Discovering Behavioral Neuroscience: An Introduction to Biological Psychology [5 ed.] 0357798244, 9780357798249

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Laura A. Freberg

Discovering Behavioral Neuroscience An Introduction to Biological Psychology

5th Edition

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Fifth Edition

Discovering Behavioral Neuroscience An Introduction to Biological Psychology

Laura A. Freberg California Polytechnic State University, San Luis Obispo

Australia Brazil Canada Mexico Singapore United Kingdom United States ●

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This is an electronic version of the print textbook. Due to electronic rights restrictions, some third party content may be suppressed. Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. The publisher reserves the right to remove content from this title at any time if subsequent rights restrictions require it. For valuable information on pricing, previous editions, changes to current editions, and alternate formats, please visit www.cengage.com/highered to search by ISBN#, author, title, or keyword for materials in your areas of interest. Important Notice: Media content referenced within the product description or the product text may not be available in the eBook version.

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Discovering Behavioral Neuroscience: An Introduction to Biological Psychology, Fifth Edition Laura A. Freberg SVP, Product for Cengage Academic: Cheryl Costantini

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Printed in the United States of America Print Number: 01 Print Year: 2023

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To My Family Roger, Kristin and Scott, Karen, Karla, and Marcus

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

About the Author

Courtesy of Laura A. Freberg

Laura A. Freberg is Professor of Psychology at California Polytechnic State University, San Luis Obispo, where she teaches courses in Introductory Psychology and Biological Psychology. With the late John Cacioppo and Steph Cacioppo of the University of Chicago, Laura is the co-author of four editions of Discovering Psychology: The Science of Mind for Cengage. She is author of An Introduction to Applied Behavioral Neuroscience: Biological Psychology in Everyday Life for Taylor & Francis. She is also lead author of Research Methods in Psychological Science. Laura completed her undergraduate and graduate studies at UCLA, where her thinking about psychology and neuroscience was shaped by Eric Holman, John Garcia, O. Ivar Lovaas, Larry Butcher, Jackson Beatty, John Libeskind, Donald Novin, Frank Krasne, and F. Nowell Jones. She was privileged to study neuroanatomy with Arnold Scheibel, and she investigated the effects of psychoactive drugs on learning and memory under the direction of Murray Jarvik and Ronald Siegel in the UCLA Neuropsychiatric Institute. As a capstone to her education, Laura completed her dissertation with Robert Rescorla, then at Yale University. Laura’s teaching career began when she taught her first college course at Pasadena City College at the age of 23 while still a graduate student at UCLA. Beginning in 2011,

to better understand the needs of the online education community, she also began teaching for Argosy University Online, including courses in Social Psychology, Sensation/ Perception, Cognitive Psychology, Statistics, Research Methods, and Writing in Psychology. She has also redesigned her Cal Poly introductory and biopsychology courses according to QOLT standards to be administered completely online. She has received Faculty Member of the Year recognition from the Cal Poly Disabilities Resource Center three times (1991, 1994, and 2009) for her work with students with disabilities. She enjoys experimenting with technology and social media in the classroom. Laura enjoys collaborating with daughters Kristin Saling (Systems Engineering—U.S. Military Academy at West Point) and Karen Freberg (Communications—University of Louisville) on a variety of research projects in crisis management and public relations as well as in psychology. She served as President of the Western Psychological Association (WPA) in 2018–2019. In her spare time, Laura enjoys family time with her husband, Roger, their youngest daughter Karla, who has autism spectrum disorder, and an active menagerie including two Australian shepherds, two cats, a parakeet, who can usually be heard in her recordings for online courses, according to her students. She usually writes while consuming vast quantities of Gevalia coffee and listening to the Rolling Stones (which might be apparent in the book’s writing style), and she has been known to enjoy college football, Harley Davidsons, episodes of House of the Dragon that do not feature weddings, and The Great British Baking Show. Her ringtone is from Nintendo’s Legend of Zelda.

iv

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Brief Contents Preface

xiv

1

What Is Behavioral Neuroscience?

2

Functional Neuroanatomy and the Evolution of the Nervous System 27

3

Neurophysiology: The Structure and Functions of the Cells of the Nervous System 65

4

Psychopharmacology

5

Genetics and the Development of the Human Brain

6

Vision

7

Nonvisual Sensation and Perception

8

Movement

9

Homeostasis, Motivation, and Reward

103

209

247

Sexual Behavior

11

Sleep and Waking

12

Learning and Memory

13

Cognitive Neuroscience 419

14

Social and Affective Neuroscience

15

Neuropsychology

481

16

Psychopathology

511

Name Index

137

173

10

References

1

281

313 347 381

451

R-1 I-1

Subject Index/Glossary

I-10 v

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

About the Cover and Illustrations If you are familiar with the first four editions of this textbook, you know that we like to pick colorful visuals that portray the biology behind the behavior. For this fifth edition, we selected a confocal image of a sagittal section of a mouse cerebellum at postnatal day 7, by Valentina Cerrato. It is titled “Neuroscience is Heart.” Immunofluorescence was used to label cerebellar astrocytes (green) and proliferating cells, which incorporated BrdU (red) and Edu (blue) at postnatal day 1 and 7, respectively. Distinct 20X images were collected and automatically realigned using Photoshop © software. More striking images may be found at NeuroArt.com

Many of the illustrations in this edition were the work of my daughter, Karla, who has autism spectrum disorder. Karla loves to draw and is very excited to see her work in print. She drew these portraits of herself and of me. You will see her version of a rat in an optogenetics experiment again in Chapter 1.

vi

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Contents Preface xiv

1 | What Is Behavioral Neuroscience?

1

Neuroscience as an Interdisciplinary Field 2 Historical Highlights in Neuroscience Ancient Milestones in Understanding the Nervous System 5 The Dawn of Scientific Reasoning 5 Modern Neuroscience Begins 6 Interim Summary 1.1

5

8

Behavioral Neuroscience Research Methods 8 Microscopic Methods 9 Peripheral Methods 10 Imaging 11 Recording 13 Hyperscanning 15 Brain Stimulation 15 Lesion 18 Biochemical Methods 19 Genetic Methods 19 Interim Summary 1.2

21

Open Science and Research Ethics in Behavioral Neuroscience 22 Open Science 22 Human Participant Guidelines 22 Animal Subjects Guidelines 23 Interim Summary 1.3

24

Chapter Review ● Thought Questions ● Key Terms 25 Connecting to Research: Thinking About Yourself as Lonely or Socially Connected Can Influence Your Immune System 3 Behavioral Neuroscience Goes to Work: What Can I Do with a Degree in Neuroscience? 4 Thinking Ethically: Can We Read Minds with Neuroscience Technologies? 16 Neuroscience in Everyday Life: Can Brain Stimulation Improve My Memory? 24

2 | Functional Neuroanatomy and the Evolution of the Nervous System 27 Anatomical Directions and Planes of Section 28 Protecting and Supplying the Nervous System 29 Meninges 29 Cerebrospinal Fluid 32 The Brain’s Blood Supply 34 Interim Summary 2.1

34

The Central Nervous System 35 The Spinal Cord 36 Embryological Divisions of the Brain 38 The Hindbrain 38 The Midbrain 40 The Forebrain 42 Interim Summary 2.2

53

The Peripheral Nervous System 53 The Cranial Nerves 53 The Spinal Nerves 54 The Autonomic Nervous System (ANS) 55 The Endocrine System 58 The Evolution of the Human Nervous System 59 Natural Selection and Evolution 59 Evolution of the Nervous System 60 Evolution of the Human Brain 60 Interim Summary 2.3

62

Chapter Review ● Thought Questions ● Key Terms 62 Connecting to Research: Linking the Brain and the Immune System 32 Behavioral Neuroscience Goes to Work: So You Want to Be a Neurosurgeon? 51 Thinking Ethically: Predicting “Dangerousness” 51 Neuroscience in Everyday Life: Can I Improve My Heart Rate Variability (HRV)? 58

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viii

Contents

3 | Neurophysiology: The Structure and Functions of the Cells of the Nervous System 65 Glia and Neurons 66 Glia 66 The Structure of Neurons 70 Structural Variations in Neurons 77 Functional Variations in Neurons 77 Interim Summary 3.1

79

Generating Action Potentials 79 The Ionic Composition of the Intracellular and Extracellular Fluids 79 The Movement of Ions 80 The Resting Potential 83 The Action Potential 84 Propagating Action Potentials 86 Interim Summary 3.2

89

The Synapse 89 Gap Junctions 90 Chemical Synapses 90 Axo-Axonic Synapses 99 Interim Summary 3.3

Chapter Review Terms 101

●

100

Thought Questions ● Key

Neuroscience in Everyday Life: Should I Take Prebiotics or Probiotics? 70 Thinking Ethically: Lethal Injection 83 Connecting to Research: Are Synapse Size and Strength Related? 96 Behavioral Neuroscience Goes to Work: How Does an EEG Work? 97

4 | Psychopharmacology

103

Neurotransmitters, Neuromodulators, and Neurohormones 104 Types of Neurochemicals The Small Molecules 106 Neuropeptides 114 Gasotransmitters 115 Interim Summary 4.1

105

115

Mechanisms of Neuropharmacology 116 Agonists and Antagonists 116 Drugs Influence the Production of Neurochemicals 117 Drug Effects on Neurochemical Storage 117 Drugs Affect Neurochemical Release 117 Drugs Interact With Receptors 118

Drugs Affect Reuptake and Enzymatic Degradation Interim Summary 4.2 121

119

Basic Principles of Drug Effects 121 Administration of Drugs 121 Individual Differences in Responses to Drugs 122 Placebo Effects 122 Tolerance and Withdrawal 122 Addiction 123 Effects of Selected Psychoactive Drugs Stimulants 125 Opioids 129 Cannabis 130 Hallucinogens 132 Alcohol 132 Interim Summary 4.3

125

135

Chapter Review ● Thought Questions ● Key Terms 136 Connecting to Research: Otto Loewi and “Vagus Stuff” 106 Behavioral Neuroscience Goes to Work: Addiction Counselors 125 Neuroscience in Everyday Life: Should Psychedelics Be Used in Therapy? 133 Thinking Ethically: Drug Use Affects Future Generations 134

5 | Genetics and the Development of the Human Brain 137 The Genetic Bases of Behavior 138 From Genome to Trait 138 Sources of Genetic Variability 140 Heritability 144 Epigenetics 145 Interim Summary 5.1

149

Building a Brain 150 Prenatal Development 150 Effects of Experience on Development 157 Disorders of Early Nervous System Development 161 Interim Summary 5.2

165

The Brain Across the Life Span 166 Brain Changes From Adolescence to Adulthood 166 The Healthy Adult Brain 168 Adult Neurogenesis 170 Interim Summary 5.3

171

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Contents

Chapter Review ● Thought Questions ● Key Terms 172 Connecting to Research: Epigenetics, Gene Expression, and Stress 147 Behavioral Neuroscience Goes to Work: Genetics Counseling 148 Thinking Ethically: When Are Adolescents Responsible for Their Actions? 169 Neuroscience in Everyday Life: The Epigenetic Effects of Diet on the Nervous System 169

6 | Vision

173

Interim Summary 6.1

176

The Structure and Functions of the Visual System 177 The Human Eye 177 The Layered Organization of the Retina 180 The Photoreceptors 181 Processing by Retinal Interneurons 184 Visual Pathways 188 The Striate Cortex 190 Visual Analysis Beyond the Striate Cortex 192 Interim Summary 6.2

Thinking Ethically: Inclusive Web Design 202 Neuroscience in Everyday Life: Are You a SuperRecognizer? 206

7 | Nonvisual Sensation and Perception 209 Audition 210 Sound as a Stimulus 210 The Structure and Function of the Auditory System 212 Auditory Perception 219 Hearing Disorders 221 Interim Summary 7.1

From Sensation to Perception 174 The Visual Stimulus: Light 174 The Advantages of Light as a Stimulus 175 The Electromagnetic Spectrum 175 Light Interacts With Objects 176

195

Visual Perception 195 Bottom-Up or Top-Down? 195 Spatial Frequencies 196 The Perception of Depth 197 Coding Color 198

224

The Body Senses 224 The Vestibular System 225 Touch 227 Pain 234 Interim Summary 7.2

237

The Chemical Senses Olfaction 239 Gustation 242 Synaesthesia

239

244

Interim Summary 7.3

Chapter Review Terms 246

●

245

Thought Questions ● Key

Neuroscience in Everyday Life: Earbuds and Hearing Loss 223 Thinking Ethically: Sonic Weapons 223 Connecting to Research: Phantom Limbs, Mirrors, and Longer Noses 233 Behavioral Neuroscience Goes to Work: What Is a Perfumer? 244

The Life Span Development of the Visual System 202

8 | Movement

Disorders of the Visual System Amblyopia 204 Cataracts 204 Visual Acuity Problems 204 Blindness 205 Visual Agnosias 205

Muscles 248 Types of Muscles 248 Muscle Anatomy and Contraction 249 The Effects of Exercise on Muscle 251 The Effects of Aging on Muscles 252

Interim Summary 6.3

204

206

Chapter Review ● Thought Questions ● Key Terms 207 Connecting to Research: Hubel and Wiesel Map the Visual Cortex 191 Behavioral Neuroscience Goes to Work: 3-D Animation 199

ix

247

Neural Control of Muscles 253 Alpha Motor Neurons 254 The Motor Unit 254 The Control of Muscle Contractions 255 The Control of Spinal Motor Neurons 255 Interim Summary 8.1

258

Reflex Control of Movement 259 Reciprocal Inhibition at Joints 259 The Flexor Reflex 260

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x

Contents

Central Pattern Generators 260 Reflexes Over the Lifespan 260

Motor Systems of the Brain Spinal Motor Pathways 261 The Cerebellum 263 The Basal Ganglia 264 The Motor Cortex 265 Interim Summary 8.2

The Initiation of Eating Satiety 300

261

Healthy and Disordered Eating Defining Healthy Weight 301 Obesity 302 Disordered Eating 304 Interim Summary 9.2

269

Interim Summary 9.3

Chapter Review ● Thought Questions ● Key Terms 279 Thinking Ethically: Gene Doping by Athletes 253 Connecting to Research: Intention to Move and Free Will 268 Behavioral Neuroscience Goes to Work: Physical Therapy and the Neurologic Clinical Specialty 271 Neuroscience in Everyday Life: How to Repair a Gene 277

9 | Homeostasis, Motivation, and Reward 281 282

Interim Summary 9.1

295

Hunger: Regulating the Body’s Supply of Nutrients 296 Digestion and Storage of Nutrients 296 The Pancreatic Hormones 297

311

Neuroscience in Everyday Life: Understanding the Benefits of Fever 285 Behavioral Neuroscience Goes to Work: Nutritional Neuroscience 302 Thinking Ethically: How Dangerous Is It to Be Overweight or Obese? 305 Connecting to Research: Working for Brain Stimulation 308

10 | Sexual Behavior

288

313

Sexual Development 314 The Genetics of Sex 314 Three Stages of Prenatal Development 317 Mini-Puberty 320 Development at Puberty 321 Interim Summary 10.1

Regulating Body Temperature 282 Adaptations Maintain Temperature 283 Endothermic Responses to Heat and Cold 284 Disruptions to Human Core Temperature 285 Brain Mechanisms for Temperature Regulation 286 Thirst: Regulating the Body’s Fluid Levels Intracellular and Extracellular Fluid Compartments 288 Osmosis Causes Water to Move 289 The Kidneys 290 The Sensation of Thirst 290

307

Chapter Review ● Thought Questions ● Key Terms 311

278

Homeostasis and Motivation

301

307

Pleasure and Reward 307 Classical Research in Self-Stimulation Multiple Facets of Reward 308 Reward Pathways 309 The Neurochemistry of Reward 309 Cortical Processing of Reward 310

Disorders of Movement 270 Toxins 270 Myasthenia Gravis 271 Muscular Dystrophy 272 Polio 272 Accidental Spinal Cord Injury (SCI) 273 Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s Disease) 273 Parkinson Disease 274 Huntington Disease 276 Interim Summary 8.3

297

323

Sex Differences in Hormones, Brain Structure, and Behavior 324 The Organizing Role of Sex Hormones 324 The Organizing Role of Sex Chromosome Genes 326 Sexual Dimorphism in the Brain 326 Sex Differences in Behavior and Cognition 327 Sexual Orientation 334 Hormones and Sexual Orientation 334 Brain Structure and Sexual Orientation 335 Genetics and Sexual Orientation 337 Sexual Orientation and Cognition 337 Interim Summary 10.2

337

Biological Influences on Adult Sexual Behavior 337 The Regulation of Sex Hormones 337 Mood, Menstruation, and Childbirth 337

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

Contents

Hormones and Adult Sexual Behavior

339

Attraction, Romantic Love, Sexual Desire, and Parenting 340 Elements of Physical Attractiveness 340 Relationships Between Romantic Love and Sexual Desire 341 Reproduction and Parenting 343 Sexual Dysfunction and Its Treatment 344 Interim Summary 10.3

Chapter Review ● Thought Questions ● Key Terms 345 Behavioral Neuroscience Goes to Work: How Do Therapists Treat Gender Dysphoria? 331 Thinking Ethically: Gender and Sport 332 Connecting to Research: Simon LeVay and INAH-3 335 Neuroscience in Everyday Life: Treating Patients With Antidepressant-Induced Sexual Dysfunction 344

11 | Sleep and Waking

347

Biorhythms 348 Individual Variations in Sleep Patterns 348 Shift Work, Jet Lag, and Daylight Saving Time 351 The Body’s Internal Clocks Manage Circadian Rhythms 352 Interim Summary 11.1

358

Neural Correlates of Waking and Sleep 358 Electroencephalogram (EEG) Recordings of Waking and Sleep 358 Brain Networks Control Waking and Sleep 361 Biochemical Correlates of Waking and Sleep 366 Interim Summary 11.2

367

Why Do We Sleep? 368 Changes in Sleep Over the Lifetime 369 Possible Advantages of Sleep 370 Why Do We Dream? 372 Sleep–Wake Disorders 374 Circadian Disorders 374 Insomnia 375 Narcolepsy 375 Breathing-Related Sleep Disorders 377 Sudden Infant Death Syndrome (SIDS) 377 Sleep Talking and Sleep Walking 378 REM Sleep Behavior Disorder 378 Restless Legs Syndrome (RLS) 378 Interim Summary 11.3

Connecting to Research: A Composite Scale of Morningness 349 Thinking Ethically: Artificial Lighting and Circadian Rhythms 357 Neuroscience in Everyday Life: Do Smartphone Sleep Apps Work? 359 Behavioral Neuroscience Goes to Work: Sleep Medicine 376

12 | Learning and Memory

345

379

Chapter Review ● Thought Questions ● Key Terms 380

xi

381

Categorizing Learning and Memory Types of Learning 382 Types of Memory 384

382

Mechanisms of Synaptic Plasticity 387 Learning in Simple Organisms 387 Long-Term Potentiation (LTP) 391 Memory Consolidation 397 Reactivation and Reconsolidation 398 In Search of the Engram 398 Interim Summary 12.1

401

Neural Systems Supporting Classical Conditioning, Operant Conditioning, and Social Learning 401 Systems Supporting Classical Conditioning 401 Systems Supporting Operant Conditioning 404 Systems Supporting Social Learning 405 Neural Systems Supporting Memory 406 Systems Supporting Working Memory 406 Systems Supporting Episodic Memory 407 Systems Supporting Semantic Memory 410 Systems Supporting Procedural Memory 410 Interim Summary 12.2

411

The Effects of Stress on Learning and Memory 412 Stress and Memory Formation 413 Stress and Memory Retrieval 413 Chronic Stress and Memory 414 The Effects of Healthy Aging on Memory Interim Summary 12.3

415

416

Chapter Review ● Thought Questions ● Key Terms 416 Behavioral Neuroscience Goes to Work: What Is Neuroeducation? 387 Connecting to Research: Karl Lashley’s Search for the Engram 399 Thinking Ethically: Should We Erase Traumatic Memories? 414 Neuroscience in Everyday Life: Does Brain Training Work? 415

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xii

Contents

13 | Cognitive Neuroscience

419

Domains of Cognitive Neuroscience

14 | Social and Affective Neuroscience 451 420

Consciousness 420 The Evolution of Consciousness 420 Neural Correlates of Consciousness 420 Disorders of Consciousness 420 Hemispheric Lateralization 421 Learning About Lateralization 421 The Evolution of Lateralization 423 The Development of Lateralization 425 Implications of Lateralization for Behavior 425 Interim Summary 13.1

Emotion 452 The Evolution and Adaptive Benefits of Emotion 452 Models of Emotion 453 The Expression and Recognition of Emotion 457 Biological Correlates of Emotion 462 Emotion Regulation 465 Interim Summary 14.1

Stress and Aggression 467 Stress 467 Aggression and Violence 470 Interim Summary 14.2

429

466

474

Language 430 The Origins of Language 431 Communication in Nonhuman Animals 432 Language Models 434

Social Neuroscience 475 Social Cognition and Empathy 475 The Social Neuroscience of Prejudice 476 Loneliness 477

