion of points in the visual field caused by relative movement between the observer and environment; provides information about the relative distance of objects from the observer and of the relative direction of movement. optic nerve Bundles of axons from retinal ga nglion cells exit the eye and convey information to the lateral gen iculate nucleus. optogenetic method The use of a genetically modified virus to insert light-sensitive ion channels into the membrane of particular neurons in the brain; can depolarize or hyperpolarize the neurons when light of the appropriate wavelength is applied. oral administration Administration of a substance into the mouth so that it is swallowed. orexin A peptide, also known as hypocretin, produced by neurons whose cell bodies are located in the hypothalamus; their destruction causes narcolepsy. organ of Corti The sensory organ on the basilar membrane that contains the auditory hair cells. organic sense A sense modality that arises from receptors located within the inner organs of the body. organizational effect (of hormone) The effect of a hormone on tissue differentiation and development. orthographic dysgraphia A writing disorder in which the person can spell regularly spelled words but not irregularly spelled ones. osmometric thirst Thirst produced by an increase in the osmotic pressure of the interstitial fluid relative to the intracellular fluid, thus producing cellular dehydra tion. osmoreceptor A neuron that detects changes in the solute concentration of the interstitial fluid that surrounds it. ossicle (aliss i k11/) One of the three bones of the middle ear. oval window An opening in the bone surrounding the cochlea that reveals a membrane, against which the baseplate of the stapes presses, transmitting sou nd vibrations into the fluid within the cochlea. ovarian follicle A cluster of epithelial cells surrounding an oocyte, which develops into an ovum. overtone The frequency of complex tones tha t occurs at multiples of the fundamental frequency. oxycodone Agonist for opiate receptor. oxytocin (ox ee tow sin) A hormone secreted by the posterior pitui tary gland; causes contraction of the smooth muscle of the milk ducts, the uterus, and the male ejaculatory system; also serves as a neurotransmitter in the brain.

631

Paciniam corpuscle (pa clti11 ee1111) A vibration-sensitive cutaneous receptor, important in detecting vibration from an object being held. panic disorder A disorder characterized by episodic periods of symptoms s.uch as shortness of breath, irregularities in heartbeat, and other autonomic symptoms, accompanied by intense fear. parabelt region The second level of auditory association cortex; surrounds the belt region. parahip,pocampal cortex A region of limbic cortex adjacent to the hippocampal formation that, along with the perirhinal cortex, relays information be,tween the entorhinal cortex and other regions of the brain. parahip•pocampal place area (PPA) A region of limbic cortex on the medial temporal lobe; involved in perception of particular places ("scenies"). parasynnpathetic division The portion of the autonomic nervous system that controls functions that occur during a relaxed state. parave~ttricular nucleus (PVN) A nucleus of the hypothalamus located adjaceint to the dorsal third ventricle; contains neurons involved in control of the autonomic nervous system and the posterior pituitary gland. parietal lobe (pa n1e i tu/) The region of the cerebral cortex caudal to the frontal lobe and dorsal to the temporal lobe. parietal reach region A region in the medial posterior parietal cortex that plays a critical role in control of pointing or reaching with the hands. parkin A protein that plays a role in ferrying defective or misfolded proteins to the proteasomes; mutated parkin is a ca use of familial Parkinson's disease. Parkinson's disease A neurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements; caused! by degeneration of the nigrostriatal system. partial agonist A drug that has a very high affinity for a particular receptor but: activa tes that receptor less than the normal ligand does; serves as an agonist in regions of low concentration of the normal ligand and as an antagonist in regions of high concentrations. partial !;eizure A seizure that begins at a focus and remains localized, not generalizing to the rest of the brain. parturition (par tew ri slum) The act of giving birth. parvoce.Jlular layer One of the four outer layers of neurons in the dorsal lateral geniculate nucleus; transmits information necessary for perception of color and fine deta ils to the primary visual cortex. PCP P'hencyclidine; a drug that binds with the PCP binding site of the NMDJ\ receptor and serves as an indirect antagonist. PCPA A drug that inhibits the activity of tryptophan hydroxylase and thus irnterferes with th e synthesis of 5-HT. peptide A chain of amino acids joined together by peptide bonds. Most neuromod ulators, and some hormones, consist of peptide molecules. peptide YY3-36 (PYY) A peptide released by the gastrointestinal system after a meal in amounts proportional to the size of the meal. perception The conscious experience and interpretation of information from the senses perceptual learning Learning to recognize a particular stimulus. perfusion (per f ew zh1111) The process by w hich an animal's blood is replaced by a fluid such as a saline solution or a fixa tive in preparing the brain for histological examination. periaqu.eductal gray matter (PAG) The region of the midbrain that su rrounds the cerebral aqueduct; plays an essential role in va rious speciestypical behaviors, including female sexual behavior. periphe:ral nervous system (PNS) The part of the nervous system outside the brain and spinal cord, including the nerves attached to the brain and spinal cord. perirhinal cortex A region of limbic cortex adjacent to the hippocampal formation that, along with the parahippocampal cortex, relays information betwe~m the entorhinal cortex and other regions of the brain. persiste:nt Miillerian duct syndrome A condition caused by a congenital lack of anti-Milllerian hormone or receptors for this hormone; in a male, causes development of both male and female internal sex organs. PHA-L Phaseolus vulgaris leukoagglutinin; a protein derived from kidney beans and used as an anterograde tracer; taken up by dendrites and cell bodies and carried to the ends of the axons. phagocytosis (fagg o sy toe sis) The p rocess by w hich cells engulf and digest other cells or debris caused by cellular degeneration. phantom limb Sensations that appear to originate in a limb that has been amputated.

632

Glossary

pharmacokinetics The process by which drugs are absorbed, distributed w ithin the body, metabolized, and excreted. phase difference The difference in arriva l times of sound waves at each of the eardrums. phenylketonuria (PKU) (fee nu/ kee la 11ew ree uh) A hereditary disorder caused by the absence of an enzyme that converts the amino acid phenylalanine to tyrosine; the accumulation of phenylalanine causes brain damage unless a special diet is implemented soon after birth. pheromone (fair oh moan) A chemical released by one animal that affects the behavior or physiology of another animal; usually smelled or tasted. phonetic reading Reading by decoding the phonetic significance of letter strings; "sound reading." phonological dysgraphia A writing disorder in which the person cannot sound out words and write them phonetically. phonological dyslexia A reading d isorder in which a person can read fami liar words but has difficulty reading unfamiliar words or pronounceable non words. photopigment A protein dye bonded to retinal, a substance derived from vitamin A; responsible for transduction of visual information. photoreceptor One of the receptor cells of the retina; transduces photic energy into electrical potentials. phototherapy Treatment of seasonal affective disorder by daily exposure to bright light. pia mater The inne r layer of the meninges that clings to the su rface of the brain; thin and delicate. pineal gland (py nee u/) A gland attached to the dorsal tectum; produces melatonin and plays a role in circadian and seasonal rhythms. pitch A perceptual dimension of sound; corresponds to the fundamental frequency. place code The system by which information about different frequencies is coded by different loca tions on the basilar membrane. placebo (pla see boll) An inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug. plasticity In the nervous system, this refers to change, flexib ility or adaptation, usually in response to an experience or learning. pons The region of the metencephalon rostral to the medulla, caudal to the midbrain, and ventral to the cerebellum. pontine nucleus A large nucleus in the pons that serves as an important sou rce of input to the cerebellum. population EPSP An evoked potential that represents the excitatory postsynaptic potentials of a population of neurons. positive symptom A symptom of schizophrenia evident by its presence delusions, hallucinations, or thought disorders. positron emission tomography (PET) A functiona l imaging method that reveals the loca lization of a radioactive tracer in a living brain. posterior With respect to the central nervous system, located near or toward the tail. posterior parietal cortex The highest level of the dorsal stream of the visual association cortex; involved in perception of movement and spa tial location. posterior pituitary gland The posterior part of the pituitary gland; an endocrine gland that contains hormone-secreting terminal buttons of axons whose cell bodies lie within the hypothalamus. postganglionic neuron Neurons of the autonomic nervous system that form synapses directly with their target organ. postsynaptic membrane The cell membrane opposi te the terminal button in a synapse; the membrane of the cell that receives the message. postsynaptic potential Alterations in the membrane potential of a postsynaptic neuron, produced by liberation of neurotransmitter at the synapse. postsynaptic receptor A receptor molecule in the postsynaptic membrane of a synapse that contains a binding site for a neurotransmitter. posttraumatic stress disorder (PTSD) A psychological disorder caused by exposure to a situation of extreme danger and stress; symptoms include recurrent dreams or recollections; can interfere with social activities and cause a feeling of hopelessness. predation Attack of one animal directed at an individ ual of another species on which the attacking animal normally preys. prefrontal cortex The region of the frontal lobe rostral to the motor association cortex.