Variations in Language Processing Multilingualism 434 American Sign Language (ASL) 434

Interim Summary 14.3

434

Communication Disorders and Brain Mechanisms for Language 435 Paul Broca and Patient Tan 435 Aphasia 435 Disorders of Reading and Writing 439 Stuttering 439 Interim Summary 13.2

440

Intelligence 442 Components of Intelligence 442 Brain Structure and Intelligence 443 Intelligence and Genetics 443 Network Neuroscience and Intelligence 444 Artificial Intelligence 444 The Neuroscience of Decision Making 446 Assigning Value 446 Implementing a Choice 447 Interim Summary 13.3

Chapter Review Terms 449

●

448

Thought Questions ● Key

Connecting to Research: Savants and Lateralization 429 Behavioral Neuroscience Goes to Work: Speech and Language Pathology 441 Thinking Ethically: Performance-Enhancing Drugs for the Mind? 445 Neuroscience in Everyday Life: What Is Consumer Neuroscience? 448

Chapter Review Terms 480

●

478

Thought Questions ● Key

Connecting to Research: Facial Expressions Predict Assault 461 Thinking Ethically: Using Neuroscience to Assess “Dangerousness” 472 Behavioral Neuroscience Goes to Work: Forensic Neuropsychology 475 Neuroscience in Everyday Life: Reducing Loneliness 479

15 | Neuropsychology

481

What Is Neuropsychology? 482 Who Are the Neuropsychologists? 482 Neuropsychological Assessment 482 Neurocognitive Disorders 483 Alzheimer Disease 483 Frontotemporal Neurocognitive Disorder 487 Neurocognitive Disorder with Lewy Bodies 488 Vascular Disease (Stroke) 488 Traumatic Brain Injury (TBI) 490 Substance/Medication-Induced Neurocognitive Disorder 493 Neurocognitive Disorder Due to HIV Infection 493 Neurocognitive Disorder Due to Prion Diseases 494 Interim Summary 15.1

497

Neurocognitive Disorders Due to Other Medical Conditions 498

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Contents

Brain Tumors 498 Infections 500 Epilepsy 501 Multiple Sclerosis 503 Migraine 505

The Biochemistry of Schizophrenia Treating Schizophrenia 527

Recovery and Treatment in Neurocognitive Disorders 505 Plasticity and Recovery 505 Cognitive Reserve 506 Rehabilitation for Neurocognitive Disorders 506 Interim Summary 15.2

508

Chapter Review ● Thought Questions ● Key Terms 509 Behavioral Neuroscience Goes to Work: Preparing to Be a Clinical Neuropsychologist 482 Thinking Ethically: The Amyloid Hypothesis of Alzheimer Disease 485 Neuroscience in Everyday Life: Recognizing the Signs of a Stroke 491 Connecting to Research: Stanley Prusiner and the Prion 495

16 | Psychopathology

511

What Does It Mean to Have a Mental Disorder? 512 Autism Spectrum Disorder (ASD) 514 Causes of ASD 514 Brain Structure and Function in ASD 515 Treatment of ASD 517 Attention Deficit Hyperactivity Disorder (ADHD) 518 Causes of ADHD 519 Brain Structure and Function in ADHD 519 Treatment of ADHD 520 Interim Summary 16.1

521

Schizophrenia 521 Genetic Contributions to Schizophrenia 522 Environmental Influences on Schizophrenia 523 Brain Structure and Function in Schizophrenia 524

xiii

526

Bipolar Disorder 528 Genetics and Bipolar Disorder 529 Environmental Factors and Bipolar Disorder 529 Brain Structure and Function in Bipolar Disorder 529 Biochemistry and Treatment of Bipolar Disorder 530 Major Depressive Disorder (MDD) 530 Genetic Contributions to MDD 531 Environmental Influences on MDD 531 Brain Structure and Function in MDD 531 Biochemistry of MDD 532 Treatment of MDD 534 Interim Summary 16.2

Anxiety Disorders

535

535

Obsessive-Compulsive Disorder (OCD)

536

Posttraumatic Stress Disorder (PTSD) 538 Genetics, Brain Structure, Brain Function, and Biochemistry in PTSD 538 Treatment of PTSD 540 Antisocial Personality Disorder (ASPD) Genetics and ASPD 540 Brain Structure and Function in ASPD 540 Treatment of ASPD 541 Interim Summary 16.3

Chapter Review Terms 542

●

540

542

Thought Questions ● Key

Connecting to Research: The Androgynous Brain and Mental Health 513 Neuroscience in Everyday Life: The Gut Microbiota and Mental Disorders 514 Behavioral Neuroscience Goes to Work: Applied Behavior Analysis 518 Thinking Ethically: How Do We Know Medications Work? 533

Reference R-1 Name Index I-1 Subject Index/Glossary

I-10

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Preface “[I]n teaching, you must simply work your pupil into such a state of interest in what you are going to teach him that every other object of attention is banished from his mind; then reveal it to him so impressively that he will remember the occasion to his dying day; and finally fill him with devouring curiosity to know what the steps in connection with the subject are.” —William James (1899, p. 10) James’ goals for the classroom instructor might seem lofty to some, but many of us who teach neuroscience have enjoyed the peak experience of seeing students “turn on” to the material in just the way James describes. This is an exciting time to be a neuroscientist. Every day, science newsfeeds announce some new and dramatic breakthroughs in our knowledge about the nervous system and the human mind. Important questions raised in the past now have definitive answers. In 1890, James commented that “blood very likely may rush to each region of the cortex according as it is most active, but of this we know nothing” (vol. 1, p. 99). With today’s technology, it is safe to say we now know much more than “nothing” about this phenomenon James described. Much has changed in the field of neuroscience since our first edition of this textbook in 2006. I was unprepared, however, for the extent of the changes and updates that were needed in this 5th edition. The quantity of change far exceeded that made in any of the previous updates. The following trends shaped the changes that were made: DSM-5-TR: All diagnostic criteria have been updated to reflect this latest edition of the DSM (2022). Open Science methods: Issues of statistical power and researcher degrees of freedom have affected neuroscience as much as they have other facets of science. Students need to be aware of what constitutes good methodology before they can critically evaluate the research presented in the narrative. ENIGMA, the UK Biobank, 23andMe and other large collaborations: One creative solution to the issues of expense and statistical power in neuroscience research is the formation of large collaborative working groups. Whenever available, these studies with many thousands of diverse participants were used as the basis for conclusions. Meta-analyses, mega-analyses, and systemic reviews: Another solution to the expense of running studies with

large numbers of participants is the “meta” approach. Granted, these analyses are only as good as the quality of the underlying studies, but they’re a step in the right direction. Social trends: Today’s students expect to see themselves reflected in the material they’re asked to study. While much of neuroscience qualifies as basic science, applications to everyday life are emphasized as frequently as space allows. This edition of the text has also been subject to an expert diversity, equity, and inclusion (DEI) review. More than half of the four-year universities in the United States now offer bachelor’s degrees in neuroscience, and most offer at least a minor in the discipline. Neuroscience reflects a general academic trend of the twenty-first century, in which the walls separating specializations are giving way to new, transdisciplinary research teams, courses, and educational programs. In recognition of these changes, we modified the title of the third edition of this textbook from Discovering Biological Psychology to Discovering Behavioral Neuroscience: An Introduction to Biological Psychology. This change was welcomed by our faculty and student audiences. A greater emphasis on the neurosciences in general is also achieved by renaming some chapter titles. Psychology still provides a foundation for the study of behavioral neuroscience, as without the ability to ask the right questions about behavior and mental processes, all of the technology on the planet wouldn’t do us much good. Our current behavioral neuroscience students, however, are just as likely to be preparing for careers in the health professions, biomedical engineering, or even scientific journalism as they are in psychology. A major reflection of the transdisciplinary approach exemplified by the neurosciences is the inclusion of psychology and behavioral neuroscience content in the revised edition of the Medical College Admission Test (MCAT), beginning in 2015. One hundred years ago, the leading killers of humans were infectious diseases. Today’s top killers— heart disease, diabetes, and cancer—have far stronger relationships with behavior, not only in their causes but also in their treatments. A simple five-minute conversation with a health professional about the need to quit smoking is sufficient to lead to abstention for one year by 2 percent of patients (Law & Tang, 1995). This might not sound like much, but given the 13 percent or so of American adults who smoke and the billions of dollars their health care and lost productivity represent, the stakes are high. Imagine what could be accomplished by health care providers

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Preface

who have a deep understanding of learning, motivation, and social influences on behavior. In response to these and similar trends, the current edition of the textbook explores relevant applications to students pursuing fields of study other than psychology whenever these are relevant. This fifth edition continues and expands on the goals of the previous four: • To provide challenging, current content in a student-friendly, accessible form. • To stimulate critical thinking about neuroscience by presenting controversial and cutting-edge material. • To promote active student engagement and excitement about the neurosciences. • To integrate across chapters rather than treating them as stand-alone modules, and to encourage students to see the connections among the topics. For example, connections are made between glutamate as a chemical messenger, its role in learning, the effects of psychoactive drugs on glutamate, its role in psychosis, and its importance to the causes and treatments of stroke and epilepsy.

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Pedagogical Features We realize that a course in behavioral neuroscience can be challenging for many students, particularly those who are underprepared for science courses. To make the process of mastering behavioral neuroscience concepts easier, we have included the following features: • Accessible Writing Style Many textbooks are classified by “level,” but it is my opinion that the most complex topics can be mastered by students across a wide range of preparation if the writing style is clear. Students and instructors from the community college through the top R1 universities have kindly complimented me on the accessible writing style used in this textbook. The textbook is also widely adopted in non-English-speaking countries, which suggests that the writing style is manageable for those for whom English is not a first language. • Clear, Large, Carefully Labeled Illustrations Our medical-quality anatomical illustrations help students visualize the structures and processes discussed in each part of the textbook. Behavioral neuroscience is similar to geography in its highly visual nature, and both fields require more visual aids than most other courses. The illustrations in the textbook are augmented by a set of online animations that help the student grasp processes over time, such as the propagation of action potentials down the length of an axon. • Learning Objectives and Chapter Outlines Each chapter begins with a concise set of learning objectives designed to tap into higher levels of Bloom’s taxonomy

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as well as an outline of the chapter’s content. These features assist students in planning their learning and in becoming familiar with main terms and concepts to be covered. Margin Glossaries We regularly provide marginal definitions for many difficult terms. Unlike many textbooks, we do not restrict margin definitions to key terms only. In the electronic forms of the book, these take the form of pop-up definitions. Key Terms We provide a concise list of key terms to help students focus their learning. Behavioral neuroscience can often seem more like a foreign language course than a science course, and students benefit from guidance regarding which terms should be prioritized. Interim Summaries Each chapter features two to three interim summaries where students can catch their breath and check their mastery of the material before proceeding. These summaries feature summary points keyed to the learning objectives listed at the beginning of each chapter as well as review questions. Most interim summaries also include a helpful table that pulls together key concepts from the previous section in one convenient place. Chapter Integration To emphasize how the material fits together and to promote elaborative rehearsal, we make references to other chapters relevant to the topic at hand. Chapter Review At the end of each chapter, the student will find some thought questions that can also serve as essay or discussion prompts. The Chapter Reviews also include the list of key terms. Practice Tests In the electronic version of the textbook (see the description of Infuse), practice tests will be available for each main heading with a comprehensive practice test at the end of each chapter.

Additional Features Students have told me that the narrative of the textbook is “packed” and that skimming paragraphs is usually a recipe for disaster, as each sentence counts. In defense, I respond that we have so much to say and so little room to say it in that there is little space for fluff. At the same time, psychological science shows that spaced learning is superior to massed learning, so it is a good idea to provide regular breaks in the narrative to allow students to catch their breath and digest what they have read. We like to think of these breaks as cool stepping-stones in the flow of lava. One type of break that we used in the previous editions and continue here in the fifth is the use of interim summaries that include section summary points and review questions. Most also feature tables that pull together chunks of

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

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material in a way that makes it easy to learn. Any complex field like the neurosciences entails a bit of simple, rote memorization to form a foundation for later analysis and critical thinking. The more quickly we can bring students up to speed on the basics, the faster we can move on to higher levels of discussion. Chapter summaries include thought questions designed to push students to think more actively and deeply about what they have read. In addition to the interim and chapter summaries, each chapter includes four types of features. We recognize that “boxing” material often encourages students to overlook content unless expressly instructed to read the boxes, but we trust instructors to use these in ways consistent with their personal style. Obviously, we hope that the content is sufficiently engaging that students will read the material regardless of “what’s on the test.” • Thinking Ethically features introduce controversial, contemporary questions that require the students to use the information in the chapter in critical ways. Our students will graduate to become community leaders, and they need to be able to think ethically about future cultural choices related to the neurosciences. For example, this feature in Chapter 5: Genetics and the Development of the Human Brain asks when adolescents can be held legally responsible for their actions. Chapter 10: Sexual Behavior discusses timely issues of gender and sport. In Chapter 16: Psychopathology, we consider the file drawer problem and ask how we know whether a medication actually works. • Connecting to Research features highlight either classic or very contemporary single studies in behavioral neuroscience. This provides students with a “soft” segue into the scholarly literature, which might otherwise seem somewhat intimidating. Each feature models the organization of published research by including an introduction, the research question, summaries of the methods and results, and an overview of the conclusions. The feature emphasizes the type of critical thinking and creativity required to advance science. For example, this feature in Chapter 1 explores Covid-19 relevant research demonstrating that how you think about your level of social connectivity influences your immune system to gear up to battle either viruses or bacteria. • Behavioral Neuroscience Goes to Work features expose students to some of the many real-world career paths that relate to behavioral neuroscience. In my experience, many students are unaware of a number of these options. They love the material but have no idea how they can meld this passion with their need to find employment. In this feature in Chapter 5, we describe the role of the genetics counselor, whose insights will be increasingly important as the public obtains more information about personal genotypes. As a bridge between biological sciences and the counseling

professions, this career has become increasingly popular with my students. At least a dozen who are now enrolled or who have completed genetics counseling master’s degrees attribute their career choice to my “selling” this concept in class. • Neuroscience in Everyday Life features provide an additional opportunity for students to think critically about behavioral neuroscience in the context of relatable life experiences. Students learn strategies for reducing loneliness, consider the efficacy of smartphone sleep apps, debate whether brain training is an effective strategy, and find out whether they qualify as a super-recognizer.

New Content for the Fifth Edition This new edition contains hundreds of new citations to reflect the advances in the field that have occurred since the previous edition went to press. Textbook authors are often challenged by colleagues with questions about “why do you need a new edition?” In behavioral neuroscience, this question is easy to answer: we have so much new, exciting research to share. All terminology and descriptions of mental disorders were updated to reflect the publication of DSM-5-TR in 2022. Illustrations have also been updated to reflect the new content. Because space is so precious, illustrations are viewed as “teachable moments” that expand on or further explain the narrative rather than redundant, “pretty” placeholders. We are especially proud of our medical-quality anatomical illustrations, which have been the source of much positive feedback through the previous editions. Be on the lookout for illustrations attributed to Karla Freberg, my youngest daughter. Karla has autism spectrum disorder and takes great pleasure in producing illustrations for my books. Space does not permit me to provide an exhaustive list of the updates, but here are some of the more extensive chapter-by-chapter highlights:

Chapter 1 What Is Behavioral Neuroscience? • Included new Connecting to Research topic: The effects of loneliness on the immune system. • Added descriptions of applied areas of forensic and consumer neuroscience. • Introduced organizing principles for evaluating methods: invasiveness, spatial resolution, and temporal resolution. • Added section on peripheral methods, including facial electromyography, heart rate variance, skin conductance, eye tracking, and pupil dilation. Related the

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

Preface

use of these technologies to applied fields, such as consumer neuroscience. • Added descriptions of functional near-infrared spectrometry (fNIRS), hyperscanning, EEG microstates, transcranial electrical stimulation (tES), and functional magnetic resonance spectrometry (fMRS). • Added section on Open Science related to neuroscience, including discussion of power and fMRI studies.

Chapter 2 Functional Neuroanatomy and the Evolution of the Nervous System • Covered careers in neurosurgery in Behavioral Psychology Goes to Work feature. • Covered the prediction of “dangerousness” in Thinking Ethically feature. • Covered strategies for improving heart rate variability (HRV) in Neuroscience in Everyday Life feature. • Updated Connecting to Research feature with latest work on the brain-immune system interface. • Updated information on a number of specific structures, including reticular formation, basal ganglia, and the cingulate cortex. • Updated section on neural networks. • Added further information on heart rate variability to the section on the autonomic nervous system. • Updated information on the enteric nervous system and the gut-brain axis.

Chapter 3 Neurophysiology: The Structure and Function of the Cells of the Nervous System • Added material on reactive astrocytes. • Updated terminology related to cytoskeleton to include intermediate filaments. • Updated section on kiss and run. • Clarified ligand-gated and chemically-gated terminology. • New Connecting to Research feature based on the relationship between synapse size and strength. • New Neuroscience in Everyday Life feature on prebiotics and probiotics. • Revised Behavioral Neuroscience Goes to Work feature on how EEG works.

Chapter 4 Psychopharmacology • Updated discussion of gasotransmitters. • Updated discussion of reserpine’s effects on mood. • Updated placebo section to include nocebo controls.

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• Updated/expanded section on addiction. • Updated nicotine section with information about e-cigarettes. • Added discussion of the opioid epidemic. • Updated section on cannabis and psychosis. • Expanded section on hallucinogens. • Updated discussion of alcohol j-curve. • New Neuroscience in Everyday Life feature on using hallucinogens in therapy.

Chapter 5 Genetics and the Development of the Human Brain • Updated/expanded section on transgenerational epigenetics. • Updated/expanded section on neurogenesis. • Updated/expanded cellular migration section. • Revised sections on cellular differentiation and synapse formation. • Updated/expanded section on apoptosis. • Revised sections on synapse elimination and myelination. • Revised plasticity section, including discussion of critical periods. • Added encephalocele to neural tube disorders. • Updated fetal alcohol and FASD discussion. • Updated and revised adolescent development. • Revised section on the healthy adult brain.

Chapter 6 Vision • Deleted section on protecting the eye. • Updated discussion of bipolar cell types and ganglion cells. • Further clarified discussion of receptive fields (although this is always tough). • Refreshed Thinking Ethically feature with discussion of inclusive web design. • Refreshed Neuroscience in Everyday Life with discussion of super-recognizers.

Chapter 7 Nonvisual Sensation and Perception • • • •

Updated section on hearing disorders. Updated terminology and functions of mechanoreceptors. Included the female homunculus. Updated section on pain, gustatory receptors, and synaesthesia.

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

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• Corrected information on supertasters (number of papillae is no longer considered relevant). • Refreshed Thinking Ethically feature with discussion of sonic weapons. • Revised Neuroscience in Everyday Life feature about earbuds and hearing loss.

Chapter 8 Movement • • • • • •

Updated section on aging and muscles. Updated discussion of central pattern generators. Revised section on basal ganglia. Updated section on initiation of movement. Reworked section on mirror neurons and mirror systems. Updated discussion of myasthenia gravis, polio, spinal cord injury, amyotrophic lateral sclerosis (ALS), and Parkinson disease. • Updated Thinking Ethically feature on gene doping. • Refreshed Connecting to Research feature with a discussion of the intention to move and free will. • Refreshed Neuroscience in Everyday Life feature with new information on CRISPR.

Chapter 9 Homeostasis, Motivation, and Reward • Expanded discussion of thermoreceptors. • Updated discussion of water intoxication/hyponatremia. • Updated/expanded discussion of neurochemicals and hunger/satiety. • Updated discussion of obesity. • Updated section on the causes of eating disorders. • Expanded/updated section on pleasure and reward. • Refreshed the Neuroscience in Everyday Life feature to discuss Covid-19 and fever. • Refreshed the Connecting to Research feature to cover classic work by Olds and Milner. • Refreshed Behavioral Neuroscience Goes to Work feature to cover nutritional neuroscience. • Refreshed the Thinking Ethically feature to cover the concept of “Fat But Fit.”

Chapter 10 Sexual Behavior • Added Trisomy X syndrome. • Updated discussion of 2D:4D ratio and otoacoustic emissions. • Updated discussion of sexual dimorphism in the nervous system. • Added material on gender identity and gender-conforming behavior.

• Expanded discussion of transgender and non-binary identities. • Updated cognitive differences between men and women to include data from individuals with CAH or IGD. • Added section on empathy and aggression. • Updated/expanded section on sex, gender, and psychological disorders. • Updated discussion of sexual orientation. • Updated discussion of peripartum depression. • Updated discussion of sexual interest. • Updated discussion of symmetry and “averageness” in physical attraction. • Updated discussion of MHC and attraction. • Updated discussion of oxytocin. • Updated section on sexual dysfunction. • Refreshed Thinking Ethically feature with a discussion of gender and sport.

Chapter 11 Biorhythms • Added discussion of the role of astrocytes in SCN activity. • Updated section on the cellular clocks. • Added discussion of mu waves. • Updated discussion of NREM to use the now generally accepted Stage 3, combining Stage 3 and 4. • Added discussion of sharp-wave ripples. • Revised sections on the default mode network, REM eye movements, and REM brain activity. • Revised the memory and sleep section and the dreaming section. • Added section on circadian disorders. • Discussed controversies regarding major depressive disorder with seasonal pattern, formerly known as seasonal affective disorder (SAD).