preganglionic nE:uron The efferent neuron of the autonomic nervous system whose eoell body is located in a cranial nerve nucleus or in the intermediate hoirn of the spinal gray matter and whose terminal buttons synapse upon postganglionic neurons in the autonomic ganglia. premotor cortex A region of motor association cortex of the latera l fronta l lobe, rostral to the p rimary motor cortex. presenilin (pree sen ill in) A protein produced by a faulty gene that causes 13-amyloid precursor protein to be converted to the abnormal short form; may be a cause of Alzheimer's disease. presynaptic facili talion The action of a presynaptic terminal button in an axoaxonic synapse; increases the amount of neurotransmitter released by the postsynaptic terminal button. presynaptic inhibition The action of a presynaptic terminal button in an axoaxonic synapse; reduces the amount of neurotransmitter released by the postsynaptic terminal button. presynaptic membrane The membrane of a termina l butto n that lies adjacent to the postsynaptic membrane and through which the neurotransmitter is released. primary auditory cortex The region of the superior temporal lobe whose primary input is from the auditory system. primary motor cortex The region of the posterior frontal lobe that conta ins neurons that control movements of skeletal muscles. primary somatos·ensory cortex The region of the anterior parietal lobe whose prima ry input is from the somatosensory system. primary visual codex or striate cortex The region of the posterior occipital lobe whose p1rimary input is from the visual system. prion (pree on) A protein that can exist in two forms that differ only in their three-dimensional shape; accumulation of misfolded prion protein is responsible for hransmissible spongiform encephalopathies. progenitor cells Cells of the ventricular zone that divide and give rise to cells of the central nervous system. progesterone (pro jess ter own) A steroid hormone produced by the ovary that maintains the endometrial lining of the uterus during the later pa rt of the menstrual cycle and during pregnancy; along w ith estradiol it promotes receptivity in female mammals w ith estrous cycles. prolactin A horimone of the anterior pituitary gland, necessary for production of milk; also facilitates maternal behavior. proprioception Perception of the body's position and posture. prosody The use of changes in intonation and emphasis to convey meaning in speech besides that specified by the particular words; an important means of communication of emotion. prosopagnosia (Jm1'1 soil pag no zhn) Failure to recognize particular people by the sight of thteir faces. protanopia (pro ta 11 owe pee 11) An inherited form of defective color vision in which red and green hues are confused; "red" cones are filled with "green" cone opsin. proteasome An organelle responsible for destroying defective or degraded proteins within the cell. psychoneuroirnmunology The branch of neuroscience involved with interactions among env ironmental stim uli, the nervous system, and the immune system. psychopharmacollogy The study of the effects of drugs on the nervous system and behavior. punishing stimullus An aversive stimulus that follows a particular behavior and thus makes the behavior become less frequent. psychopharmacollogy The study of the effects of drugs on the nervous system and behavior. pure alexia Los~; of the ability to read w ithout loss of the ability to write; produced by brain damage. pure word deafness The ability to hear, to speak, and (usually) to read and write without being able to comprehend the meaning of speech; caused by damage to Wernicke's area or disruption of auditory input to this region. pursuit movement The movement that the eyes make to maintain an image of a moving object on the fovea. putamen A tele:ncephalic nucleus; one of the input nuclei of the basal ganglia; involved with control of voluntary movement. pyramidal tract The portion of the corticospinal tract on the ventral border of the medulla. pyridoxine dependency (peer i dox een) A metabolic disorder in which an infant requires la1rger-than-normal amounts of pyridoxine (vitamin B6) to avoid neurological symptoms.

Glossary

rabies A fatal viral disease that causes brain damage; usually transmitted through the bite of an infected animal. radial glia Special glia with fibers that grow radially outward from the ventricular zone to the surface of the cortex; provide guidance for neurons migrating outward during brain development. rap he nuclei (ruli fay) A group of nuclei located in the reticular formation of the medu lla, pons, and midbrain, situated along the midline; contain serotonergic neurons. rate code The system by which information about different frequencies is coded by the rate of firing of neurons in the auditory system. rate law The p rinciple that va riations in the intensity of a stimulus o r other information being transmitted in an axon are represented by variations in the rate at which that axon fires. rebound phenomenon The increased frequency or intensity of a phenomenon after it has been temporarily suppressed; for example, the increase in REM sleep seen after a period of REM sleep deprivation. receptive field That portion of the visual field in which the presentation of visual stimuli will produce an alteration in the firing rate of a particular neuron. receptor blocker A drug that binds with a recepto r but does not activate it; prevents the natural ligand from binding with the receptor. receptor potential A slow, graded electrical potential produced by a receptor cell in response to a physical stimulus. reconsolidation A process of consolidation of a memory that occurs subsequent to the original consolidation that can be triggered by a reminder of the original stimulus; thought to provide the means for modifying existing memories. red nucleus A large nucleus of the midbrain that receives inputs from the cerebellum and motor cortex and sends axons to motor neurons in the spinal cord. reduction A type of scientific explanation; a phenomenon is described in terms of the more elementary processes that underlie it. reflex An automatic, stereotyped movement that is produced as the direct result of a stimulus. reinforcing stimulus An appetitive stimulus that follows a particular behav ior and thus makes the behavior become more frequent. relational learning Learning the relationships among individual stimuli. release zone A region of the interior of the presynaptic membrane of a synapse to which synaptic vesicles attach and release their neurotransmitter into the synaptic cleft. REM sleep A period of desynchronized EEG activ ity during sleep, at which time dreaming, rapid eye movements, and muscular paralysis occur; also called paradoxical sleep. REM sleep behavior disorder A neurological disorder in which the person does not become paralyzed during REM sleep and thus acts out dreams. reserpine (ree s11r peen) A drug that interferes with the storage of monoamines in synaptic vesicles. reticular formation A large network of neural tissue located in the central region of the brain stem, from the medulla to the diencephalon. reticulospinal tract A bundle of axons that travels from the reticular formation to the gray matter of the spinal cord; controls the muscles responsible for postural movements. retina The neural tissue and photoreceptive cells located on the inner surface of the posterior portion of the eye. retinal (rett i 11ahl) A chemical synthesized from vitamin A; joins with an opsin to form a photopigment. retinal disparity The fact that points on objects located at different distances from the observer will fall on slightly different locations on the two retinas; provides the basis for stereopsis. retrograde Jn a direction along an axon from the terminal buttons toward the cell body. retrograde amnesia Amnesia for events that preceded some disturbance to the brain, such as a head injury or electroconvulsive shock. retrograde labeling method A histological method that labels cell bodies that give rise to the terminal buttons tha t form synapses with cells in a particular region. reuptake The reentry of a neurotransmitter just liberated by a terminal button back through the presynaptic membrane, thus terminating the postsynaptic potential. rhodopsin (roh dopp sin) A particular ops in found in rods.