Chapter 12 Learning and Memory • Added material on social learning • Expanded and clarified discussion of long-term potentiation (LTP) • Updated spatial learning and LTP section. • Revised section on memory updating. • Added information on engram cells. • Updated sections on systems supporting different types of learning and memory. • Separated sections on the effects of stress and healthy aging on memory. • Updated the discussion of stress effects on memory.

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

Preface

• Updated Behavioral Neuroscience Goes to Work feature on neuroeducation. • Revised Neuroscience in Everyday Life feature to ask whether brain training really works.

Chapter 13 Cognitive Neuroscience • Added introductory section on consciousness and disorders of consciousness. • Updated section on lateralization, including development, emotion, music, and gender. • Added information about language and self-domestication. • Updated information about genetics and the origins of language. • Updated sections on language models, multilingualism, dyslexia, and stuttering. • Updated section on intelligence, including network neuroscience and artificial intelligence. • Updated section on decision making. • Refreshed Neuroscience in Everyday Life to cover consumer neuroscience.

Chapter 14 Social and Affective Neuroscience • Changed the title to reflect current terminology in neuroscience. • Simplified coverage of classic emotion models and added discussion of primal versus constructed emotion and emotion versus reason. • Updated discussion of universal emotions and cultural contributions to emotion. • Updated emotion regulation section. • Expanded section of aggression and violence to distinguish more clearly between proactive and reactive aggression. • Updated biochemistry of aggression section to include cortisol/testosterone interactions. • Added new section on social neuroscience, with subsections on social cognition and empathy, prejudice, and loneliness. • Refreshed Behavioral Neuroscience Goes to Work feature with information on forensic neuropsychology. • Refreshed Neuroscience in Everyday Life feature with information on reducing loneliness.

Chapter 15 Neuropsychology • Updated all sections using terminology and content from DSM-5-TR. • Added section on frontotemporal neurocognitive disorder.

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• Added section on neurocognitive disorder with Lewy bodies. • Updated sections on neuropsychological assessment. • Discussed controversies over the amyloid hypothesis of Alzheimer disease. • Updated genetics, cellular correlates, and network effects of Alzheimer disease. • Updated section on treatment of stroke. • Updated traumatic brain injury (TBI) section, especially material on military blast TBI, repeated TBI (chronic traumatic encephalopathy), and treatments of TBI. • Updated section on neurocysticercosis. • Added section on cognitive outcomes of SARS-CoV-2. • Updated section on multiple sclerosis. • Distinguished between functional and structural neuroplasticity in rehabilitation. • Distinguished between near and far transfer in rehabilitation. • Refreshed Thinking Ethically feature to cover the amyloid hypothesis in Alzheimer disease. • Refreshed Connecting to Research feature with key prion paper by Stanley Prusiner.

Chapter 16 Psychopathology • Updated all terminology and content based on DSM-5-TR. • Expanded discussion of mental disorder terminology to include disorder, disability, disease, and difference. • Distinguished between familial heritability and SNPbased heritability. • Expanded general discussion of anxiety. • Refreshed Connecting to Research feature to cover the androgynous brain and mental health (one of the toprated papers of 2021). • Refreshed Thinking Ethically feature to discuss how we know when medications work. • Refreshed the Neurscience in Everyday Life feature with a discussion of the gut microbiota and mental disorders.

Cengage Infuse Cengage Infuse for Discovering Behavioral Neuroscience 5e is the first-of-its-kind digital learning platform that leverages Learning Management System (LMS) functionality so instructors can enjoy simple course set-up and intuitive management tools. No need to learn a new technology; utilize the familiar functionality of your LMS and use content as-is from day one.

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

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The dynamic Cengage ebook empowers students to read, highlight, take notes, and/or listen to the full textbook online. Bringing the value, concepts, and applications of the printed test to life, the ebook is available not only through the LMS but is also accessible through the Cengage mobile app.

Instructor Ancillaries Online Instructor’s Manual: The manual includes learning objectives, key terms, a detailed chapter outline, a chapter summary, lesson plans, discussion topics, student activities, media tools, a sample syllabus, and an expanded test bank. The learning objectives are correlated with the discussion topics, student activities, and media tools. Online PowerPoints: Helping you make your lectures more engaging while effectively reaching your visually oriented students, these handy Microsoft PowerPoint® slides outline the chapters of the main text in a classroom-ready presentation. The PowerPoint® slides are updated to reflect the content and organization of the new edition of the text. Cengage Learning Testing, Powered by Cognero®: Cengage Learning Testing, Powered by Cognero®, is a flexible online system that allows you to author, edit, and manage test bank content. You can create multiple test versions in an instant and deliver tests from your LMS in your classroom.

Acknowledgments I view this text as a work in progress. Please take a moment to share your thoughts and suggestions with me: lfreberg@ calpoly.edu. You can also find me on Facebook, on Twitter as @biopsych, and on my blog: http://www.laurafreberg .com/blog. I am happy to Zoom in to classrooms to help with a lecture or two (Vision seems to be one topic faculty are happy to hand off). I can also share my own recorded lectures for my students. I am enormously grateful for the team that Cengage assembled to help make this book a reality. First, I would like to thank my professional colleagues who reviewed the many drafts of one or more of the five editions: John Agnew, University of Colorado at Boulder James E. Arruda, Mercer University Giorgio Ascoli, George Mason University Ronald Baenninger, Temple University Aileen Bailey, St. Mary’s College of Maryland Jeffrey S. Bedwell, University of Central Florida Steve Bradshaw, Bryan College Virginia Bridwell, Bellevue College Gayle Brosnan-Watters, Slippery Rock University

John P. Bruno, Ohio State University Allen E. Butt, Indiana State University Deborah Carroll, Southern Connecticut State University David A. Cater, John Brown University James Chrobak, University of Connecticut, Storrs Cynthia Cimino, University of South Florida James R. Coleman, University of South Carolina Sherry Dingman, Marist College Aaron Ettenberg, University of California, Santa Barbara Bob Ferguson, Buena Vista University Thomas M. Fischer, Wayne State University John P. Galla, Widener University Cynthia Gibson, Creighton University Ben Givens, Ohio State University Karen Glendenning, Florida State University C. Hardy, Columbia College James G. Holland, University of Pittsburgh Richard Howe, College of the Canyons Joyce Jadwin, Ohio University Robert A. Jensen, Southern Illinois University Katrina Kardiasmenos, Bowie State University Joshua Karelitz, Pennsylvania State University, New Kensington Camille Tessitore King, Stetson University Norman E. Kinney, Southeast Missouri State University Paul J. Kulkosky, Colorado State University Pueblo Gloria Lawrence, Wayne State College Simon Levay Charles F. Levinthal, Hofstra University David R. Linden, West Liberty State College Michael R. Markham, Florida International University Richard Mascolo, El Camino College Robert Matchock, Penn State University, Altoona Janice E. McPhee, Florida Gulf Coast University Jody Meerdink, Nebraska Wesleyan University Melinda Meszaros, Clarke College Maura Mitrushina, California State University Northridge Robert R. Mowrer, Angelo State University Mark Nawrot, North Dakota State University Irene Nielsen, Bethany College, Lindsborg Terry Pettijohn, Ohio State University, Marion David W. Pittman, Wofford College Joseph H. Porter, Virginia Commonwealth University Jerome L. Rekart, Rivier College John C. Ruch, Mills College Ronald Ruiz, Riverside City College Lawrence J. Ryan, Oregon State University Carl Samuels, Glandale Community College Anthony C. Santucci, Manhattanville College Virginia F. Saunders, San Francisco State University Royce Simpson, Spring Hill College Don Smith, Everett Community College Marcello Spinella, Richard Stockton College of New Jersey Sheralee Tershner, Western New England College C. Robin Timmons, Drew University Barbara Vail, Rocky Mountain College

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

Preface

Rachael Volokhov, Kent State University, Salem Dana Wallace, Jamestown College Linda L. Walsh, University of Northern Iowa Frank M. Webbe, Florida Institute of Technology Kimberly Wear, High Point University Stephen P. Weinert, Cuyamaca College Yeuping Zhang, Lewis and Clark College Margaret H. White, California State University Fullerton Xiojuan Xu, Grand Valley State University Robert M. Zacharko, Carleton University Phillip Zoladz, Ohio Northern University The many instructors who responded to market research surveys and interviews over the past several years have also contributed greatly to the text and its ancillaries. I would like to give a special thank you to several colleagues. Jason Spiegelman of the Community College of Baltimore County provided patient and thoughtful insights with his thorough review of issues related to diversity, equity, and inclusion. He also included the occasional side comment guaranteed to make me smile. Skirmantis Janusonis of the University of California, Santa Barbara, has provided not only encouragement but also gentle suggestions for improved accuracy. Skirmantis kindly provided me with an opportunity to photograph some of his human brains (one appears in Chapter 1), and he shared an image of his fantastic dissection of the hippocampus for us to use in Chapter 2. Simon LeVay is a gifted researcher and a truly elegant writer. His careful review of the chapter on sexual behavior for the first edition is deeply appreciated. I am indebted to Simon for pointing out many important studies included in the sections on sexual orientation and gender differences in cognition. Marie Banich at the University of Colorado at Boulder provided her expert opinions on the art program, and Gayle Brosnan-Watters at Arizona Christian University contributed many helpful suggestions as a reviewer and while working with me on an earlier edition of the Test Bank. John Cacioppo

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of the University of Chicago generously shared his considerable insight into the social aspects of neuroscience. Konstantinos Priftis of the University of Padova supplied several helpful corrections to the second edition. Robert Matchock of the University of Pennsylvania, Altoona, has been a friendly voice of encouragement beginning with the first edition. The late Larry Butcher of UCLA, one of my former professors, provided valuable assistance in the fine-tuning of my cholinergic pathway image in Chapter 4. Rick Howe and the students and faculty of the psychology department at College of the Canyons in California not only took the time to meet with me to share their reactions to the first edition but fed me cookies as well. At Cengage, Colin Grover, Cazzie Reyes, and Marta Healey-Gerth product managers for psychology, championed my text through this edition. Tricia Hempel, senior content manager for this fifth edition, was my sounding board and partner every step of the way. Sara Greenwood, art director, guided our design to new heights in appeal and usability. One faculty adopter referred to the design as “Steve Jobs-esque,” which we view as the ultimate compliment. I would also like to thank the many other capable and creative professionals at Cengage who contributed to this project in ways large and small over the years of its development. Finally, I would like to thank my family for their patience and support. Roger, my husband of 50 years, read every word, helped me choose photos, and even contributed some of our original sketches when I had trouble articulating what I wanted to show. My daughters, Kristin, Karen, and Karla, frequently offered their encouragement and perspectives. As I mentioned earlier, my daughter Karla enthusiastically contributed a number of illustrations to the book. My Australian shepherds, Ronnie and Rosie, waited patiently by my desk until it was time to clear the mind with a walk through some beautiful San Luis Obispo scenery. I am very much indebted to all. Laura A. Freberg

Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

Chapter 1 Learning Objectives L01

Classify the subfields of neuroscience and explain how behavioral neuroscience fits within the field.

L02

Interpret the significance of the major historical highlights in the study of the nervous system.

L03

L04

L05

L06

Differentiate the brain imaging technologies, including CT, PET, SPECT, MRI, fMRI, fNIRS, and DTI. Assess the use of microscopic, peripheral, recording, hyperscanning, stimulation, optogenetic, lesion, and biochemical methods in behavioral neuroscience. Analyze the relative strengths and weaknesses of twin studies, adoption studies, and molecular genetics for understanding behavior.

What Is Behavioral Neuroscience? Chapter Outline Neuroscience as an Interdisciplinary Field Historical Highlights in Neuroscience

Ancient Milestones in Understanding the Nervous System The Dawn of Scientific Reasoning Modern Neuroscience Begins

Interim Summary 1.1 Behavioral Neuroscience Research Methods

Microscopic Methods Peripheral Methods Imaging Recording

Hyperscanning Brain Stimulation Lesion Biochemical Methods Genetic Methods Interim Summary 1.2 Open Science and Research Ethics in Behavioral Neuroscience

Open Science Human Participant Guidelines Animal Subject Guidelines

Interim Summary 1.3 Chapter Review

Evaluate the contributions of open science approaches and ethical research practices to progress in behavioral neuroscience. Connecting to Research: Thinking About Yourself as Lonely or Socially Connected Can Influence Your Immune System Behavioral Neuroscience Goes to Work: What Can I Do with a Degree in Neuroscience? Thinking Ethically: Can We Read Minds with Neuroscience Technologies? Neuroscience in Everyday Life: Can Brain Stimulation Improve My Memory? 1

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What Is Behavioral Neuroscience?

Neuroscience is the interdisciplinary study of the nervous system, whose ultimate goal is to understand brain and nervous system function and neurological disease at many levels (UCLA, 2021). The term “neuroscience” was coined by Francis O. Schmitt, who established MIT’s Neurosciences Research Program in 1962. Neuroscientists strive to understand the functions of the brain and nervous system across several levels of analysis, using molecular, cellular, synaptic, network, computational, and behavioral approaches (refer to Figure 1.1). You might think of this field as analogous to Google Earth. We can zoom in to observe the tiniest details and then zoom back out again to get the “big picture.” Beginning at the most microscopic stage, the molecular neuroscientist explores the nervous system at the level of the molecules that serve as its building blocks. We will cover their work in our chapters on neural cell physiology (Chapter 3), psychopharmacology (Chapter 4), and genetics (Chapter 5). Starting with DNA, RNA, and the proteins resulting from gene expression, the molecular neuroscientist attempts to understand the chemicals that build the system and make neural functioning possible. Zooming out just a bit from the molecular level of analysis, we find the cellular neuroscientist hard at work outlining the structure, physiological properties, and functions of single cells found within the nervous system. These isolated cells would be of no use unless they could forge connections, which they do at junctions we call synapses. Synaptic neuroscience examines the strength and flexibility of neural connections, which underlie complex processes such as learning and memory. Beyond the single synapse, we find that interconnected neurons form pathways or networks. In contemporary neuroscience, we are experiencing a move away from the idea that “this structure engages in this function” to ideas that more accurately reflect neural networks. We are more likely to say that “this structure participates in a network connecting these other structures to engage in this type of processing.” Zooming out to perhaps the most global point of view, we find behavioral neuroscience, also known as biological psychology, which is the primary focus of this textbook. Behavioral neuroscientists use all the previous levels of analysis, from the molecular up through

neuroscience The interdisciplinary study of the nervous system, whose ultimate goal is to understand brain and nervous system function and neurological disease at many levels. behavioral neuroscience/biological psychology The study of the biological correlates of behavior, emotions, and mental processes.

Figure 1.1 The Neurosciences: Building from Molecule to Behavior

Behavioral

Network

Synaptic

Computational

iStock.com/Henrik5000

Neuroscience as an Interdisciplinary Field

Cellular

Molecular

Courtesy of Laura Freberg

Chapter 1

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the network, in their efforts to understand the biological correlates of behavior. The relationship between biology and behavior is reciprocal—biology can impact our behavior, and behavior, including your thoughts and emotions, impacts biology. The experiment described in the Connecting to Research feature illustrates this reciprocal relationship. The way you think about your degree of social connection to others can influence your immune system’s response to viruses and bacteria. Like the neurosciences in general, behavioral neuroscience looks at the activity of the nervous system in health and in cases of illness, injury, and psychological disorder. Subspecialties within behavioral neuroscience include cognitive neuroscience, or the study of the biological correlates of information processing, learning and memory, decision making, and reasoning. We investigate these topics in depth in the chapters on sensation and perception

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Neuroscience as an Interdisciplinary Field

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Connecting to Research Thinking About Yourself as Lonely or Socially Connected Can Influence Your Immune System The Question: Does loneliness affect the functions of the immune system?

One of the key aspects of behavioral neuroscience that we introduce in this chapter is the reciprocal nature of the relationship between biology and behavior. Most of us are quite familiar and comfortable with the idea that our biology can influence our behavior, but the influence of behavior on biology is perhaps less obvious. Cole et al. (2015) describe the remarkable influence our perception of social isolation has on the actions of our immune system. Before we explore this research, please consider the following questions and rate them on a scale from 1 (never) to 4 (often). How often do you:

Method The researchers took blood samples and administered standard assessments of loneliness to 108 older adults. The blood samples were used to analyze relative expression of immune system genes.

Results Once loneliness is perceived, it begins a cascade of responses, many of which are well below the threshold of conscious awareness. Cole et al. (2015) established that people responded to loneliness by downgrading their immune responses to viruses while gearing up their responses to bacteria.

1. Feel that you lack companionship? 2. Feel left out? 3. Feel isolated from others? Your total score should be somewhere between 3 and 12, with 10 being the cut-off for high loneliness (Hughes et al., 2004). If your score is on the high side, please note that high loneliness is typical among young adults. Also note that loneliness is a perception of isolation, not necessarily reality. Some people surrounded by friends and loved ones can still feel lonely while others are content with a pet.

Azndc/Getty Images

Conclusions

Figure 1.2 Biology and Behavior Form Reciprocal Relationships. Feeling lonely changes the way your immune system behaves.

(Chapters 6 and 7), learning and memory (Chapter 12), and cognition (Chapter 13). Social and affective neuroscience, covered in Chapter 14, explores the interactions between the nervous system, emotions, and our human social environment and behavior. In addition to basic laboratory research, behavioral neuroscience also features many practical applications. Chapters 15 and 16 explore the assessment and treatment

As we know all too well from the Covid-19 pandemic, viruses love close contact. This means that socially connected people are at greater risk from viruses. In contrast, among our hunter-gatherer ancestors, isolated humans were more exposed to predators and hostile humans, putting them at greater risk from bacteria entering the body through cuts and scrapes. Over the millennia, our perceptions of our social connectivity acquired the ability to signal our immune systems to address the greater threat. It is ironic that the very same preventive measures used during the Covid-19 pandemic, such as social distancing, stay-at-home, and lockdowns, could have reduced our immune system’s ability to fight the virus by increasing loneliness. If your loneliness score was on the high side, do not despair. Many steps can be taken to reduce loneliness, such as initiating small conversations with people you meet every day, like the barista who makes your coffee. A number of these small interactions can provide the same sense of human connectivity as one or two deep connections.

of neurological and psychological disorders from the neuroscience perspective. Forensic neuroscience applies neuroscience principles to the understanding and management of criminal behavior. Neuroeducation attempts to improve the educational experience based on our understanding of how the brain learns. Consumer neuroscience and neuroeconomics focus on the biological correlates of choice. Organizational neuroscience seeks to illuminate

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Chapter 1

What Is Behavioral Neuroscience?

the biological underpinnings of group performance and leadership. Health neuroscience incorporates the “mind” into the overall understanding of physical health. Finally, behavioral neuroscience has enjoyed a productive and exciting relationship with robotics and artificial intelligence. Computational neuroscience runs parallel to the types of neuroscience described so far, but it draws from computer science, electrical engineering, mathematics, and physics to produce models of the nervous system from the molecular level up through the behavioral level of analysis. The predictions from these computational models can then be tested against living systems, forming a cooperative symbiosis with researchers in other areas of neuroscience. One of the practical applications of computational neuroscience is the use of neural decoding, or the use of neural activity to estimate what the brain is doing, in the development of sophisticated prosthetic devices. These devices can use neural activity to figure out the brain’s intentions to move in certain ways or perceive certain types of input as touch.

These various levels of analysis complement rather than compete with one another. Because of the diversity of skills needed to pursue each of these approaches, neuroscience is an interdisciplinary field of study, reaching across the traditional academic departments of biology, chemistry, psychology, medicine, mathematics, physics, engineering, statistics, and computer science. The need for a better understanding of the nervous system has never been greater. In 2017, about 200 million Americans (about 60% of the population) experienced at least one neurological condition, ranging from tension headaches and migraines to strokes and dementia (GBD 2017 US Neurological Disorders Collaborators, 2021). The cost of these conditions in terms of health care and lost productivity is close to $800 billion (Gooch et al., 2017). Connections between biology and behavior are not just relevant to neurological disease. They also inform our understanding of health in general. Compared to 100 years ago, when most people died from infectious diseases, today’s killers (cancer, diabetes, heart disease) are tightly linked to behavior. Reflecting the recognition

Behavioral Neuroscience Goes to Work What Can I Do with a Degree in Neuroscience? One of the pleasures of teaching courses in behavioral neuroscience occurs when a student suddenly falls in love with the field. “This is for me,” the student might say, but the question that usually follows is, “But how can I make a living doing this?” The answers to this question are as diverse as the field. Because neuroscience is so broad, opportunities can be found down many different paths. Like many other fields, neuroscience has more opportunities for people with more education. Many practicing neuroscientists have medical degrees, PhDs, or both. This does not mean that jobs are unavailable for people with undergraduate degrees, however. People with undergraduate degrees can be employed as research assistants in pharmaceutical firms, universities, and government agencies. Some neuroscience graduates work in substance abuse counseling or in mental health facilities. Neuroscience is used in some unexpected places as well. A growing trend in advertising agencies is to use brain imaging and other technologies to gauge public reactions to advertising. Web and application designers use eye-tracking technology to evaluate the user experience (UX), such as whether a person processes the important features of a webpage and has an enjoyable time while doing so. The ongoing burst in neuroscience technologies is likely to continue to shape the field, and additional

opportunities are likely to emerge. In the meantime, any student interested in neuroscience would benefit from gaining the best possible skills in general science, research methods, mathematics, and statistics.

MONOPOLY919/Shutterstock.com

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Figure 1.3 Consumer Neuroscience One of the possible careers associated with neuroscience is the application of neuroscience principles and methods to understanding purchase choices made by consumers. This augmented reality technology might help retailers predict the effects of product display on consumer attention and action.

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Historical Highlights in Neuroscience

of the role of behavior in illness, the standardized Medical College Admission Test (MCAT) for medical school applicants now contains a sizable number of questions about psychology and behavioral neuroscience. Illness is only part of the human equation. We also need to understand how the nervous system responds in typical ways to promote well-being, including better relationships, better parenting, better child development, and better thinking and learning. Through improved understanding of the nervous system and its interactions with behavior, scientists and practitioners will be more thoroughly prepared to tackle the significant challenges to health and well-being faced by contemporary world populations.

Historical Highlights in Neuroscience The history of neuroscience parallels the development of tools for studying the nervous system. Early thinkers made progress despite limited scientific methods and technologies.

Ancient Milestones in Understanding the Nervous System Our earliest ancestors had at least a rudimentary understanding about the brain’s essential role in maintaining life. Archaeological evidence of brain surgery suggests that as many as 7,000 years ago, people tried to cure others by drilling holes in the skull, a process known as trephining or trepanation (refer to Figure 1.4). Because some skulls

Figure 1.4 Prehistoric Brain Surgery

New York Public Library/Science Source

As far back in history as 7,000 years ago, people used trepanation (trephining), or the drilling of holes in the skull, perhaps to cure “afflictions” such as demonic possession. Regrowth around some of the holes indicates that at least some of the patients survived the procedure. More recently, trephining has resurfaced as a DIY (do it yourself) process, possibly as a type of self-injurious behavior.

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have been located that show evidence of healing following the drilling procedure, we can assume that the patient lived through the procedure and that this was not a postmortem ritual. What is less clear is the intent of such surgeries. Possibly, these early surgeons hoped to release demons or relieve feelings of pressure (Clower & Finger, 2001). The Edwin Smith Surgical Papyrus (about 1600 BCE) represents the oldest known medical writing in history, yet it features many sophisticated observations (Breasted, 1930). The Egyptian author of the Papyrus clearly understood that paralysis and a lack of sensation in the body resulted from nervous system damage. Cases of nervous system damage were usually classified as “an ailment not to be treated,” indicating the author’s understanding of the relatively permanent damage involved. Building on the knowledge taken from ancient Egypt, the Greek scholars of the fourth century BCE proposed that the brain was the organ of sensation. Hippocrates (460–379 BCE) correctly identified epilepsy as originating in the brain, although the most obvious outward signs of the disorder were muscular convulsions (refer to Chapter 15). Galen (130–200 CE), a Greek physician serving the Roman Empire, made careful dissections of animals (and we suspect of the mortally wounded gladiators in his care as well). Galen believed erroneously that the ventricles played an important role in transmitting messages to and from the brain, an error that influenced thinking about the nervous system for another 1,500 years (Aronson, 2007).

The Dawn of Scientific Reasoning The French philosopher René Descartes (1596–1650) argued in favor of mind–body dualism. For Descartes and other dualists, the mind is neither physical nor accessible to study through the natural sciences. In contrast, the modern neurosciences are based on monism rather than dualism. The monism perspective proposes that the mind is the result of activity in the brain, which can be studied scientifically. Descartes’s ideas were very influential, and even today, some people struggle with the idea that factors such as personality, memory, and logic simply represent the activity of neurons in the brain. Later in the chapter, our discussion of research ethics presents another legacy of Descartes’s ideas. Because many shared his view of animals as mechanical, not sentient, beings, experiments were carried out on animals that seem barbaric to many modern thinkers. In 1865, Claude Bernard (1813–1878) wrote that “the science of life is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen” (Bernard, 1865/1927, p. 15). Between 1500 and 1800, scientists made considerable progress in describing the structure and function of the nervous system. The invention of the light microscope by Anton van Leeuwenhoek in 1674 opened a whole new level of analysis. Work by Luigi Galvani and

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Chapter 1

What Is Behavioral Neuroscience?

Emil du Bois-Reymond established electricity as the mode of communication used by the nervous system (refer to Figure 1.5). British physiologist Charles Bell (1774–1842) and French physiologist François Magendie (1783–1855) demonstrated that information travels in one direction, not two, within sensory and motor nerves.

Modern Neuroscience Begins As late as the beginning of the twentieth century, many scientists, including Italian researcher Camillo Golgi, continued to support the concept of the nervous system as a vast, interconnected network of continuous fibers. Others, including the Spanish anatomist Santiago Ramón y Cajal, argued that the nervous system was composed of an array of separate, independent cells, like the one he illustrated in Figure 1.6. Cajal’s concept is known as the Neuron Doctrine. Golgi and Cajal shared the Nobel Prize for their work in 1906. Ironically, Cajal used a stain invented by Golgi to prove that Golgi was incorrect. The road to our current understanding of the nervous system has not been without its odd turns and dead ends. The notion that specific body functions are controlled by certain areas of the brain, called localization of function, began with an idea proposed by Franz Josef Gall (1758–1828) and elaborated on by Johann Gasper Spurzheim (1776–1832). These otherwise respectable

scientists proposed a “science” of phrenology that maintained that the structure of people’s skulls could be correlated with their individual personality characteristics and abilities. A phrenologist could “read” a person’s character by comparing the bumps on that person’s skull to a bust showing the supposed location of each trait (refer to Figure 1.7). Although misguided, Gall and Spurzheim’s work did move us away from the metaphysical, nonlocalized view of the brain that had persisted from the time of Descartes. Instead, Gall and Spurzheim proposed a more modern view of the brain as the organ of the mind, composed of interconnected, cooperative, yet relatively independent functional units. Further evidence in support of the localization of function in the brain began to accumulate. In the mid1800s, a French physician named Paul Broca correlated the damage he observed in patients with their behavior and concluded that language functions were localized in the brain (refer to Chapter 13). Incidentally, it was also Broca who brought the practice of trepanation, described earlier in this chapter, to the attention of the scientific community (Clower & Finger, 2001). In 1870, Gustav Theodor Fritsch (1838–1927) and Eduard Hitzig (1838–1907) described how electrically stimulating the cortex of a rabbit and a dog produced movement on the opposite side of the body. The localization of function in the brain became a generally accepted concept.

Figure 1.5 Luigi Galvani Demonstrated a Role for Electricity in Neural Communication

The Print Collector/Heritage Images/Alamy Stock Photo

Luigi Galvani and his wife Lucia Galeazzi Galvani discovered that electrical stimulation would contract the leg muscles of frogs. Their experiments not only established an understanding of the electrical nature of neural communication but also inspired Mary Shelley to write Frankenstein.

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Historical Highlights in Neuroscience

Figure 1.6 Improvements in Microscopic Methods Opened a New World Santiago Ramón y Cajal used microscopic stains developed by his rival, Camillo Golgi, to view single nerve cells. These observations supported Cajal’s Neuron Doctrine, which states that the nervous system is made from individual cells, like the one illustrated in Cajal’s beautiful drawing of a Purkinje cell from the human cerebellum.

executive functions. When a person consumes alcohol, however, the cortical inhibition might fail, leaving the lower parts of the brain to initiate a bar fight. We will meet Hughlings Jackson again in Chapter 15, in which his contributions to the understanding of epilepsy will be discussed. Progress in the neurosciences over the past 100 years accelerated rapidly as new methods became available for studying the nervous system. Charles Sherrington not only coined the term synapse (defined as the point of communication between two neurons) but also conducted extensive research on reflexes and the motor systems of the brain (refer to Chapter 8). Otto Loewi demonstrated chemical signaling at the synapse (refer to Chapter 3) using an elegant research design that he claims came to him while asleep. Sir John Eccles, Bernard Katz, Andrew Huxley, and Alan Hodgkin furthered our understanding of neural communication. You will meet many more contemporary neuroscientists as you read the remainder of this text. The ranks of neuroscientists continue to grow, with membership in the Society for Neuroscience expanding from 500 members in 1969 to approximately 36,000 members in 95 countries as of 2022 (Society for Neuroscience, 2022).

Figure 1.7 Phrenology Bust Franz Josef Gall and his followers used maps like this one to identify traits located under different parts of the skull. Bumps on the skull were believed to indicate that the underlying trait had been “exercised.” Although Gall’s system was an example of bad science, the underlying principle that functions could be localized in the brain turned out to be valuable.

More support for the mind’s physical, nonmystical nature was provided by physiologists and psychophysicists (refer to Chapters 6 and 7). Hermann von Helmholtz (1821–1894) demonstrated that the mind has a physical basis by asking participants to push a button as soon as they felt a touch. The participants reacted faster when their thigh was touched than when their toe was touched because the more distant signal from the toe would take more time to reach the brain. The founding of modern neuroscience has often been attributed to the British neurologist John Hughlings Jackson (1835–1911). Hughlings Jackson proposed that the nervous system was organized as a hierarchy, with simpler processing carried out by lower levels and more sophisticated processing carried out by higher levels, such as the cerebral cortex. For example, we normally inhibit aggressive behaviors, associated with activity in lower levels of the brain, by engaging our higher cortical Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

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Santiago Ramón y Cajal/Wikimedia Commons

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Chapter 1

What Is Behavioral Neuroscience?

Interim Summary 1.1 Summary Points 1.1 1. Neuroscience is the field that explores the structures, functions, and development of the nervous system in illness and in health. Behavioral neuroscience is the branch of the neurosciences that studies the correlations between the structures and functions of the nervous system and behavior. (LO1) 2. Although some periods of enlightenment regarding the relationship between the nervous system and behavior emerged among the Egyptians and Greeks, the major advances in behavioral neuroscience required technological innovation and have been relatively modern. (LO2)

3. Highlights in the neuroscience timeline include discoveries regarding the electrical and chemical nature of neural communication, the control of sensation and motor functions by separate nerves, the role of single cells as building blocks for the nervous system, and the localization of functions in the brain. (LO2) Review Questions 1.1 1. How would you describe the goals and methods of the interdisciplinary field of neuroscience? 2. What historical discoveries contributed to our modern understanding of the brain and behavior? Which concepts actually led us in the wrong direction?

Summary Table 1.1: Highlights in the Neuroscience Timeline Historical Period

Significant Highlights and Contributions

Ca. 3000 BCE

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Ca. 400 BCE− 200 CE

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1600–1800

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Galen makes accurate observations from dissection; however, he believed erroneously that fluids transmitted messages. René Descartes suggests mind-body dualism.

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Anton van Leeuwenhoek invents the light microscope.

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Galvani and du Bois-Reymond discover that electricity transmits messages in the nervous system.

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Bell and Magendie determine that neurons communicate in one direction and that sensation and movement are controlled by separate pathways. Gall and Spurzheim make inaccurate claims about phrenology, but their notion of the localization of function in the nervous system is accurate.

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Paul Broca discovers the localization of speech production.

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Fritsch and Hitzig identify the localization of motor function in the cerebral cortex.

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1900–Present

Hippocrates recognizes that epilepsy is a brain disease.

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1800–1900

Egyptians discard brain during mummification process; however, published case studies indicate accurate observations of neural disorders.

Ramón y Cajal declares that the nervous system is composed of separate cells; he shares the 1906 Nobel Prize with Camillo Golgi. John Hughlings Jackson explains brain functions as a hierarchy, with more complicated functions carried out by higher levels of the brain.

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Charles Sherrington coins the term synapse; he wins the Nobel Prize in 1932.

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Otto Loewi demonstrates chemical signaling at the synapse; he wins the Nobel Prize in 1936.

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Sir John Eccles, Andrew Huxley, and Alan Hodgkin share the 1963 Nobel Prize for their work in advancing our understanding of the way neurons communicate.

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Bernard Katz receives the 1970 Nobel Prize for his work on chemical transmission at the synapse.

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Society for Neuroscience counts about 36,000 members in 2022.

Behavioral Neuroscience Research Methods The methods described in this section have helped neuroscientists discover the structure, connections, and functions of the nervous system and its components. From the

level of single molecules to the operation of large parts of the nervous system, we now can make detailed observations that would likely astonish the early pioneers of neuroscience. The choice of methods depends very much on the goals and research questions of the neuroscientist. Each method has its share of strengths and weaknesses, but the use of multiple methods to answer a single

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Behavioral Neuroscience Research Methods

research question can usually compensate for any gaps in a particular method. Neuroscience methods differ along several dimensions (refer to Figure 1.8). First, we evaluate methods based on invasiveness, or the amount of harm associated with a method. A method that requires surgery, for example, is more invasive than one that does not. Methods also vary in the quality of their spatial and temporal resolution. A method with good spatial resolution will provide detailed structural images, while a method with good temporal resolution will provide information without delay. These factors are especially important in behavioral neuroscience as we often want to correlate a localized neural response with a stimulus.

Microscopic Methods Microscopic, or histological, methods provide the means for observing the structure, organization, and connections of individual cells. The naked eye can perceive objects that are at least 0.2 mm in size. To see anything smaller requires

Figure 1.8 Comparing Neuroscience Methods We can compare neuroscience methods along the dimensions of invasiveness, spatial resolution, and temporal resolution to find the best choice for our research question. Invasiveness refers to the amount of harm associated with a method. Intracranial electroencephalograms (IEEG) require surgery, so they are at the higher end of invasiveness. In contrast, electroencephalograms, taken with surface electrodes, are non-invasive. Methods with good spatial resolution (lower numbers of millimeters between dots that can be distinguished) provide better detail. Methods with good temporal resolution (fewer seconds between a neural event and its recording) allow researchers to more easily correlate neural events with their recordings in time. Invasiveness 20 15 Millimeters

Spatial Resolution

EEG

10

MRS

5 0

fMRI

IEEG MEG .001

.01

SPECT

.1

1.0

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magnification (refer to Figure 1.9). Magnification alone does not guarantee a clear image, however, as you probably have noticed when you’ve zoomed in on an image on your computer. You just get the same blurry image with bigger pixels. Our ability to see small structures also depends on spatial resolution, or the ability to tell two points of light apart. Overcoming the natural scatter of light within the tissue being observed, which makes the image look blurry, is the main challenge of all microscopic technologies. Today’s light microscope can magnify an image 1,000 times while maintaining adequate spatial resolution, allowing scientists to observe a feature as small as a synapse. Because of the way our visual systems process visible light, discussed in Chapter 6, using a light microscope to magnify images beyond about 1,000 times compromises resolution to an unacceptable degree. Fortunately, other methods have been discovered that maintain both high levels of magnification and resolution. Electron microscopy can resolve images at the level of the nanoscopic scale, or between 1–100 nanometers. A nanometer is one billionth of a meter. In other words, these methods are about one million times more powerful than the naked eye. Before using either light or electron microscopy, tissue must be prepared for viewing in a series of steps. Tissue must be thin enough to allow light (or electrons) to pass through it without too much scatter. Brain tissue is fragile and somewhat watery, which makes the production of thin enough slices impossible without further treatment. To solve this problem, the first step in the histological process is to “fix” the tissue, either by freezing it, dehydrating it, or treating it with formalin, a liquid containing the gas formaldehyde. Formalin not only hardens the tissue, making it possible to produce thin slices, but it also preserves the tissue from breakdown by enzymes or bacteria. Freezing the tissue accomplishes these objectives as well. The resulting samples can be embedded in gelatin, paraffin wax, or plastic to provide further stability and ease of slicing. Once tissue is fixed, it is sliced or “sectioned” by a special machine known as a microtome (refer to Figure 1.10). Some microtomes look and work like a miniature version of the meat slicers found in most delicatessens. The tissue is pushed forward while a sliding blade moves back and forth across the tissue, producing slices. Other microtomes use a vibrating knife, similar to your electric toothbrush. These are particularly useful when sectioning tissue that is not frozen. For viewing tissue under the light microscope, tissue slices between 10 and 80 μm (micrometers) thick are prepared. A micrometer is one one-millionth of a meter or one

PET 100 1000

Seconds Temporal Resolution Source: MIT http://web.mit.edu/kitmitmeg/whatis.html Figure 5

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invasiveness A measure of the degree of harm involved with a method. spatial resolution The ability to see fine detail in an image. temporal resolution The ability to obtain information without delay.

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Chapter 1

What Is Behavioral Neuroscience?

one-thousandth of a millimeter. Electron microscopes require slices of less than 1 μm. Sectioning a single rat brain produces several thousand slices. The fragile slices are stored in a saline solution and then mounted on slides for viewing. Naked eye 100mm Even when fixed and mounted on slides, nerve Rat brain tissue would appear nearly transparent under the Light microscope microscope if it were not for a variety of special10mm Brain ized stains. Researchers select a stain depending Electron microscope on the features they wish to examine. For example, 1mm to make a detailed structural analysis of a small number of single cells, the best choice is a Golgi Cell body stain, named after its discoverer, Camillo Golgi. 100mm On the other hand, you might be more interested Dendrites in identifying clusters of cell bodies, the major bulk 10mm of the nerve cell, within a sample of tissue. In this case, you would select a Nissl stain. A myelin stain 1mm would allow you to follow pathways carrying inforSynapses mation from one part of the brain to another by staining the insulating material that covers many Dendritic spines 100nm nerve fibers. If you know where a pathway ends Synaptic vesicles but would like to discover its point of origin, you should use horseradish peroxidase. When this 10nm enzyme is injected into the end of a nerve fiber, it travels backward toward the cell body. Antibodies, Ion channels proteins normally produced by the immune system 1nm to identify invading organisms, can be combined DNA with a variety of dyes to highlight particular proteins found in cells in a process known as immunoIons and 0.1nm atoms histochemistry (IHC). The microscopic methods described so far come with a death sentence. They cannot be used on living organisms, which, of course, we want to study. Newer optical methods provide the ability to study living organisms non-invasively (Ntziachristos, 2010). FluFigure 1.10 Using a Microtome to orescent microscopy works by labeling a specimen with a Section Patient H. M.’s Brain particular fluorophore, a chemical that emits light when excited by light (refer to Figure 1.11). Photoacoustic microsResearchers at UC San Diego broadcast the careful seccopy “listens” to the absorption of light by different tissue tioning of the brain of the late Henry Molaison, otherwise known as the famous amnesic patient H. M., via streaming components. Optical microscopy methods have allowed video on the Internet. Molaison’s temporal lobe surgery researchers to identify patterns of neural activity while a and the resulting memory deficits he experienced are mouse decided to take a drink of water (Kauvar et al., 2020).

Figure 1.9 Size of Objects Visible Using Various Microscopy Methods

familiar to all students of psychology.

Peripheral Methods

The Brain Observatory

10

Several non-invasive methods are used by scientists interested in emotion and attention, including facial electromyography (fEMG), heart rate variability (HRV), the skin conductance response (SCR; also known as a Galvanic skin response), eye tracking, and pupil dilation (Niedziela et al., 2021). Facial electromyography (fEMG) evaluates the movement of facial muscles associated with emotional facial electromyography (fEMG) The recording of the activity of facial muscles used to assess the quality and intensity of emotional expression.

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Behavioral Neuroscience Research Methods

Alvin Telser/Science Source

Figure 1.11 A Fluorescent Micrograph of Taste Buds in a Rat

expression (refer to Chapter 14). Recordings through electrodes placed on the surface of the skin above facial muscles can distinguish between positive and negative emotions (happiness versus sadness) and measure the intensity of the emotional expression (refer to Figure 1.12). In Chapter 2, you will learn about the autonomic nervous system (ANS), which obtains feedback and provides instructions to glands and organs. The ANS produces arousal through the action of one of its components, the sympathetic nervous system, and relaxation through the action of another component, the parasympathetic nervous system. Heart rate variability (HRV) can provide insight into the balance between these two systems over time. Our hearts do not beat at perfectly regular intervals such as once per second—there is variance. When we are aroused, stressed, or paying attention, our HRV is reduced (heart beats become more regular), due to sympathetic

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dominance. When we alternate arousal and relaxation, our HRV increases because there is more balance between the two systems. Higher HRV over time is an indicator of better health and less stress. The skin conductance response (SCR) takes advantage of the fact that skin conducts electricity better when you are aroused. Sweat glands are activated by the sympathetic (arousal) nervous system, and sweat changes the way electricity is passed from one electrode on the surface of the skin to another. As a result, the SCR can be used to measure general arousal. Eye tracking and pupil dilation are assessed with wearable technology. Eye tracking tells the researcher where and how long the eyes are focused. Pupil dilation is yet another measure of arousal, as sympathetic activation increases pupil size. In addition, pupil dilation is greater in response to positive stimuli than to negative or neutral stimuli (Nunnally et al., 1967).