633

rimonali>ant A drug that blocks CBl receptors. rod One of the receptor cells of the retina; sensitive to light of low intensity. rostral "Toward the beak"; with respect to the central nervous system, in a direction along the neuraxis toward the front of the face. round window An opening in the bone surrounding the cochlea of the inner ear that permits vibrations to be transmitted, via the oval window, into the fluid in the cochlea. rubrosp•inal tract The system of axons that travels from the red nucleus to the spinal cord; controls independent limb movements. Ruffini corpuscle A touch-sensitive cutaneous receptor, important in detecting stretching or static force against the skin, important in proprioception. saccadit: movement (s11'1 kad ik) The rapid, jerky movement of the eyes used in scanning a visual scene. saccule (sak yule) One of the vestibular sacs. sagittal section (sadj i tu/) A slice through the brain parallel to the neuraxis an1d perpendicular to the ground. saltato~y conduction Conduction of action potentials by myelinated axons. Tiile action potential appears to jump from one node of Ranvier to the neims are not relieved after trials of several different treatments. tricycliaresis Difficulty in moving the facial muscles voluntarily; caused by damage to the face region of the primary motor cortex or its subcortical connections. voltage-dependent ion channel An ion channel that opens or closes according to the va1lue of the membrane potential. volumetric thirst Thirst produced by hypovolemia. vomeronasal org2m (VNO) (voah mer oh 11ay wl) A sensory organ that detects the presenc•e of certain chemicals, especially when a liquid is actively sniffed; mediates the effects of some pheromones. Wemicke's area A region of the auditory association cortex on the left temporal lobe 0 1f humans, which is important in the comprehension of words and the p:roduction of meaningful speech. Wemicke's aphasia A form of aphasia characterized by poor speech comprehension and fluent but meaningless speech. Whitten effect l rhe synchronization of the menstrual or estrous cycles of a group of females, which occurs only in the presence of a pheromone in a ma le's urine. whole-word reading Reading by recognizing a word as a whole; "sight reading." withdrawal symptom The appearance of symptoms opposite to those prod uced by a drug when the drug is administered repeatedly and then suddenly no longer taken. Wolffian system The embryonic precursors of the male internal sex organs. zeitgeber (ts ite ga!y ber) A stimulus (usually the light of dawn) that resets the biological clock that is responsible for circadian rhythms. zolpidem An indirect agonist for the GABAA receptor; used to treat insomnia.

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26(1), 41-46. Breitve, M. H., Chwiszczuk, L. J., Hy.nnin1~n, M. J., Rongve, A., Bmnnick, K., Janvin, C., & Aarsland, D. (2014). A systematic review of cognitive decline in dementi-225, 225/ depolarizing, 224 endplate potential, 224 extension, 223, 223/ extrafusal muscle fibers, 223, 224/ flexion, 223, 223/ gamma motor axon, 224/ gamma motor neuron, 223 Golgi tendon organ, 224/, 225 intrafusal muscle fibers, 223, 224/ motor end plates, 224 motor unit, 223 muscle length detectors, 225 muscle spindles, 223, 224/ myofibrils, 223, 224/ myosin, 223, 224/, 225/ neuromuscular junction, 223-224, 225/ Pacinian corpuscle, 224/ receptor responses, 226/ sensory feedback, 225-226 stretch receptors, 225 striated, 223 twitch, 224 Music perception, I9:>-194 Mutations, 10 selective advantage, 10-ll Myasthenia gravis, 24 Myelencephalon, 69 medulla oblongata, 611, 69 Myeline sheath, 26/, 27, 31 tracts, 27 white matter, 27