Imaging Modern imaging techniques provide significant advantages over autopsy, the study of the body after death. With current imaging technologies, we can watch the living brain as it engages in processes such as reading (Chapter 13) or heart rate variability (HRV) A measure of the variability in the spacing of heartbeats believed to reflect a person’s level of stress. skin conductance recording (SCR) A measure of general arousal taken with surface electrodes placed on the skin; also known as a Galvanic skin response. eye tracking A method for identifying where a person is looking and for how long. pupil dilation A measure of general arousal and positive or negative reactions to visual stimuli.

Figure 1.12 Facial Electromyography Identifies Movements of Facial Muscles Associated with Emotions

Courtesy of Karla Freberg

Electrodes placed on the surface of the skin above major muscles involved with emotional expression can provide detailed information about the quality and intensity of emotion.

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12

Chapter 1

What Is Behavioral Neuroscience?

emotional response (Chapter 14). We can identify differences in the ways the brains of serial murderers function compared with the brains of typical people (Chapter 16). The first brain imaging technology, computerized tomography (CT), was introduced in 1971. Based on x-rays, CT technology provided the first high-resolution look at a living brain. Although it provides excellent structural information, a CT scan cannot distinguish between a living brain and a dead one. In other words, the CT scan provides no information regarding activity levels in the brain. This, along with the risks associated with x-rays, limits the usefulness of CT in helping us answer research questions about behavior. The next major breakthrough in imaging technology was the development of the positron emission tomography, or PET, scan, which allowed researchers to observe brain activity for the first time. PET scans do not provide much useful information about brain structure, however. PET brain studies combine radioactive tracers with a wide variety of molecules, including oxygen, water, neurochemicals, and drugs. A closely related procedure, single photon emission computed tomography (SPECT), is less expensive than PET but provides even less visual detail. Magnetic resonance imaging, or MRI, developed in 1977, has become a standard medical diagnostic tool and a valuable research asset. MRI takes advantage of the fact that diverse types of brain tissue are made of different components. “Gray matter,” or tissue largely made up of the cell bodies of nerve cells, contains large amounts of protein and carbohydrates. Nerve fibers, or “white matter,” are covered by insulating material that is mostly fat. The fluid surrounding the cells of the brain is essentially salt water. These components, protein/carbohydrates, fats, and water, behave differently when exposed to MRI methods, leading to stronger signals from one type relative to another. The stronger signals are assigned a darker color in the resulting image. Each small area of tissue is assigned a voxel, which is a three-dimensional version of a pixel. Functional MRI (fMRI), developed in the early 1990s, allows us to correlate brain activity with the presentation of a stimulus, the presence of an emotional state, or the performance of a particular task in living humans. A “resting state” fMRI, taken when a participant relaxes in the scanner, helps us identify the strength of networks. Unlike the single images that comprise an MRI, fMRI features a series of images taken closely together in time. Functional MRI takes advantage of positron emission tomography (PET) An imaging technique that provides information regarding the localization of brain activity. magnetic resonance imaging (MRI) An imaging technique that provides very high-resolution structural images. voxel Short for “volume pixel.” A pixel is the smallest distinguishable square part of a two-dimensional image. A voxel is the smallest distinguishable box-shaped part of a three-dimensional image. functional MRI (fMRI) A technology using a series of MRI images taken one to four seconds apart to assess the activity of the brain.

the fact that active neurons require more oxygen than less active neurons and that variations in blood flow to a particular area will reflect this need. Using a series of images provides a way to track these changes in blood flow over time. The use of fMRI to track blood flow in the brain was previewed in the nineteenth century by America’s first official psychologist, William James, who was impressed by the observations of Italian physiologist Angelo Mosso on patients with head injuries. Due to the nature of these injuries, in which some of the patients’ skull bones were missing or damaged, Mosso (1881) was able to measure and correlate blood flow with the patients’ mental activities. James’ reflections on Mosso’s work sound very contemporary: “Blood very likely may rush to each region of the cortex according as it is most active, but of this we know nothing” (James, 1890, p. 99). Mosso’s observations were confirmed by Roy and Sherrington (1890), who reported the existence of “an automatic mechanism by which the blood supply of any part of the cerebral tissue is varied in accordance with the activity of the chemical changes which underlie the functional action of that part” (p. 105). How does fMRI track cerebral blood flow? Hemoglobin, the protein molecule that carries oxygen within the blood, has different magnetic properties when combined with oxygen or not (Ogawa et al., 1990). Consequently, signals from a voxel will change depending on the oxygenation of the blood in that area, known as the Blood Oxygenation Level Dependent (BOLD) effect. Let’s look at an example of the author’s own results of a standard demonstration conducted at the Brain Imaging Laboratory at the University of California, Santa Barbara (refer to Figure 1.13). Scans were taken as the author alternated 20-second intervals of remaining very still with 20-second intervals of touching her right thumb to each of the other digits of her right hand one at a time. The image highlights the voxels that showed changes in activity correlated with movement and stimulation. The features of fMRI that have made this a “gold standard” method include its relative safety, excellent spatial resolution, and ability to identify changes in activity. Drawbacks include its relatively poor temporal resolution and high cost. Temporal resolution, once again, refers to the delay between neural activity and its measure. The nervous system works on the scale of milliseconds (a millisecond is one one-thousandth of a second), but peak blood flow to an area might occur four to six full seconds after the activation of relevant neurons. This makes the job of associating changes in the fMRI signals with the events that produce them quite challenging. Because high costs (about $1000 per hour) limit the number of participants a researcher can use, fMRI has also been criticized as under-powered and low in reproducibility. Power is a statistical concept involving the odds of demonstrating real effects. If your study is under-powered, often due to a small number of participants, you might miss a subtle but important effect. Reproducibility lies at

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Behavioral Neuroscience Research Methods

Figure 1.13 Functional Magnetic Resonance Imaging (fMRI) Tracks Cerebral Blood Flow This image demonstrates the use of fMRI to identify parts of the brain (the red and yellow areas) that became selectively active when the author engaged in a “finger tap” exercise (touching each digit of her right hand one by one with her thumb).

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An alternative to fMRI is functional near-infrared spectroscopy (fNIRS). This non-invasive technology involves exposing the head to near-infrared light (light just outside of the visual spectrum; refer to Chapter 6). As in the case of fMRI, this technology distinguishes between blood that is carrying a rich supply of oxygen and blood that is not. Functional NIRS has several advantages over fMRI. It is relatively less expensive. The participant can move around and respond normally to sound (the magnets used in fMRI are very noisy). The temporal resolution of fNIRS is superior to fMRI, but its spatial resolution is not as good.

the heart of scientific integrity and refers to the ability of other scientists to run your study again and produce the same results. Estimates of ideal numbers of participants for fMRI studies are often quite different from the median number of 25 reported in scientific journals. In studies of task-related changes in brain activity (e.g., think of a face or a building), the ideal number of participants is probably well over 100 (Turner et al., 2018). Brain-wide association studies (BWAS), which link brain structure and function to a construct such as cognitive ability or depression, potentially require thousands of participants (Marek et al., 2022). Scientists are coping with these challenges by combining their efforts into shared databases. For example, the Adolescent Brain Cognitive Development (ABCD) study features imaging data from nearly 12,000 participants (Casey et al., 2018). The same machinery used for MRI and fMRI can also be used for diffusion tensor imaging (DTI). This technique allows researchers to map connectivity in the brain by tracking the movement of water in the fiber pathways of the nervous system (Le Bihan & Breton, 1985; Moseley et al., 1990; refer to Figure 1.14). DTI cannot, however, tell us about the direction of information flow. DTI not only identifies neural pathways, but it also illuminates their relative integrity or health. You might have heard people say that drinking “a little” alcohol while pregnant is okay. However, using DTI, researchers have shown that even small amounts of prenatal alcohol exposure can produce significant changes in the integrity of children’s neural networks (Long & Lebel, 2022).

Although perhaps less dramatic than the imaging techniques, methods that allow researchers to record the electrical and magnetic output of the brain continue to be useful. As we will discuss in greater detail in Chapter 3, nerve cells generate small electrical charges across their membranes, much like miniature batteries. Any electrical current will generate magnetic fields. Although small in scale, this electrical and magnetic activity can be recorded using electrodes either on the surface of the scalp or brain or embedded within the brain tissue itself. The Electroencephalogram (EEG) The first electroencephalogram (EEG) recordings of the human brain’s electrical activity, measured through electrodes placed on the scalp, were made by a German psychiatrist, Hans diffusion tensor imaging (DTI) Use of MRI technology to trace fiber pathways in the brain by tracking the flow of water. functional near-infrared spectrometry (fNIRS) A method of measuring brain activity similar to fMRI using near-infrared light exposure. electroencephalogram (EEG) The recording of the brain’s electrical activity through electrodes placed on the scalp.

Figure 1.14 Diffusion Tensor Imaging (DTI) Using MRI technology, the flow of water down the length of nerve fibers can be imaged to construct maps of the fiber pathways of the brain.

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Living Art Enterprises/Science Source

Courtesy of Laura Freberg

Recording

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Chapter 1

What Is Behavioral Neuroscience?

Berger, in 1924. Berger noted that the recordings varied during wakefulness, sleep, anesthesia, and epilepsy. Chapters 11 and 15 investigate the relationships between the EEG and these states of consciousness in greater detail. Today, EEG is recorded through up to 256 surface electrodes embedded in a flexible cap worn by the participant. EEG features superb temporal resolution but relatively poor spatial resolution. Recordings reflect activity from outer parts of the brain instead of deeper structures. Event-Related Potentials (ERPs) A variation of basic EEG technology is the recording of event-related potentials (ERPs). This technique allows researchers to correlate the timing of activity of cortical neurons recorded through scalp electrodes with stimuli presented to the participant. EEG recordings of reactions to many presentations of a stimulus are averaged, reducing the variance or “noise” inevitably present in single recordings (refer to Figure 1.15). The result is a pattern of regular waves, identified as P (positive or upward) or N (negative or downward) with their latency or time of appearance.

Hence, a P300 wave is a positive wave occurring 300 ms after a stimulus. Abnormalities of the P300 wave have been observed in cases of alcohol dependence (Yuan et al., 2022) and Alzheimer disease (Hedges et al., 2014). More recently, improvements in the ability to analyze ERP data have allowed researchers to identify brain microstates, which have been referred to as “atoms of thought” (Koenig et al., 1999, p. 209). These researchers identified abnormal microstates in the recordings taken of people diagnosed with schizophrenia.

2 mv

20 mv

Magnetoencephalography (MEG) Magnetoencephalography (MEG) allows researchers to record the brain’s magnetic activity (Cohen, 1972). Active neurons put out tiny magnetic fields. By “tiny,” we mean that the fields generated by neural activity are about one billion times smaller than Earth’s magnetic field and about 10,000 times smaller than the field surrounding a typical household electric wire. The major advantage of recording magnetism rather than electrical activity from the brain relates to the interference of the skull bones and other tissues separating the brain from the electrodes, which prevents a large amount of the brain’s electrical activity from being recorded using event-related potential (ERP) An alteration in the EEG recording EEG. In contrast, the skull bones and tissues allow magproduced in response to the application of a particular stimulus. netism to pass through without any reduction. In addimagnetoencephalography (MEG) A technology for recording the tion, recordings of the magnetic fields produced by the magnetic output of the brain. brain can be taken much faster than either fMRI or PET scans, providing a momentby-moment picture of brain activity. MEG has the added Figure 1.15 Event-Related Potentials (ERPs) advantage of being silent, as The analysis of event-related potentials allows researchers to map the brain’s EEG response to opposed to the loud hamenvironmental stimuli. In this example, a characteristic waveform emerges when responses mering sound produced by to the presentation of a tone are averaged over 100 trials. the magnets used in MRI. Consequently, MEG provides Single EEG + researchers with an importrecording ant technique for studying brain responses to sound. Electrode Amplifier MEG uses sensors known as superconducting quantum interference devices, or SQUIDs, which convert magnetic energy into electrical impulses that can be recorded – and analyzed. Because MEG 100 200 300 400 500 600 700 does not provide any anaStimulus Time (msec) tomical data, researchers ERP superimpose MEG record+ (average ings on three-dimensional of 100 or images obtained with MRI more EEG (refer to Figure 1.16). This recordings) combination provides simul– taneous information about 100 200 300 400 500 600 700 brain activity and anatomy. Stimulus Time (msec) An exciting improvement in MEG technology was the

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Behavioral Neuroscience Research Methods

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Figure 1.16 Magnetoencephalograpy (MEG) (a) To record the tiny magnetic fields generated by the brain, a series of supercooled sensors known as superconducting quantum interference devices (SQUIDs) are arrayed around the participant’s head. (b) The results of the MEG recording are superimposed on an MRI image. This example illustrates the participant’s response to a tone. (a) Subject Undergoing MEG Procedure

(b) MEG Results Superimposed on an MRI Image R

L

SQUID array

development of a more mobile recording device (Boto et al., 2018). The participant still had to stay in a room that shielded the MEG system from the Earth’s magnetic field, but this more mobile technology holds great promise for improving our understanding of brain correlates of behavior. Single-Cell Recordings Single-cell recording provides the neuroscientist with the ability to assess the activity of single neurons using tiny microelectrodes. In single cell recordings, a microelectrode is surgically placed just outside a cell of interest in a living animal. This allows the researcher to detect and record the rate of action potentials produced by the cell. This technique was used to identify mirror neurons, or neurons that fire in response to an action, such as reaching for a banana, whether the reaching is done by a monkey or an experimenter (Caggiano et al., 2011; Di Pellegrino et al., 1992). Intracellular recordings are made by impaling a single cell with a microelectrode. In Chapter 3, we will discuss how Nobel laureates Hodgkin and Huxley used this technique to demonstrate the ionic basis of the electrical signals we call action potentials. In contemporary neuroscience, intracellular recordings have given way to the more precise patch clamp techniques, which allow researchers to study single channels that allow ions to move across a cell membrane.

relative synchrony of neural activity during a social interaction (Wang et al., 2018). Hyperscanning can make use of any one of several imaging and recording technologies, including fMRI, fNIRS, or EEG. Functional NIRS is particularly useful in hyperscanning as its relative mobility allows for more natural social interactions. Hyperscanning has been used to investigate cooperation among lovers (Pan et al., 2017), music performances (Acquadro et al., 2016), interactions between parents and their children (Nguyen et al., 2020), and group creativity (Lu et al., 2021).

Brain Stimulation One of the important questions raised in behavioral neuroscience asks about the localization of functions within the brain and nervous system. Although this question can be approached with several techniques, we can begin by artificially stimulating the area in question and watching for resulting behavior. Interpretation of the results of stimulation research must be done with great caution. Because brain structures are richly connected with other areas of the brain, stimulating one area will also affect the other areas to which it is connected. Electrical stimulation of the brain can be applied during neurosurgery. As unpleasant as it may sound to you, most neurosurgery is conducted under local, not general, anesthesia. The tissues of the brain itself lack receptors for pain.

Hyperscanning Human beings are essentially social animals, so it is natural for behavioral neuroscientists to be interested in the biological correlates of social behavior. Hyperscanning, or the simultaneous recording of brain activity from more than one individual, provides information about the

single-cell recording The recording of the activity of single neurons through microelectrodes surgically implanted in the area of interest. hyperscanning A method of simultaneously recording brain activity from two or more individuals using fMRI, fNIRS, or EEG.

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Chapter 1

What Is Behavioral Neuroscience?

Thinking Ethically Can We Read Minds with Neuroscience Technologies? et al., 2019). Perhaps you think of “mind reading” as closer to the idea of someone reading your thoughts or unspoken words than images of goldfish. That prospect, too, might be within reach. Researchers have been able to use artificial intelligence and EEG to decode single imagined words (Panachakel & Ramakrishnan, 2021). While this approach represents a remarkable improvement for people unable to speak, it also raises profound ethical concerns about privacy and consent. Consumer-grade brain-computer-interface (BCI) equipment, popular in gaming, entertainment, and selfhelp, has the potential to extract sensitive information from users without their knowledge (Ienca et al., 2018). In a proof-of-concept study, researchers were able to distinguish a participant’s real personal information from an array of false alternatives by analyzing the P300 wave in recorded ERPs (Martinovic et al., 2012). The extracted information included pin codes, bank information, month of birth, geographical location, and recognition of known faces. These ongoing developments speak to an urgent need to expand our legal rights to privacy to include “mental privacy.” Unfortunately, public awareness of these issues remains low.

Forward Inference

Reverse Inference Geoff B Hall

© Prime Minister’s Office, Finland/photographer: Nikolai Jakobsen

In the 2002 film Minority Report, Tom Cruise plays a police officer who arrests people for crimes they have not yet committed. How close are we to knowing what people are planning to do before they actually do it? Perhaps closer than you think. Current imaging technologies, such as fMRI, do not exactly allow us to “read” the human mind. Such efforts are hampered by the problem of reverse inference, or the assumption that a given pattern of brain activity can be used to identify a mental state (refer to Figure 1.17). Forward inference is easy. We provide a stimulus or task to the participant and observe the corresponding brain activity. Because each part of the brain can be activated by so many different things, however, reverse inference is much more complex. We want to avoid the mistakes made in an opinion piece in the New York Times that suggested their participants’ brain activity meant that they were “battling unacknowledged impulses to like Mrs. Clinton” (Iacoboni et al., 2007, para. 6). This does not mean that we gain zero insights into thought from neuroscience technologies. Researchers recorded fMRI data while participants viewed images, such as an airplane or goldfish, and then used the data to reconstruct images that are similar to the originals (Shen

Figure 1.17 Forward and Reverse Inference. In forward inference, we associate an observed activity in the brain with the presence of a stimulus. In reverse inference, we interpret an observed activity in the brain to reflect a particular mental state. Because parts of the brain, including the anterior cingulate cortex (ACC; in yellow above right), participate in diverse processes, it is risky to assume that we know what activity in a particular area means. Activity in the ACC does not automatically suggest that people viewing a photo of Hillary Clinton were “battling unacknowledged impulses to like Mrs. Clinton” (Iacoboni et al., 2007, para. 6).

Once the bone and the tissues covering the brain are anesthetized, the surgeon can work on the brain of the conscious patient without causing pain. Why would we put people through such an unpleasant experience? Although brains are similar in many ways from person to person, individual differences frequently do occur. By stimulating an area of the exposed brain with a small amount of electricity and

assessing any changes in behavior, the surgeon can identify the area’s functions. This approach has allowed surgeons to place stimulating electrodes accurately to treat Parkinson disease (refer to Chapter 8), depression, and obsessive-compulsive disorder (OCD; refer to Chapter 16). Neuroscientists can also apply current through a surgically implanted microelectrode, stimulating electrical

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Behavioral Neuroscience Research Methods

signaling by cells adjacent to the microelectrode’s tip. Resulting behaviors can be correlated with the location of the stimulation. In Chapter 9, we will discuss the work of Olds and Milner (1954), who demonstrated that rats would push a lever to obtain electrical stimulation in particular parts of the brain. In other words, rats were willing to perform work to obtain the stimulation, which seemed to produce feelings of reward or pleasure. Robert Heath (1963) implanted electrodes in a patient with the sleep disorder narcolepsy (refer to Chapter 11) and allowed the patient to push a button that administered a brief electrical stimulus. The patient was able to describe his reactions to stimulation of each of the 14 electrodes implanted in his brain. One of the electrodes, which the patient activated most frequently, elicited sexual arousal. Electrical stimulation is used in treatment as well as in research (refer to Figure 1.18). Encouraged by the

Figure 1.18 Deep Brain Stimulation In research, brain stimulation is typically used to identify the possible functions of a part of the brain. Brain stimulation has also been used to treat Parkinson disease and, less frequently, obsessive compulsive disorder and major depressive disorder.

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improvements provided by electrical deep brain stimulation in patients with the movement disorder Parkinson disease, discussed in Chapter 8, physicians have begun to surgically implant electrodes in the brains of individuals with depression and obsessive compulsive disorder who were not responding to more conventional treatments (Clair et al., 2018; Wu et al., 2021). Repeated transcranial magnetic stimulation (rTMS) is a non-invasive stimulation method that consists of magnetic pulses delivered through a single coil of wire encased in plastic that is placed on the scalp (refer to Figure 1.19). Low frequency rTMS (about one pulse per second) provides an interesting technique for temporarily changing brain activity immediately below the stimulation site (Merton & Morton, 1980). Magnetic fields, as we mentioned in the section on magnetoencephalography, pass freely through the skull bones to reach the brain, producing weak electrical currents on its surface. Depending on the area of the brain that is stimulated and the strength of the magnetism used, the stimulated area of the brain can be excited or inactivated temporarily. Deeper structures cannot be affected by this technique. The U.S. Food and Drug Administration (FDA) has approved the use of rTMS for a variety of conditions, including obsessive-compulsive disorder (OCD), major depressive disorder (MDD), and smoking cessation. Efforts to use rTMS to improve cognitive function, however, have been disappointing (de Boer et al., 2021). repeated transcranial magnetic stimulation (rTMS) A technique for stimulating the cortex at regular intervals by applying a magnetic pulse through a wire coil encased in plastic and placed on the scalp.

Figure 1.19 Repeated Transcranial Magnetic Stimulation (rTMS)

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Philippe Garo/Science Source

Living Art Enterprises/Science Source

Repeated TMS changes the activity of the cortex underlying the stimulator. The technique is used for research purposes and potentially could be used for treating hallucinations, depression, and migraine headaches.

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Chapter 1

What Is Behavioral Neuroscience?

A similar non-invasive stimulation approach to rTMS is repeated transcranial electrical stimulation (tES). As discussed previously, the skull bones block electricity more effectively than magnetism, so tES has a more surface effect on brain activity than rTMS. Nonetheless, tES is being investigated as a possible approach to improving memory in individuals with Alzheimer disease (refer to Chapter 15; Bréchet et al., 2021) and a number of psychological disorders, including depression (Cho et al., 2022). Optogenetics provides the ability to use light to stimulate specific neural cells. Molecules are genetically inserted into specific neurons in the brain, which then allows neural function to be modified by light (Boyden et al., 2005). In other words, light can be used to turn living neurons on and off (refer to Figure 1.20). This stimulation is much more precise than that provided by the electrical stimulation through surgically inserted microelectrodes described earlier. Optogenetics begins with the identification of opsins, or light-sensitive proteins, found in single-celled organisms such as algae. Genetic material is then modified to produce the opsin in only one specific type of cell. This modified genetic material is inserted into a virus, which is then injected into the brain of a mouse. The virus infects many cells, of course, but the modified genetic material ensures that only one type of cell will make the opsin protein. Light stimulation is provided through optical fibers attached to the skull or surgically implanted. Optogenetics might be particularly useful in identifying abnormal activity in neural circuits associated with psychological disorders (Steinberg et al., 2015). Before this technology could be applied to humans, however, several problems must be solved (Häusser, 2021). Among the challenges to be overcome are the safe delivery of modified genes, long-term safety of the neural modifications, and a reasonable way of delivering light to the right neurons.

Figure 1.20 Optogenetics

Karla Freberg

After injecting a virus with instructions for a particular type of cell to become light sensitive, exposing the brain to a laser excites the treated cells.

Lesion A lesion is an injury to neural tissue and can be either naturally occurring or deliberately produced. As was the case with stimulation, the primary purpose of lesion analysis is to assess the probable function of an area. Behavior observed prior to the lesion can be compared with behavior occurring after the lesion, with changes attributed to the area that was damaged. Once again, interpretation must be done very carefully. Lesions not only damage a particular area of the brain but also damage any nerve fibers passing through that area. Neuropsychologists (refer to Chapter 15) evaluate naturally occurring lesions that result from injury or disease, gaining a great deal of information about the function of the brain. Many examples of this type of analysis will be discussed in the remainder of the text. Paul Broca correlated the damage he observed in the brain of his deceased patient “Tan” and the clinical observations about Tan’s speech impairment he made while Tan was alive (refer to Chapter 13). A classic example of the use of deliberate lesions in animals identified a role for the ventromedial hypothalamus (VMH) in satiety (Hoebel & Teitelbaum, 1966; refer to Figure 1.21). When this area is electrically stimulated, an animal will stop eating. When this area is lesioned, the animal eats so much that its body weight can double or even triple (refer to Chapter 9). Deliberate lesions are performed in several ways. In some studies, large areas of brain tissue are surgically removed. In this case, we might refer to the procedure as ablation rather than lesion. Lesions can be experimentally produced when a microelectrode is surgically inserted into the area of interest. The electrode is insulated except at the very tip to prevent damage to cells lining the entire pathway of the electrode. Heat is generated at the tip of the electrode, effectively killing a small population of cells surrounding the tip. Small lesions can also be produced by applying neurotoxins, chemicals that specifically kill neurons, into the area of interest through a surgically implanted micropipette. Chemically produced lesions have the advantage of harming only the cell bodies of neurons while leaving the nerve fibers traveling through the area intact. Conversely, fiber pathways can be chemically lesioned while sparing adjacent cell bodies. Obviously, both heat-produced and chemically produced lesions result in permanent damage to the brain. A reversible type of lesion can be produced by cooling an area using a

transcranial electrical stimulation (tES) A method for delivering electrical current to the brain through surface electrodes. optogenetics The genetic insertion of molecules into specific neurons that allows the activity of the neurons to be controlled by light. lesion Pathological or traumatic damage to tissue.

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Behavioral Neuroscience Research Methods

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Figure 1.21 Lesion To investigate the function of a particular part of the brain (a), a radio frequency current is passed through the tips of insulated electrodes that have been surgically implanted (b). Resulting changes in behavior are correlated with the lesions produced (c).

Lesions

(a) Section of Brain to Be Lesioned

(b) Electrodes Inserted

surgically implanted probe. When the area is chilled, the neurons are unable to function. However, when the area returns to normal temperatures, normal behavioral function is restored. This allows a single animal to serve as its own control by comparing its behavior before, during, and after the temporary lesion.

Biochemical Methods As we will discuss in Chapters 3 and 4, the brain and nervous system are unusually well protected, compared to the other organs in the body, from circulating toxins. As a result, if a researcher wishes to investigate the effects of chemical stimulation in the brain, these normal protective mechanisms often must be bypassed. Obviously, some chemicals naturally gain access to the brain, resulting in psychoactive effects. Many other chemicals are blocked from exiting the blood supply into neural tissue. For example, most agents used for cancer chemotherapy simply circulate through the brain without leaving the blood supply, adding to the challenges of treating brain tumors (refer to Chapter 15). Different methods used to administer drugs to a subject include eating, inhaling, chewing, and injecting the drug (refer to Chapter 4). These methods result in the delivery of quite different concentrations of a drug into the blood supply within a given period. For research purposes, chemicals can be directly administered to a specific region of the brain through the surgical implantation of micropipettes. Chemicals can also be injected into the lateral ventricles, fluid-filled areas in the cerebral hemispheres (refer to Chapter 2), that will then diffuse throughout the brain. It is often desirable to identify and quantify the chemicals that naturally exist in a particular location in the brain. Using implanted micropipettes, small amounts of extracellular fluid are filtered from the area of the brain surrounding the tip of the pipette for analysis. This technique is known as microdialysis. Microdialysis allows researchers to identify which neurochemicals are active in

(c) Resulting Lesions

a precise location as well as the approximate quantity of these chemicals. The invasiveness of microdialysis means that researchers interested in obtaining this type of information from humans must look elsewhere. The previously mentioned PET and SPECT methods can help identify areas in which a neurochemical of interest is particularly active. Alternately, functional magnetic resonance spectroscopy (fMRS), using the same technical principles as MRI and fMRI, is especially useful in identifying changes in neurochemical activity during cognitive tasks (Stanley & Raz, 2018). This noninvasive technology could provide valuable insights in cases of psychological disorder or cognitive decline.

Genetic Methods Many researchers strive to identify the interactions between genetic and environmental variables on a particular behavior, such as vulnerability to a psychological disorder (refer to Chapter 5). Family Studies Early observations that certain psychological disorders seemed to run in families led to more systematic investigations of twins and adopted individuals. The natural comparison between monozygotic (identical) and dizygotic (fraternal) twins provides some insight into the relative contributions of heredity and environment. Monozygotic twins share an identical set of genes, while fraternal twins average about 50 percent of their genes in common, just like any other pair of non-twin siblings. Yet, both types of twins are more likely to share experiences than non-identical siblings. microdialysis A technique for assessing the chemical composition of a very small area of the brain. functional magnetic resonance spectrometry (fMRS) A non-invasive method for assessing changes in the activity of neurochemicals in the brain.

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Chapter 1

What Is Behavioral Neuroscience?

Genetic influences in twin studies are often communicated using a concordance rate, a type of statistical probability. Given the existence of a trait in one twin, the concordance rate for the other twin estimates the probability of the other twin having the trait. For example, in the case of bipolar disorder, we find concordance rates among monozygotic twins between 39 and 43 percent (O’Connell et al., 2022). If one identical twin has bipolar disorder, the other has a 39–43 percent likelihood of also being diagnosed with the disorder. Note that this is not 100 percent, so a person’s genetics alone rarely determine an outcome. Another approach to investigating the influences of heredity and environment is to compare the similarities of adopted individuals to their biological and adoptive parents. Similarities to the biological parents suggest a stronger role for heredity, while similarities to the adoptive parents suggest a stronger role for the environment. Adoption studies have been used to assess the relative contributions of heredity and environment to schizophrenia, intelligence, and criminality. Interpretation of adoption studies remains difficult because adoptive families are quite similar to one another due to the screening process they undergo. The biological parents of the children they adopt go through no such screening and are vastly more diverse. Similar environments magnify genetic influences. Heritability, or the amount that a trait varies in a population due to genetics, is influenced by the environment. For example, if you planted seeds under ideal conditions (good soil, lots of sunlight, regular watering), the differences in height you observe among your mature plants are largely due to genetics. In contrast, if you planted seeds under more variable conditions, the resulting plants would reflect the contributions of both genetic and environmental factors. As in the case of the ideal conditions for our plants, genetic influences on children’s outcomes might be magnified by the similar environments provided by adoptive parents. Molecular Genetics Methods in molecular genetics help scientists associate genotypes (the underlying DNA) and phenotypes (the outwardly observable trait or behavior). Commonly, these efforts take the form of either forward or reverse genetic screens (refer to Figure 1.22). concordance rate The statistical probability that two cases will agree; usually used to predict the risk of an identical twin of developing a condition already diagnosed in the other twin. heritability The amount that a trait varies in a population due to genetics. molecular genetics A field of study that attempts to link the features of organisms to their underlying DNA. forward genetic screen A method that begins with a phenotype and attempts to discover its underlying genetic correlates. genome-wide association study (GWAS) A method using the entire genome to search for individual genes that vary between particular phenotypes.

Figure 1.22 Genetic Screens To perform a forward genetic screen, the researcher starts with a phenotype and tries to identify the genes necessary for the trait. In reverse genetic screening, a gene of interest is manipulated, and the results of the manipulation on the phenotype are observed. Forward genetic screens

Reverse genetic screens

Discover gene underlying phenotype

Phenotype resulting from alteration

A forward genetic screen is used to identify genes that seem important in the development of a phenotype. To perform a forward screen, the researcher locates individuals with the phenotypical trait of interest (e.g., schizophrenia) and then attempts to identify the genes necessary for exhibiting the trait. Early methods for conducting forward screens included linkage studies and candidate gene studies. Linkage studies help researchers identify the locations of genes related to a specific phenotype. Genes that are located closer together on a chromosome are statistically more likely to be inherited together. Candidate gene research looks at the frequency of one or a few specific genes in people with and without a phenotype. Candidate genes are selected for investigation due to their logical relationships with a trait, such as the role of particular proteins in the metabolism of alcohol in the development of alcohol dependence. Because of technological improvements, researchers can now consider the entire genome, a procedure known as a genome-wide association study (GWAS). These studies often incorporate data from hundreds of thousands of participants. Instead of beginning with a hypothesis regarding the participation of particular genes in a phenotype, GWAS simply looks at whether any genes are correlated with a phenotypical trait of interest. GWAS data have identified strong genetic correlations among major types of psychological disorders, such as schizophrenia and bipolar disorder (refer to Chapter 16). Many scientists are now trying to use GWAS methods to find genes that differentiate among disorders more effectively (Peyrot & Price, 2021).

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Behavioral Neuroscience Research Methods

A reverse genetic screen, in contrast to most forward screens, usually involves testing one gene at a time. The researcher first selects a gene and then observes what phenotypical changes occur in its absence. Specially engineered, defective versions of genes (knockout genes) are inserted into the chromosomes of animals. The normal version of these genes encodes for a specific protein. Knockout genes take the place of the normal genes but fail to produce the specific protein. Using this method, researchers can assess the roles of particular genes and the proteins they encode. For example, genes related to maintaining sleep-wake cycles are often implicated in psychological disorders. Rhesus monkeys with a knockout version of one of these genes displayed symptoms similar to schizophrenia (von Schantz et al., 2021).

Interim Summary 1.2

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4. Recording techniques include measurements of the brain’s overall electrical and magnetic outputs. In addition, recordings can also be made of the activity of single cells or parts of cells. (LO4) 5. Stimulation and lesion techniques can be used to assess the function of particular areas of the brain. Electrical and magnetic stimulation can enhance or reduce the activity of the brain. (LO4) 6. Biochemical methods allow for the artificial stimulation of the nervous system with chemicals as well as the assessment of the biochemical environment in an area of particular interest within the nervous system. (LO4) 7. Genetic methods, including twin studies, adoption studies, and genetic screens, allow researchers to assess the role of our genetic inheritance in the relationship between the nervous system and behavior. (LO5)

Summary Points 1.2 Review Questions 1.2

1. Improvements in microscopic methods provided the means for examining the nervous system at the microscopic level. (LO4)

1. What are the relative strengths and weaknesses of the major imaging methods?

2. Peripheral methods, including fEMG, HRV, SCR, eye tracking, and pupil dilation, provide information about arousal, attention, and emotion. (LO3)

2. What challenges are involved with the interpretation of data from imaging, stimulation, and lesion research?

3. Imaging technologies, including CT scans, PET scans, MRI, fMRI, fNIRS, and DTI, have built on knowledge gained through autopsy regarding the structure and function of the brain. (LO3)

reverse genetic screen The replacement of a gene of interest with a knockout version to discover the effects of the gene on the resulting phenotype.

Summary Table 1.2: Methods in Behavioral Neuroscience Method

Function

Microscopic methods

Studying the microscopic structure of the nervous system

Peripheral methods

Studying arousal, attention, and emotion

Positron emission tomography (PET)/Single photon emission computerized tomography (SPECT)

Studying the relative activity of nervous system structures/Localizing areas of high activity of tagged biochemicals

Magnetic resonance imaging (MRI)

Studying structure in fine detail

Functional MRI (fMRI)

Studying richly detailed structural information and the activity of the nervous system

Functional near-infrared spectroscopy (fNIRS)

Studying the activity of the nervous system

Diffusion tensor imaging (DTI)

Studying fiber pathways in the nervous system

Electroencephalogram (EEG)

Studying brain activity, primarily during sleep and waking or seizures

Event-related potential (ERP) recording

Studying the brain’s response to specific stimuli using an adapted EEG

Magnetoencephalography (MEG)

Studying brain activity (continued)

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Chapter 1

What Is Behavioral Neuroscience?

Summary Table 1.2: Methods in Behavioral Neuroscience (Continued) Method

Function

Hyperscanning

Studying the synchrony in brain activity of multiple participants

Single-cell recordings

Identifying the stimulus responsible for activating an individual neuron

Electrical stimulation and lesion

Identifying behavior linked to a particular location in the nervous system

Optogenetics

Using light to initiate neural activity

Repeated transcranial magnetic stimulation (rTMS)

Producing changes in cortical activity

Microdialysis

Identifying particular chemicals in a very small location of the brain

Functional magnetic resonance spectroscopy (fMRS)

Identifying changes in neurochemical activity

Family studies (twin and adoption studies)

Studying contributions of genetic and nongenetic factors to behavior

Genetic screens

Linking particular genes with phenotypical traits

Open Science and Research Ethics in Behavioral Neuroscience Science is an ongoing process, not a static entity, and our knowledge is always being updated and improved. Outright fraud is fortunately rare, but various questionable research practices on the part of well-intentioned scientists can lead to invalid results. By today’s standards, many classic studies, such as the famous Stanford Prison Study (Haney et al., 1973), are hopelessly flawed. Many other studies have not replicated. Replication, or the repeating of a methodology producing the same results, is at the heart of the self-correcting nature of the scientific method. Not only have methods changed, but our thinking about the protection of research participants, both humans and animals, has also evolved dramatically over the years.

Open Science The purpose of open science initiatives is to increase the “openness, integrity, and reproducibility” of science (Center for Open Science, 2022). What exactly does this mean? Isn’t science already doing these things? How does open science apply to behavioral neuroscience? Practicing open science requires rethinking on the part of the entire scientific community, including university administrations, funding agencies, and publishers of academic journals. Countermeasures to common scientific flaws include processes like public pre-registration of methods and hypotheses, which helps prevent open science Initiatives aimed at improving the openness, integrity, and reproducibility of scientific research.

after-the-fact searching for significant results in a study that otherwise “didn’t work.” Publishers are encouraged to accept more replications and studies supporting null hypotheses (e.g., this new medication is no better than a placebo after all) rather than just publishing studies with statistically significant effects. University administrators and funding agencies must consider the quality, not quantity, of scientists’ research, including their participation in replications and studies with null effects. Behavioral neuroscience is subject to the same open science concerns as all other fields of science. In this chapter, you have read about problems associated with under-powered studies, particularly those using expensive brain imaging technologies. Under-powered studies are relatively less likely to replicate successfully. Neuroscientists have attempted to address these issues by sharing datasets using FAIR principles (Findable, Accessible, Interoperable, and Reusable; Wilkinson et al., 2016). These principles ensure that datasets, such as files of individual brain images, are clearly identified and described, enhancing sharing. We don’t want to leave you with the impression that we don’t know what we’re doing in science. We do, but we must also remember to practice our best critical thinking skills while maintaining a healthy dose of intellectual humility.

Human Participant Guidelines The Greek physician and scholar Hippocrates set a standard for ethical behavior in the sciences that has certainly stood the test of time (refer to Figure 1.23). Hippocrates wrote in the Epidemics: “As to diseases, make a habit of two things—to help, or at least do no harm.” In our search for knowledge, what controls are in place to ensure that Hippocrates’ rule of “do no harm” is respected by those entrusted with the lives and welfare of research participants?

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Open Science and Research Ethics in Behavioral Neuroscience

Protection for research participants in the United States begins with the federal government and its regulations making up the Common Rule and the Revised Common Rule (U.S. Department of Health and Human Services, 2017). These standards apply to any researcher obtaining federal funds. Most universities require compliance with federal ethical standards regardless of funding source. In addition, guidance is provided by professional societies, such as the American Psychological Association (APA) and the Society for Neuroscience (SfN). To evaluate compliance with ethical standards, each university maintains institutional review boards (IRBs) for human research and institutional animal care and use committees (IACUCs) for animal research. These committees are composed of faculty members with expertise in the appropriate areas, plus at least one faculty member from a nonscience discipline. In addition, the boards include a community member, so the university is not simply policing itself behind closed doors. The principal areas of protection for human participants are voluntary participation, informed consent, minimizing risk, and confidentiality. Coercing people to serve as research participants is unacceptable, and incentives for participation cannot be so large as to be coercive. To know whether they wish to volunteer, potential participants must give informed consent based on a clear statement of what they will experience in the study. The risk of harm must be as low as possible and offset by advantages to the participants. In most cases, it should not be possible to connect a participant’s data with any identifying information.

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These principles seem straightforward, but applying them appropriately can be complicated. For example, a person volunteering to contribute to a genetics biobank is literally providing information from entire families and communities, which might contain members who would otherwise object. How do we justify the administration of an inactive placebo medication to a control group, which might be viewed as “harmful” if the experimental drug appears to be effective? These are not easy questions.

Animal Subjects Guidelines While the exact number of research animals in U.S. laboratories is difficult to pin down, somewhere in excess of 95% are rats and mice. The remaining percentages are mostly fish and birds, with only a tiny number of non-human primates. The use of cats and dogs is exceedingly rare and usually in the context of investigations of animal cognition. Neuroscientists have been able to model a number of important human behaviors, including movement, learning, memory, sleep, and social behavior, in the simple fruit fly Drosophila melanogaster (refer to Figure 1.24). Researchers strive to meet the “3Rs” of animal research: reduce the number of animals used, replace the

Figure 1.24 Drosophila in Space Because of their many genetic similarities to humans, the fruit fly Drosophila makes a useful subject for experiments. NASA’s Max Sanchez is preparing a fruit fly colony for launch on a space shuttle for a trip to the International Space Station.

Figure 1.23 Human Research Ethics

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NASA/Ames

AP Images/Uncredited

One of the studies that provoked today’s concerns with the safety of human research participants was the Tuskegee Syphilis Study conducted between 1932–1972, in which impoverished African-American men infected with syphilis were not even aware that they were in a research study at all. When effective treatments became available during the course of the study, they were not offered to the participants, among many other serious ethical lapses. In this 1950s photo, a physician in Tuskegee, Ala., draws blood from one of the study’s participants.

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Chapter 1

What Is Behavioral Neuroscience?

Neuroscience in Everyday Life Can Brain Stimulation Improve My Memory? Students rely on their memory skills to master and use new information. Patients with Alzheimer disease and similar neurodegenerative conditions experience progressively worsening memory functions. Even in cases of healthy aging, memory lapses can be embarrassing and upsetting. What if we could use brain stimulation to make a person’s memory better? Researchers report that the use of non-invasive stimulation, such as rTMS or tES, can enhance a person’s memory performance (Goldthorpe et al., 2020; Hebscher et al., 2021; Rosenblum & Dresler, 2021). Nonetheless, the picture remains complicated. Memory, as we’ll learn in Chapter 12, can take different forms. The way you process memories for how to drive your car is different from the way you remember the function of the amygdala. Brain stimulation has larger effects on some aspects of memory than on others. Stimulation effects interact in complex ways with personal characteristics,

use of animals with other options, and refine methods to ensure the most humane treatment possible (Russell & Burch, 1959). It is also expected that animals will be provided with excellent care and housing. As in the case of human participants, regulations governing the use of animals in research have changed considerably over time. As you read this textbook, you might be concerned about the ethical implications of some of the research described. As your author, I would welcome the opportunity to discuss your concerns with you.