N Nan:olepsy cataplexy, 276 flip-flop circuits and, 273 humor and, 274 hypnagogic hallucinations, 276 orexin and, 2n sleep attacks, 276 sleep paralysis, 276 treatment, 2n Natural selection, 9, 10 chromosomes and, 10 evolution of behavioral traits, 9-11 mutations and, 10 selective advantage, 10-11 Neandertha Is, 11- 12 Neostrnitum system, 95 Neoteny, 13 Nerve energies, 6 Nerves, 25/ Nervous system, 6-7, 56/, 478-479 anatomical terms, 56-58 attention-deficit/hyperactivity disorder (AOHO), 494-497 autism spectrum disorder (ASD), 489-493 brain development, 479-184 CNS (central nervous system), 24, 54-55 meninges, 53-60, 58/ neural plate development, 479/ neural tube, 479 neuraxis, 56 neurons, 25-29 pia mater, 58 P S (peripheral nervous system), 24,54-55 psychopharmacology and, 79/ Rett syndrome, 489 sub-117, 114/ Neural communication, 34-35 Neural connections, 4132/ Neural control ejaculation, 305 erection,305 female sexual behavior, 307-308 immune system, 574-575 male sexual behavior, 305-307 maternal behavior, 318-320 pair bond formation, 309-310 paternal behavior, 320-321 REM transition, 272- 274 sleep, 264-265 Neural integration, 48, 48/ Neural tube, 479 Neuraxis, 56 anatomical direction, 56, 57/ anterior, 56, 57/ caudal, 56, 57/ contralateral, 56 dorsal, 56, 57/ inferior, 56, 57/ ipsilateral, 56 lateral, 56, 57/ medial, 56, 57/ posterior, 56, 57/ rostra I, 56, 57/ superior, 56, 57/ ventral, 56, 57/ Neurochemical resean:h methods, 130-133, 1331 Neuroendocrine control of menstrual

cycle, 296/

Neuroethics, 16 Neurogenesis, 2 adult brain, 484/ exen:ise and, 561/ Neurological disorders cerebrovascular accidents, 506-510 degenerative disorders, 51:>-528 infectious d isease and, 530-532 seizures, 502-505 traumatic brain injury (TBI), 510-512 tumors, 500-502 Neurology, 17 Neuromagnetometers, 124 Neuromodulators, 51 Neuromuscular junction, 223-224,

225/

Neuron communication, 42 Neurons, 2, 24 acetylcholinergic, 93/ alcohol,3 axons, 25, 26/ cell body, 25, 26/ cell membrane, 27 cytoplasm, 27-28, 28/ cytoskeleton, 27, 27-28 dendrites, 25, 26/, 28/ dendritic spines, 28/, 42 intemeurons, 24, 25/ losing, 2 membrane, 28/ microscopy, 113/ microtubules, 27, 28/ mitochondria, 28/ motor neurons, 24, 25/ myelin sheath, 26/, 28/ neurochemjca( production, 130-131 nucleus, 28, 28/ sensory neurons, 24, 25/ soma, 25, 26/ synaptic connections, 28/ termina l buttons, 25, 26/, 27, 28/ Neuropeptides (NPY)

anorexiia nervosa and, 397 hunger and, 383 substance abuse and, 598 Neuroscience, 3 careers, 17 cognitive neuroscience, 17 diversity in, 8 education path, 18/ obel l?rizes, 81 1eurosecrctory cells, 67 Neurotransmitter-dependent ion ch.lnnels, 45, 47 Neurotransmitters, 42 acetylcholine, 901 ACh (acetylcholine) and, 92-94 amino .acids, 89-92 binding sites, 42 CNSand,901 deactivation, 88 depolarization, 42 dopamine, 901 endocannabinoids, 901 exocytosis, 44 G-protein-coupled receptors, 46 GABA (gamma-animobutyric acid), 89,.901 glutamate, 89, 901 histamiine, 901 hyperpolarization, 42 ion channels and, 45-46 lipids, 102-103 monoamines, 94-101 norcpinephrine I epinephrine, 901 opioids, 901 peptides, 101-102 PNSand,901 postsynaptic potentials, 42 receptors, 45-46, 46/ release, 44-45, 44/ drugs and, 87 rcuptake, 4&49/, 88 ~rotonin, 901

slorage-, drugs and, 87 synaptiic transmission, drugs and,

85--86, 86/ synthesis, drugs and, 86-87 vesicle transporters, 87 Nicotine .abuse brain mechanisms, 607-611 cessation, insula damage and, 610/ dopamine release and, 609/ treatme nt, 618-619/ N ight terrors, 278 N igrostri.ata l system, 95 Nissie sulbstance, 112 Nitric oxide synthase, 437 NMDA receptor, 90, 90/, 435/ alcohol and, 612/ classic-394

BMI,388 drug treatment, 392-393 environmental factors, 389

gastric surgery, 388/ genetic factors, 390-391 heredity and, 390 Naltrexone/Bupropion and, 394/ NEAT (nonexen:ise activity thermogenesis), 389 physical activity factors, 389-390 Pima Indians, 390 stress and, 391 surgical interventions, 391-392 thrifty phenotype, 390 treatment, 391-394 Obsessions, 585 Obsessive-compulsive disorder (OCD),585 acral lick dermatitis, 586 brain changes, 586-587 capsulotomy and, 587 cingulotomy and, 587 D-cycloserine (DCS) and, 587/ environmental factors, 586 genetics, 586 onychophagia,586 streptococcal hemolytic infection,

586/ symptoms, 5851 tic disorders, 586 Tourette's syndrome, 586 treatment, 587-589 trichotillomania, 587 Obstructive hydrocephalus, 59 Occipital lobe, 61, 63/ Oculomotor nerves, 72f Odor mapping, 217-218 Odor perception, 218 Odorants, 219 masking, 220 Olfaction hormonal and neural pathways, 320/ materna l behavior and, 319 odor mapping, 217-218 odor perception, 21 S-219 odorant masking, 220 odorant quality, 219-220 olfactory processing, 217 olfactory receptors, 216-217 transcution, 218 Olfactory bulbs, 72, 217, 217/ clusters, 219/ zones,219/ Olfactory epithelium, 216 Olfactory glomeruli, 217 Olfactory information coding, 219/ Olfactory mucosa, 217/ Olfactory nerves, 72f Olfactory pathway, 218/ Olfactory receptors, 216-217 glomeruli connection, 218/ Olfactory system, 217/ Oligodendrocytes, 30, 31 multiple sclerosis, 32 node of Ranvier and, 40 Olivocochlear bundle, 184 Onychophagia, 586 Operant conditioning, learning and, 404, 405, 4051

basal ganglia and, 411-412 nucleus accumbens (NAC), 413/ reinforcement and, 412-415 ventral tegmental area and (VTA),413/ Opiate abuse, treatment, 616-618 Opiate-induced analgesia, 209/ Opiates, 101 brain mechanisms, 605/~6 µopiate receptor, 606/

716 Subject Index Opioids, 901 abused drugs, 5931 enkephal ins, 102 receptors, 102 Opium, 101 Opponent-color system theory, 155, 156-157 Optic chiasm, 67 Optic flow, 172, 173 Optic nerve, 72/, 143/ Optogenetic methods of neural stimulation, 127-129, 128/ Orbits, eye, 143 Orexigenic chemicals, 393 Orexin narcolepsy and, 277 sleep/wake cycle and, 271- 272, 271/ Organ of Corti, 181/ Organelles, 28 Organic senses, 200, 2001 Organizational effects of hormones, 290, 2901 aggression, 336-337 defeminization, 298 masculinization, 298 sexual orientation and, 311 testosterone, 298/ testosterone and social aggression, 335/ Organum vasculosum of the lam ina terminalis (OVLT), 365 Orientation perception extrastriate cortex, 171-175 striate cortex, 171 Orientation sensitivity, 171/ Orthographic dysgraphia, 474 Osmoreceptors, 365, 365/ Osmosis, 365 Osometric thirst, 364, 364-366, 366/ Otoconia, 197 Outer ear, 180 Ovarian follicles, 295

corpus luteum, 296 progesterone, 296 Ovarian hormones, sexual activity of women, 299-300 Overtones, 188, 188/ Oxidative stress, sleep and, 260-261 Oxycodone, 101 Oxytocin, 296 pair bonding and, 309