Interim Summary 1.3 Summary Points 1.3 1. Open science initiatives aim to ensure that science promotes openness, integrity, and reproducibility. (LO6) 2. Research ethics agreed on by government agencies, universities, and individual researchers are designed to protect both human participants and animal subjects from harm. (LO6) 3. In addition to being protected from physical and psychological harm, human participants must not be coerced into participation, and their confidentiality must be strictly maintained. (LO6) 4. Animal subjects must be protected from unnecessary pain and suffering. Researchers must establish

such as a person’s level of education. Electrical stimulation produced improvements in the working memory (refer to Chapter 12) of well-educated, but not poorly educated, adults (Berryhill & Jones, 2012). In case you’re anxious to buy any of the stimulation devices available on Amazon, please consider the following carefully. When these devices are used in laboratory settings, they are considered safe, but in the hands of non-experts, things can go badly wrong. Electrodes can burn the skin or be misplaced with the effect of simulating the wrong part of the brain. Safety protocols, such as length and frequency of exposure, cannot be ensured at home. Most importantly, we still have much to learn about the use of this technology, including its long-term effects. For now, perhaps the best choice of action is to rely on old-fashioned studying, although we strongly recommend that you study according to the best insights from cognitive science (refer to Chapter 12).

the necessity of using animal subjects and are obligated to provide excellent housing, food, and veterinary care. (LO6) Review Questions 1.3 1. Which aspect of open science do you think will produce the greatest benefits? 2. What further considerations would you recommend for the protection of human participants and animal research subjects?

Summary Table 1.3: Ethical Principles Participants

Ethical Principles No coercion

Human participants

Informed consent Minimal Risk Confidentiality Necessity

Animal subjects

Excellent food, housing, vet care Avoidance of pain and distress

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Chapter Review

Chapter Review Tho u g h t Q u e st ion s 1. How have societal factors influenced scientific discovery in the past? What aspects of our current environment act to enhance or hinder scientific understanding in behavioral neuroscience? 2. Which of the methods outlined in this chapter have the greatest potential for producing further advancements in our understanding of brain and behavior? 3. Which of the methods outlined in this chapter have the most potential for practical applications, such as detecting deception?

Key Ter ms behavioral neuroscience/biological psychology (p. 2) concordance rate (p. 20) diffusion tensor imaging (DTI) (p. 13) electroencephalogram (EEG) (p. 13) event-related potential (ERP) (p. 14) eye tracking (p. 11) facial electromyography (fEMG) (p. 10) forward genetic screen (p. 20)

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functional MRI (fMRI) (p. 12) functional magnetic resonance spectroscopy (fMRS) (p. 19) functional near-infrared spectroscopy (fNIRS) (p. 13) genome-wide association study (GWAS) (p. 20) heart rate variability (HRV) (p. 11) heritability (p. 20) hyperscanning (p. 15) invasiveness (p. 9) lesion (p. 18) magnetic resonance imaging (MRI) (p. 12) magnetoencephalography (MEG) (p. 14) microdialysis (p. 19) molecular genetics (p. 20) neuroscience (p. 2) open science (p. 22) optogenetics (p. 18) positron emission tomography (PET) (p. 12) pupil dilation (p. 11) repeated transcranial magnetic stimulation (rTMS) (p. 17) reverse genetic screen (p. 21) single-cell recording (p. 15) skin conductance recording (SCR) (p. 11) spatial resolution (p. 9) temporal resolution (p. 9) transcranial electrical stimulation (tES) (p. 18) voxel (p. 12)

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Chapter 2 Learning Objectives L01

Distinguish among the major anatomical directional terms and planes of section.

L02

Describe the locations and functions of the meninges, cerebrospinal fluid, and cerebral arteries.

L03

Identify the major divisions and functions of the spinal cord.

L04

Explain the functions of the major structures found in the hindbrain, midbrain, and forebrain.

L05

L06

L07

Describe the structure and functions of the cerebral cortex. Identify the structures and functions of the peripheral nervous and endocrine systems. Discuss the evolution of the human nervous system.

Functional Neuroanatomy and the Evolution of the Nervous System Chapter Outline Anatomical Directions and Planes of Section Protecting and Supplying the Nervous System

Meninges Cerebrospinal Fluid The Brain’s Blood Supply

Interim Summary 2.1 The Central Nervous System

The Spinal Cord Embryological Divisions of the Brain The Hindbrain The Midbrain The Forebrain

Interim Summary 2.2 The Peripheral Nervous System

The Cranial Nerves The Spinal Nerves The Autonomic Nervous System The Endocrine System

The Evolution of the Human Nervous System

Natural Selection and Evolution Evolution of the Nervous System Evolution of the Human Brain

Interim Summary 2.3 Chapter Review

Connecting to Research: Linking the Brain and the Immune System Behavioral Neuroscience Goes to Work: So You Want to Be a Neurosurgeon? Thinking Ethically: Predicting “Dangerousness” Neuroscience in Everyday Life: Can I Improve My Heart Rate Variability (HRV)? 27

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Chapter 2

Functional Neuroanatomy and the Evolution of the Nervous System

Anatomical Directions and Planes of Section Navigating around the three-dimensional human brain is similar to describing the geography of our three-dimensional Earth. Without a vocabulary to describe the location of one area relative to others, we would quickly get lost. Instead of north, south, east, or west, anatomists have their own sets of directional terms. Although it might seem to be a lot of work to memorize these terms, the payoff comes when you can locate structures easily by their names. The ventromedial hypothalamus could simply be memorized,

rostral A directional term meaning toward the head of a four-legged animal. caudal A directional term meaning toward the tail of a four-legged animal. ventral A directional term meaning toward the belly of a four-legged animal. dorsal A directional term meaning toward the back of a four-legged animal.

but by knowing that ventral means toward the belly side of an animal and medial means toward the midline, you will know exactly where to look in the hypothalamus for this structure. Because anatomical directions for human beings are complicated by the fact that we walk on two legs, we’ll start off with the simpler case of the four-legged animal. Structures that are located toward the head end of the animal are rostral, from the Latin word for “beak.” In other words, the head of a dog is rostral to its shoulders. Structures located toward the tail end of the animal are caudal, from the Latin word for “tail.” For example, the dog’s ears are caudal to its nose, and its hips are caudal to its shoulders. Structures located toward the belly side are ventral (Latin for “belly”), while structures toward the back are dorsal (Latin for “back”). If you have trouble keeping these last two straight, it might help to remember that scary dorsal shark fin cutting through the water in the film Jaws. Like geographical terms, these anatomical terms are relative to another place. Just as New York is north of Florida but south of Canada, the dog’s ears are caudal to its nose but rostral to its shoulders. Why are anatomical directions different in people? As presented in Figure 2.1, our two-legged stance puts

Figure 2.1 Anatomical Directions Anatomists use directional terms to name and locate structures. Because standing upright puts an 80-degree angle in the human neuraxis at the junction of the brainstem and cerebral hemispheres, the dorsal surface of the human brain also forms an 80-degree angle with the dorsal spinal cord. Dorsal

Superior

Rostral

Brain Midline Spinal cord

Caudal Ventral

Brain Neuraxis

Proximal

Spinal cord Posterior

Anterior

Distal

Rostral Ventral

Dorsal Caudal

Inferior

Lateral

Lateral Medial

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Protecting and Supplying the Nervous System

a bend in the neuraxis, an imaginary line that runs the length of the spinal cord through the brain. This bend occurs at the junction of the brainstem and the forebrain, discussed in detail later in the chapter. In the four-legged animal, the neuraxis forms a straight line running parallel to the ground. The dorsal parts of the animal’s brain are in line with the dorsal parts of the spinal cord. In humans, the dorsal parts of our forebrain form an 80-degree angle with the dorsal parts of the brainstem and spinal cord, so the dorsal part of the brain is on the top of your head, but the dorsal part of the spinal cord runs along your back. In contrast, a second set of anatomical terms (anterior–posterior, superior–inferior) does not change with the bending of the neuraxis. You can think of the ceiling of your classroom as superior, the floor as inferior, the front wall as anterior, and the back wall as posterior. Using this set of terms, the rostral part of your brain and the ventral part of your spinal cord would both be referred to as “anterior.” Additional directional terms refer to the midline, an imaginary line that divides us into approximately equal halves. If two structures are ipsilateral, they are both on the same side of the midline. My left arm and left leg are ipsilateral to each other. If structures are on opposite sides of the midline, we say they are contralateral. My right arm and left leg are contralateral to each other. Structures close to the midline are referred to as medial, and structures to the side of the midline are called lateral. My heart is medial to my shoulders, and my ears are lateral to my nose. Similar terms include proximal, which means close to the center, and distal, which means far away from the center. Usually, we use these two terms to refer to limbs. My toes are distal relative to my knees, and my shoulders are proximal relative to my elbows. Although directional terms help us find our way around the nervous system, we also need a way to view three-dimensional structures as flat images on a page. Anatomists have found it useful to make particular cuts or sections in the nervous system to view the structures in two rather than three dimensions. The choice of how to make the section can be arbitrary. Different structures are often more easily viewed with one section than with others. Traditionally, we use the coronal, sagittal, and horizontal sections, which are presented in Figure 2.2. Coronal sections, also known as frontal sections, divide the nervous system from front to back. Sagittal sections are parallel to the midline, allowing us a side view of brain structures. The special section that divides the brain into two relatively equal halves is known as a midsagittal section. The third type of section is the horizontal section, also known as an axial or transverse section, which divides the brain from top to bottom. You will be presented with many examples of each type of section in this chapter and in the remainder of the text.

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Protecting and Supplying the Nervous System Because of the obvious importance of the brain, it is one of the most protected organs in your body. The bony skull protects the brain from all but the most serious blows. It is important to note, however, that the skull bones are not fully mature in infants. The infant is born with skull bones that can overlap each other, somewhat like the tectonic plates of the earth. This design aids the movement of the baby’s head through the birth canal. In a young baby with very light or no hair, you can often perceive a pulse at the top of the head between the skull bones, known as a soft spot or fontanel. It takes about 18 months for human skull bones to fuse completely.

Meninges Although the bones offer the best defense, even the baby with a soft spot enjoys substantial protection of its brain provided by three layers of membranes, or meninges, that surround the nervous system (refer to Figure 2.3). The outermost layer of the meninges is known as the dura mater, which literally means “hard mother” in Latin. Our word durable comes from the same root. The

neuraxis An imaginary line that runs the length of the spinal cord to the front of the brain. anterior A directional term meaning toward the front. posterior A directional term meaning toward the rear. superior A directional term meaning toward the top. inferior A directional term meaning toward the bottom. midline An imaginary line dividing the body into two equal halves. ipsilateral A directional term referring to structures on the same side of the midline. contralateral A directional term referring to structures on opposite sides of the midline. medial A directional term meaning toward the midline. lateral A directional term meaning away from the midline. proximal A directional term that means closer to center; usually applied to limbs; opposite of distal. distal A directional term meaning farther away from another structure, usually in reference to limbs; opposite of proximal. coronal/frontal section An anatomical section dividing the brain front to back, parallel to the face. sagittal section An anatomical section that is parallel to the midline. midsagittal section A sagittal section that divides the brain into two approximately equal halves. horizontal/axial/transverse An anatomical section that divides the brain from top to bottom. meninges The layers of membranes that cover the central nervous system (CNS). dura mater The outermost of the three layers of meninges.

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Figure 2.2 Planes of Section Anatomists use the sagittal, coronal, and horizontal sections to view three-dimensional structures as two-dimensional images. Sagittal Dorsal or superior

Rostral or anterior

Caudal or posterior

Sagittal

Ventral or inferior

Coronal

Coronal Dorsal or superior

Horizontal

Lateral

Medial

Medial

Lateral

Ventral or inferior Horizontal Lateral

Medial

Rostral or anterior

Caudal or posterior Medial

Lateral

Figure 2.3 The Skull and Three Layers of Membrane Protect the Brain In addition to the protection provided by the skull bones, the brain and spinal cord are covered with three layers of membranes known as meninges. Going from the skull to the brain, we find the dura mater, the arachnoid layer, and the pia mater. Between the arachnoid and pia mater layers is the subarachnoid space, which contains cerebrospinal fluid (CSF). There is no CSF in the peripheral nervous system (PNS).

Skin of scalp Bone of skull Dura mater Arachnoid membrane Subarachnoid space Pia mater Artery Brain

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Protecting and Supplying the Nervous System

reference to “mother” might have originated from early comparisons between the protective membranes and the blankets used to swaddle infants. The dura mater is composed of leather-like tissue that follows the outlines of the skull bones. Below the dura mater is the arachnoid layer. This more delicate layer gets its name from the fact that its structure looks like a spider’s web in cross-section. The innermost layer is the pia mater, or “pious mother.” This nearly transparent membrane sticks closely to the outside of the brain. Between the arachnoid and pia mater layers is the subarachnoid space, with “sub” meaning below. These three layers cover the brain and spinal cord. Once nerves leave the bony protection of the skull bones and vertebrae of the back, they are referred to as peripheral nerves and are protected by several layers of connective tissue instead. For many years, neuroanatomists believed that the brain was “immune privileged.” This means that the brain does not respond in the same way as the rest of the body to infections or tumors. For example, tissue transplanted

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into the brain does not provoke an immune response, while tissue transplanted elsewhere does. Immune privilege was puzzling, however. Infection-provoked inflammation is known to play important roles in disorders such as Alzheimer disease, autism spectrum disorder, multiple sclerosis, and schizophrenia. If the brain is cut off from the immune system, how does brain inflammation occur? A first step in resolving the mystery was the discovery of a lymphatic system within the dura mater (Aspelund et al., 2015; Louveau et al., 2015a; Louveau et al., 2015b; refer to Figure 2.4). Some cerebrospinal arachnoid layer The middle layer of the meninges covering the central nervous system (CNS). pia mater The innermost of the layers of meninges in the CNS. subarachnoid space A space filled with cerebrospinal fluid (CSF) that lies between the arachnoid and pia mater layers of the meninges in the central nervous system (CNS).

Figure 2.4 Surveillance of the CNS by the Immune System The following steps allow the immune system to initiate responses in the CNS: (1) Antigens (toxins or foreign material) enter the CSF in the subarachnoid space; (2) Within the dura mater, dendritic cells (a type of leukocyte) capture antigens and “present” them to T-cells that (3) congregate within the blood-filled sinuses of the dura mater; (4) T-cells and macrophages form “hubs” at the dural sinus.

Source: Adapted from Rustenhoven, J., Drieu, A., Mamuladze, T., de Lima, K. A., Dykstra, T., Wall, M., Papadopoulos, Z., Kanamori, M., Salvador, A. F., Baker, W., Lemieux, M., Da Mesquita, S., Cugurra, A., Fitzpatrick, J., Sviben, S., Kossina, R., Bayguinov, P., Townsend, R. R., Zhang, Q., Erdmann-Gilmore, P., … Kipnis, J. (2021). Functional characterization of the dural sinuses as a neuroimmune interface. Cell, 184(4), 1000–1016.e1027. doi:10.1016/j.cell.2020.12.040.

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Connecting to Research Linking the Brain and the Immune System Up until quite recently, anatomists believed that the body’s lymphatic system did not include the brain, leading to the notion that the brain is “immune privileged.” Hints that this might not be the case began to emerge from an improved understanding of autism spectrum disorder, Alzheimer disease, and multiple sclerosis. What was missing was evidence of a direct link between the brain and immune system. A first step in solving this mystery was the identification of a lymphatic drainage system within the meninges (Louveau et al., 2015a; Louveau et al., 2015b). This important work, however, did not specify where and how the immune system could monitor the CSF for antigens (toxins or foreign substances) as it drained from the brain. That piece of the puzzle was solved in a second study (Rustenhoven et al., 2021).

The Question: Where and how are CNS antigens monitored by the immune system? Methods The researchers evaluated mice and human tissue from autopsies using an extensive list of genetic editing and sequencing methods coupled with immunohistochemistry methods and multiple microscopy methods (refer to Chapter 1).

fluid (CSF; refer to the next section) drains through this system, washing antigens (toxins or foreign material) toward the back of the brain. Standing guard in the permeable or “leaky” sinuses, or blood-filled cavities, of the dura mater are large numbers of immune cells, surveilling the draining CSF for signs of invaders. If the immune cells detect something that shouldn’t be there, they initiate an immune response (Rustenhoven et al., 2021). These results suggest that some disorders might be better understood as communication problems between the brain and immune system rather than problems within the brain itself.

cerebrospinal fluid (CSF) The special plasma-like fluid circulating within the ventricles of the brain, the central canal of the spinal cord, and the subarachnoid space. ventricle One of four hollow spaces within the brain that contain CSF. choroid plexus The lining of the ventricles, which secretes the CSF. central canal The small midline channel in the spinal cord that contains CSF.

Results The researchers demonstrated that the immune system monitors the draining CSF for antigens where the vessels carrying the CSF come into close proximity to sinuses, or blood-filled cavities, in the dura mater. As the antigens gather near the sinuses, they are “presented” across the relatively permeable (leaky) membranes to waiting immune cells within the blood circulation.

Conclusions Immune responses such as inflammation can be dangerous to the brain, so it is advantageous that immune processes take place on the margins of the brain rather than more centrally. These findings shed further light onto the role of the immune system in neurodegenerative disorders (refer to Chapters 5 and 15). Evidence of disturbed immune responses in patients with Parkinson disease, Alzheimer disease, and multiple sclerosis (refer to Chapters 8 and 15) are consistent with the current results. Further understanding of how the immune system interfaces with the brain can lead to improvements in the prevention and treatment of many neurodegenerative conditions.

Cerebrospinal Fluid Cerebrospinal fluid (CSF) is secreted within hollow spaces in the brain known as ventricles. Within the lining of the ventricles, the choroid plexus converts material from the nearby blood supply into CSF. CSF circulates through the central canal of the spinal cord and four ventricles in the brain: the two lateral ventricles, one in each hemisphere, and the third and fourth ventricles in the brainstem. The cerebral aqueduct connects the third and fourth ventricles. The fourth ventricle is continuous with the central canal of the spinal cord, which runs the length of the cord at its midline. The ventricles and the circulation of CSF are presented in Figure 2.5. Below the fourth ventricle, there is a small opening that allows the CSF to flow into the subarachnoid space that surrounds both the brain and spinal cord. A connection also exists between the subarachnoid space and the inner ear. New CSF is made constantly at a rate of approximately 600–700 mL (about 20–23 oz) per day, with the entire supply being turned over about four times per day. The old CSF is reabsorbed into the veins at the top of the head. CSF is very similar in composition to the clear plasma of the blood. Because of its weight and composition, CSF

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Protecting and Supplying the Nervous System

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Figure 2.5 Cerebrospinal Fluid Circulates through the Ventricles, Spinal Cord, and Subarachnoid Space Cerebrospinal fluid (CSF) is produced by the choroid plexus that lines the walls of the ventricles. From the lateral ventricles, the CSF flows through the third and fourth ventricles and into the central canal of the spinal cord. At the base of the cerebellum, CSF exits into the subarachnoid space and is reabsorbed by veins near the top of the head. Third ventricle

Anterior horns of lateral ventricles

Lateral ventricles

Lateral ventricle

CSF is reabsorbed into bloodstream.

Third ventricle

Cerebral aqueduct

CSF is produced by choroid plexus.

Fourth ventricle

Fourth ventricle CSF flows into subarachnoid space. Base of spinal cord

Inferior horns of lateral ventricles

Central canal (a) Lateral View

essentially floats the brain within the skull. This has several advantages. If you bump your head, the fluid acts like a cushion to soften the blow to your brain. In addition, nerve cells (neurons) respond to appropriate input, not to pressure on the brain. Pressure can often cause neurons to fire in maladaptive ways, such as when a tumor causes seizures by pressing down on a part of the brain. By floating the brain, the CSF prevents neurons from responding to pressure and providing false information. In addition to its “floating” function, the CSF supports the central nervous system by circulating nutrients and removing waste products. The CSF also provides a pathway through which neurochemicals can diffuse to more distant locations (refer to Chapter 4). Because there are several narrow sections in this circulation system, blockages sometimes occur, leading to hydrocephalus, which literally means water on the head (refer to Figure 2.6). Hydrocephalus can be treated by the installation of a shunt to drain off excess fluid or with surgery that makes an opening in the bottom of one ventricle

(b) Midsagittal View

or between two ventricles to enhance drainage. People treated with a shunt system must continue to use a shunt for the rest of their lives. In some cases, children are born with hydrocephalus. If untreated, hydrocephalus can cause intellectual disability, as the large quantity of CSF prevents the normal growth of the brain. Some adults also experience blockages of the CSF circulatory system due to the growth of tumors or scar tissue. They, too, must be treated with shunts and/or surgery. CSF moves through a completely self-contained and separate circulation system that never has direct contact with the blood supply. Because the composition of the CSF is often important in diagnosing diseases, a spinal tap is a common, though extremely unpleasant, procedure. In a spinal tap, the physician withdraws some fluid from the subarachnoid space surrounding the spinal cord through a needle. This is usually done in the lumbar region of the spinal cord in the lower back. Consequently, the procedure is often referred to as a lumbar puncture or LP.