p Pacinian corpuscles, 200, 201 I Pain, 203 ACC (anterior cingulate cortex) and, 206-207 brain regions involved, 2081 components, 206-208 cutaneous senses, 200 emotional components, 206, 207/ endogenous modification of sensitivity, 208-209 insensitivity, 179 long-term emotional implications, 207/ nociceptive information, 207/ nociceptors, 203 phantom limbs, 208, 208/ placebo analgesia, 209-211, 210/ reasons for, 206 sensory components, 206, 207/ stress, brain and, 571 unpleasantness, 207/ Pair bonds forming, 309-310 oxytocin and, 309 Pancreas, glucose and, 369 Panic d isorder, 581, 5821 fluvoxamine and, 583/ Parahippocampal cortex, 420 Parahippocampal place area (PPA), 165, 165/ Parasympathetic d ivision of ANS, 75 Paraventricular nucleus of the hypotha lamus (PVN), 284 hunger and, 384

Parental behavior hormona l control, maternal behavior, 317-318 maternal behavior of rodents, 316-317 neural control, 318-321 Parietal cortex, 247 anterior intraparietal sulcus, 247 Parietal lobe, 61, 63/ Parietal reach region, 247 Parieto-occipital cortex, 169/ PARK2 gene, 250 Parkinson's disease, 95, 241 basal ganglia, 518/ brain comparison, 241/ causes, 515-516 deep brain stimulation (DBS), 518 dopamine and, 95, 607/ gene therapy, 519 internal division of the globus pallidus (GP), 517 L-OOPA and, 87, 516-517 Lewy bodies, 514, 515/ loss of function, 515 parkin, 515, 515/ PET scan, 133/ pham1acological treatment, 516/ proteasomes, 515 surgical treatment, 517, 519/ timeline of treatments, 520/ toxic gain of function, 515 treatments, 516-519 ubiquitin, 515 Parturition, 317 Parvocellu lar layers of LGN, 149, 1581, 159f 348 emotional perception and, 348/ Patellar reflex, 227 Paternal behavior neural control, 32G-321 testosterone and, 321, 321/ PCP (phencyclidine), 91 PCPA (p-chlorophenylalanine), 87 tryptophan and, 99 Peptide YY3-36 (PYY), 378 Peptides, 51, 130 drugs that act on, 1031 endogenous opioids, 101 localization, 131/ Perception, 3 vision and, 141 Perceptual learning, 406 amnesia and, 429 cortex and, 417-418 extrastriate cortex and, 418f 419 hippocampal damage and, 429 prefrontal cortex and, 419 short-memory and, 418-419 visua l memory retrieval, 418/ Perfusion, 111 Periaqueductal gray matter, 68f 69 Peripheral nervous system (PNS), 24, 54-55 autonomic nervous system (ANS), 73-75, 751 cerebrospinal fluid (CSF), 58 cranial nerves, 55, 71-72 motor neurons, 24 neurotransmitters and, 901 peripheral ganglia, 55 postganglionic neuron, 74/ preganglionic neuron, 74/ Schwann cells, 31- 32 sensory neurons, 24 somatic nervous system, 751 spinal nerves, 55, 72-73 supporting cells, 31-32 Peripheral vision, 146-147 Perirhinal cortex, 420 Peritoneal cavity injection, 80 Persistent Miillerian duct syndrome, 292 Persona l moral judgments, 3431 PET (positron emission tomography) scan, 106-107 Parkinson's patient, 133/ PFC (prefrontal cortex), 152/ PHA-L, 115

Phagocytosis, 30 Phantom limb pain, 208, 208/ Pharmacokinetics absorption, 80-81 .. 80/ cocaine in blood plasma, 81/ distribution, 80/, 81 excretion, 80f 82 inhalation, 81 insu fflation, 81 intracerebral administration, 80-Sl intracerebroventriicular (TCV) ad ministratio•n, 81 intramuscular (JM) injection, 80 intraperitoneal (lP) injection, 80 intravenous (IV) injection, 80 metabolism, BOf S:2 oral adrninistratio•n, 81 repeated administration, 83-84, 84/ routes of adrninisttration, 80-Sl subcutaneous (SC) injection, 80 sublingual administration, 81 topical administr