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Figure 2.6 Hydrocephalus Results from Blockage in the Circulation of Cerebrospinal Fluid (CSF)

DIOMEDIA Inc

This photograph shows a baby born with the condition of hydrocephalus, which results when the normal circulation of cerebrospinal fluid (CSF) is blocked. Note the large size of the baby’s head, which has expanded to accommodate all of the CSF. Untreated, hydrocephalus causes intellectual disability, but today, shunts installed to drain off the excess fluid can prevent any further damage to the child’s brain. This type of image is made possible by the work of neurologist Ray Chun, who developed the “Chun gun,” a non-invasive way of lighting the head to diagnose hydrocephalus. The scatter of light differs when excess CSF is present. Previously, physicians drained all the CSF from around the brain and replaced it with air, oxygen, or helium and then x-rayed the brain.

The Brain’s Blood Supply Although the brain makes up only about 2 percent of your body weight, it is the target of about 15 to 20 percent of the blood pumped by the heart. The brain is served by a network of about 400 miles of capillaries, enough to stretch from San Francisco to Los Angeles. Having a rich blood supply is essential because neurons are more vulnerable to oxygen deprivation than other types of cells in the body due to their very high metabolic rate. Even brief interruptions to the brain’s blood supply can cause permanent cell death or damage (refer to Chapter 15). The brain is served by the carotid arteries on either side of the neck as well as by the vertebral arteries that travel up through the back of the skull. Once inside the skull, the carotid arteries branch to form the anterior and middle cerebral arteries. The vertebral arteries give rise to a carotid artery One of the two major blood vessels that travel up the sides of the neck to supply the brain. vertebral artery One of the important blood vessels that enters the brain from the back of the skull.

basilar artery, which joins the carotid arteries at the base of the brain to form the circle of Willis. The posterior cerebral arteries originate at this junction (refer to Figure 2.7). This circular configuration helps minimize the damage to the brain that would result from the blockage of a major artery.

Interim Summary 2.1 Summary Points 2.1 1. Anatomical directions help us locate structures in the nervous system. In four-legged animals, rostral structures are located toward the head, caudal structures are located toward the tail, dorsal structures are located toward the back, and ventral structures are located toward the belly. In humans, the dorsal parts of our brain form an 80-degree angle with the dorsal parts of the spinal cord. Additional terms that do not vary with the body’s orientation in space include anterior (toward the front), posterior (toward the back), superior (top), and inferior (bottom). (LO1)

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The Central Nervous System

Figure 2.7 The Brain Has a Generous Supply of Blood Blood reaches the brain either through the carotid arteries on either side of the neck or through the vertebral arteries entering through the base of the skull. Once inside the skull, the carotid arteries branch to form the anterior and middle cerebral arteries. The vertebral arteries give rise to a basilar artery, which joins the carotid arteries at the base of the brain to form the circle of Willis. The posterior cerebral arteries originate at this junction.

Circle of Willis

Posterior cerebral artery

Anterior cerebral artery Middle cerebral artery

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floats and cushions the brain. CSF circulates through the four ventricles of the brain, the central canal of the spinal cord, and the subarachnoid space. (LO2) 5. The brain is supplied with blood through the carotid and vertebral arteries. (LO2) Review Questions 2.1 1. When considering your nervous system and that of your dog or cat, what anatomical direction terms would be the same or different? 2. Why do we have cerebrospinal fluid (CSF), and where in the nervous system is it found?

The Central Nervous System

Carotid artery

We divide the entire nervous system into two components: the central nervous system (CNS) and the Vertebral peripheral nervous system (PNS). artery The CNS includes the brain and spinal cord. The brain measures about 5½ in (140 mm) wide, 6½ in (167 mm) long, and 32/3 in (93 mm) high, Area of cortex served by: and weighs about 3 lb (1.5 kg). It contains about Anterior cerebral artery 86 billion nerve cells that make about 15 trillion connections. The spinal cord contains about one Middle cerebral artery billion nerve cells, reaches a length of about 18 in Posterior cerebral (45 mm) in men and 17 in (43 mm) in women, artery and weighs about 1.2 oz (35 g). The diameter of the spinal cord ranges between 0.4 in (1 cm) and 0.6 in (1.5 cm), or about the thickness of your thumb. The PNS contains all the nerves that exit the brain and spinal cord, carrying sensory and motor messages to and from the other parts of the body. The tissue of the CNS is encased in bone, but the 2. Ipsilateral structures are on the same side of the tissue of the PNS is not. Figure 2.8 summarizes the genmidline, and contralateral structures are on oppoeral organization of the central and peripheral nervous site sides of the midline. Structures near the midline systems. are medial, and structures away from the midline Although the neurons in both the CNS and PNS are are lateral. In limbs, proximal structures are closer similar, there are some differences between the two systo the body center, and distal structures are farther tems. CSF circulates around the CNS but not within the away. (LO1) PNS. In addition, damage to the CNS is considered per3. Coronal or frontal sections divide the brain from manent, but some recovery can occur in the PNS. front to back. Sagittal sections are parallel to the midline and give us a side view of the brain. Horizontal (or axial or transverse) sections divide the central nervous system (CNS) The brain and spinal cord. brain from top to bottom. (LO1) peripheral nervous system (PNS) The nerves exiting the brain 4. Three layers of meninges protect the central nervous system: the dura mater, the arachnoid, and the pia mater. Nerves in the PNS are sheathed by connective tissue. Cerebrospinal fluid (CSF)

and spinal cord that serve sensory and motor functions for the rest of the body. spinal cord A long cylinder of nervous tissue extending from the medulla to the first lumbar vertebra.

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(a bone in the spine, or vertebral column). The neurons making up the spinal cord are found in The nervous system has two major components, the central nervous system (CNS), the upper two thirds of the verwhich includes the brain and spinal cord, and the peripheral nervous system (PNS), tebral column. The spinal cord which contains all the nerves that exit the brain and spinal cord. is shorter than the vertebral column because the cord itself THE NERVOUS SYSTEM stops growing earlier in a child’s development than the bones in the vertebral column do. RunThe central The peripheral ning down the center of the nervous system nervous system spinal cord is the central canal, through which CSF circulates. The spinal nerves exit The somatic The autonomic The brain between the bones of the vernervous system nervous system tebral column. The bones are cushioned from one another The spinal with disks. If any of these disks The sympathetic cord degenerate, pressure is exerted nervous system on the adjacent spinal nerves, producing a painful pinched nerve. Based on the points of The parasympathetic exit, we divide the spinal cord nervous system into 31 segments, as presented in Figure 2.9. Starting closest to the brain, there are eight cervical nerves that serve the area of the head, neck, and arms. We refer to the neck brace used after a whiplash injury as a cervical collar. Below the cervical nerves are the 12 thoracic nerves, which serve most of the torso. You may have heard the term thoracic surgeon used to identify a surgeon who specializes in operations involving the chest, such as heart or lung surgeries. Five lumbar nerves The Spinal Cord come next, serving the lower back and legs. If people complain of lower back pain, this usually means they have The spinal cord is a long cylinder of nerve tissue that lumbar problems. The five sacral nerves serve the backs extends like a tail from the medulla, the most caudal of the legs and the genitals. Finally, we have the single structure of the brain, down to the first lumbar vertebra coccygeal nerve. We will discuss these nerves in greater detail in relation to touch in Chapter 7. Although the spinal cord weighs only 2 percent as much vertebral column The bones of the spinal column that protect and as the brain, it is responsible for several essential functions. enclose the spinal cord. The spinal cord is the original information superhighway. cervical nerve One of eight spinal nerves that serves the area of the head, neck, and arms. When viewed in a horizontal section, much of the cord thoracic nerve One of twelve spinal nerves that serves the torso. appears white. White matter is made up of nerve fibers lumbar nerve One of five spinal nerves that serves the lower back known as axons, the branches of neurons that carry signals and legs. to other neurons. The tissue’s white appearance is due to a sacral nerve One of five spinal nerves that serves the backs of the fatty material known as myelin, which covers most human legs and the genitals. axons. When the tissue is preserved for study, the myelin coccygeal nerve The most caudal of the spinal nerves. repels staining and remains white, resembling the fat on a white matter An area of neural tissue primarily made up of steak. These large bundles or tracts of axons are responsimyelinated axons. ble for carrying information to and from the brain. Axons

Figure 2.8 The Organization of the Nervous System

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The Central Nervous System

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immediately pull your body away from the source of the pain. This time, three types of neurons The spinal cord is divided into cervical, thoracic, lumbar, sacral, and coccygeal segments. are involved: a sensory neuron, The spinal nerves exit either side of the cord between the surrounding bony vertebrae. a motor neuron, and an interVentral neuron between them. Because few neurons are involved, this Spinal Central withdrawal reflex produces very nerve canal rapid movement. Other spinal reflexes help us coordinate the Cervical actions of the autonomic nervous system, which we discuss later in the chapter, produce goosebumps when we’re cold, and manage our blood presWhite Gray Thoracic sure when we stand up to keep matter matter us from fainting. Most of these simple reflexes involve neural circuits that are located to one side or the other of the midline Lumbar Dorsal within a single segment of the spinal cord. Sacral The spinal cord also manages a number of more comCoccygeal plex reflexes, known as central pattern generators, that help us move rhythmically. These reflexes allow us to alternate movements, such as shifting our from sensory neurons that carry information about touch, weight automatically from one leg to the other while walkposition, pain, and temperature travel up the dorsal parts ing, or to synchronize movement, such as hopping. Cenof the spinal cord. Axons from motor neurons, responsitral pattern generators are characterized by circuits that ble for movement, travel in the ventral parts of the cord. cross the midline of the spinal cord. (Axons will be discussed in more detail in Chapter 3.) Damage to the spinal cord results in loss of sensation There appears to be a gray butterfly or letter H shape (of both the skin and internal organs) and loss of voluntary in the center of the cord. Gray matter consists of areas movement in parts of the body served by nerves located primarily made up of cell bodies (refer to Chapter 3). The below the damaged area. Some spinal reflexes are usutissue’s gray appearance occurs because the cell bodies ally retained. Muscles can be stimulated, but they are not absorb some of the chemicals used to preserve the tissue, under voluntary control. A person with cervical damage, which stains them a pinkish gray. The neurons found in such as the late actor Christopher Reeve (Superman), the dorsal horns of the H receive sensory input, and neuhas quadriplegia (quad meaning “four,” indicating loss of rons in the ventral horns of the H pass motor information control over all four limbs). All sensation and ability to on to the muscles. These ventral horn cells participate in either voluntary movement or spinal reflexes. Without any input from the brain, the spinal cord gray matter An area of neural tissue primarily made up of cell neurons are capable of some important reflexes. The knee bodies. jerk, or patellar reflex, that your doctor checks by tapping dorsal horns Gray matter in the spinal cord that contains sensory your knee is an example of one type of spinal reflex. This neurons. reflex is managed by two types of neurons. One type of ventral horns Gray matter in the spinal cord that contains motor neurons. neuron processes the sensory information coming to the cord from muscle stretch receptors (refer to Chapter 8). reflex An involuntary action or response. These neurons communicate with spinal motor neurons patellar reflex The knee-jerk reflex; a spinal reflex in which tapping below the knee produces a reflexive contraction of the that respond to input by contracting a muscle, causing quadriceps muscle of the thigh, causing the foot to kick. your foot to kick. Spinal reflexes also protect us from withdrawal reflex A spinal reflex that pulls a body part away from injury. If you touch something hot or step on something a source of pain. sharp, your spinal cord produces a withdrawal reflex. You

Figure 2.9 The Anatomy of the Spinal Cord

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Table 2.1 | Embryological Divisions of the Brain Division

Subdivision

Structures

Ventricle

Forebrain (Prosencephalon)

Telencephalon

Cerebral cortex

Lateral ventricles

Hippocampus Amygdala Basal ganglia Diencephalon

Thalamus

Third ventricle

Hypothalamus Midbrain (Mesencephalon)

Mesencephalon

Hindbrain (Rhombencephalon)

Metencephalon

Tectum

Cerebral aqueduct

Tegmentum Cerebellum

Fourth ventricle

Pons Myelencephalon

move the arms, legs, and torso are lost. A person with lumbar-level damage has paraplegia. Use of the arms and torso is maintained, but sensation and movement in the lower torso and legs are lost. In all cases of spinal injury, bladder and bowel functions are no longer under voluntary control, as necessary input from the brain to the sphincter muscles does not occur. Currently, spinal damage is considered permanent, but significant progress is being made in repairing the spinal cord (refer to Chapters 5 and 15).

Embryological Divisions of the Brain Early in embryological development, at about gestational week four, the brain forms three bulges: the hindbrain (rhombencephalon), midbrain (mesencephalon), and forebrain (prosencephalon; refer to Chapter 5). Together, the hindbrain and midbrain make up the brainstem. Later hindbrain The most caudal division of the brain, including the medulla, pons, and cerebellum. midbrain The division of the brain lying between the hindbrain and forebrain, including the superior and inferior colliculi, periaqueductal gray, red nucleus, and substantia nigra. forebrain The division of the brain containing the diencephalon and the telencephalon. brainstem The hindbrain and midbrain. pons A structure located in the metencephalon between the medulla and midbrain that participates in the management of states of consciousness. cerebellum A structure located in the metencephalon that participates in balance, muscle tone, muscle coordination, some types of learning, and possibly higher cognitive functions in humans. myelencephalon/medulla The most caudal part of the hindbrain; contains several cranial nerve nuclei and participates in the management of breathing, heart rate, and blood pressure. nuclei Collections of cell bodies that share a function.

Medulla

in embryological development, the midbrain makes no further divisions, but the hindbrain divides into the myelencephalon, or medulla, and the metencephalon, which includes the pons and cerebellum. The forebrain divides further into the diencephalon and telencephalon. Cephalon, by the way, refers to the head. Table 2.1 outlines these divisions and the major structures we will find in each.

The Hindbrain The structures of the brainstem are presented in Figure 2.10. We will begin our exploration of the brainstem in the hindbrain, located just above the spinal cord, which contains both the myelencephalon and metencephalon. If you place your hand on the back of your neck and tilt your head backwards, the flexion point is the approximate dividing line between your spinal cord and brain. The Medulla (Myelencephalon) The gradual swelling of tissue above the cervical spinal cord marks the most caudal portion of the brain, the medulla, or myelencephalon. The medulla, like the spinal cord, contains large quantities of white matter. The vast majority of information passing to and from higher structures of the brain must still pass through the medulla. Instead of the butterfly appearance of the gray matter in the spinal cord, the medulla contains a number of nuclei, or collections of cell bodies with a shared function. These nuclei are suspended within the white matter of the medulla. Some of these nuclei contain cell bodies whose axons make up several of the cranial nerves, which are part of the peripheral nervous system serving the head and neck area. Other nuclei manage essential functions such as breathing, heart rate, and blood pressure. Damage to the medulla is typically fatal due to its control over these vital functions.

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found at this level of the brainstem are the cochlear nucleus and the vestibular (a) This sagittal section displays many of the important structures found in the brainstem. nucleus. These structures (b) With the cerebral hemispheres removed, we can identify spatial relationships between are examples of cranial nerve the major structures of the brainstem. The key-to-slice allows us to view a horizontal section nuclei, or processing cenof the medulla and several of the important structures found at this level of the brain. ters for cranial nerves. The Forebrain fibers communicating with Reticular formation Thalamus these nuclei arise in the inner ear (refer to Chapter 7). The Locus cochlear nucleus receives coeruleus information about sound, Cerebellum and the vestibular nucleus Midbrain receives information about Pons the position and movement Cochlear nucleus of the head. This vestibular Raphe nuclei input helps us keep our balVestibular nucleus ance (or makes us feel motion Medulla (a) sickness on occasion). The reticular formation, Raphe nucleus Vestibular Cochlear Thalamus nucleus nucleus (Diencephalon) which begins in the medulla, extends through the pons and Midbrain (Mesencephalon) into the midbrain. Reticular Pons nuclei in the pons are nec(Metencephalon) essary for the production of Reticular formation rapid-eye-movement (REM) Reticular formation sleep, which is discussed in greater detail in Chapter 11. Medulla Cerebellum The raphe nuclei, which (Myelencephalon) (Metencephalon) (b) form a column within the reticular formation, influence mood, states of arousal, Along the midline of the upper medulla, we find aggression, appetite, and sleep. The locus coeruleus also the caudal portion of a structure known as the reticular regulates arousal, sleep, and mood. formation. The reticular formation, shown in Figure 2.10, The second major part of the metencephalon, the is a complex collection of nuclei that runs along the midcerebellum, is also shown in Figure 2.10. The cerebelline of the brainstem from the medulla up into the midlum looks almost like a second little brain attached to brain. The structure gets its name from the Latin reticulum, the dorsal surface of the brainstem. Its name, cerebellum, or network. The more than 100 nuclei and circuits within actually means “little brain” in Latin. The use of “little” the reticular formation play important roles in the reguis misleading because the cerebellum actually contains lation of consciousness and arousal (refer to Chapter 11), more neurons than the rest of the brain combined. When movement, pain, and habituation (Wang, 2009). Habituation (refer to Chapter 12) refers to the learned reduction in response to an unchanging, unimportant source of inforreticular formation A collection of brainstem nuclei located near the midline from the rostral medulla up into the midbrain that mation. For example, you might tune out the sound of your regulates consciousness, arousal, movement, and pain. air conditioner after it has been running for some time.

Figure 2.10 Structures of the Brainstem

The Pons and Cerebellum (Metencephalon) The metencephalon contains two major structures, the pons and the cerebellum. The pons, which also appears in Figure 2.10, lies immediately rostral to the medulla. Pons means “bridge” in Latin, and one of the roles of the pons is to form connections between the medulla and higher brain centers as well as with the cerebellum. As in the medulla, large fiber pathways with embedded nuclei are found in the pons. Among the important nuclei

metencephalon The division of the hindbrain containing the pons and cerebellum. cochlear nucleus A group of cell bodies in the pons that receives information about sound from the inner ear. vestibular nucleus A group of cell bodies in the pons that receives input about the location and movement of the head from sensory structures in the inner ear. raphe nuclei Nuclei located in the pons that participate in the regulation of sleep, arousal, mood, appetite, and aggression. locus coeruleus A structure in the pons that participates in arousal, sleep, and mood.

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viewed with a sagittal section, the internal structure of the cerebellum resembles a tree. White matter, or axons, forms the trunk and branches, while gray matter, or neural cell bodies, forms the leaves. A traditional view of the cerebellum emphasized its role in coordinating voluntary movements, maintaining muscle tone, and regulating balance. Input from the spinal cord tells the cerebellum about the current location of the body in three-dimensional space. Input from the cerebral cortex, by way of the pons, tells the cerebellum about the movements you intend to make. The cerebellum then processes the sequences and timing of muscle movements required to carry out the plan. Damage to the cerebellum affects skilled movements, including speech production. Because the cerebellum is one of the first structures affected by the consumption of alcohol, most sobriety tests, such as walking in a straight line or pointing in a particular direction, are actually tests of cerebellar function. Along with the previously mentioned vestibular system, the cerebellum contributes to the experience of motion sickness. The cerebellum is now believed to be responsible for much more than balance and motor coordination. In spite of its lowly position in the hindbrain, the cerebellum is involved in some of our most sophisticated information processing, including executive functions and emotional processing (Koziol et al., 2014; Schmahmann, 2010). In the course of evolution, the size of the cerebellum has kept pace with increases in the size of the cerebral cortex. One of the embedded nuclei of the cerebellum, the dentate nucleus, has become particularly large in monkeys and humans. A part of the dentate nucleus, known as the neodentate, is found only in humans. In addition to language difficulties, patients with cerebellar damage also experience subtle deficits in cognition and perception. As we will discuss in Chapter 12, the cerebellum participates in learning (Raymond & Medina, 2018). In cases of autism spectrum disorder, in which language, cognition, and social awareness are severely affected, abnormal development of the cerebellum is frequently observed (van der Heijden et al., 2021). Although neuroscientists do not agree on its exact function, most theories propose a cerebellum that can use past experiences to make corrections and automate behaviors whether they involve motor systems or not.

The Midbrain The midbrain, or mesencephalon, presented in Figure 2.11, has a dorsal or top half known as the tectum, or “roof,” and a ventral, or bottom half, known as the tegmentum, or “covering.” In the midbrain, CSF is contained in a small channel at the midline known as the cerebral aqueduct. The cerebral aqueduct separates the tectum from the tegmentum and links the third and fourth ventricles. Although the adult midbrain is relatively small compared with the other portions of the brainstem, it still contains a complex array of nuclei (refer to Table 2.2). Surrounding the cerebral aqueduct are cell bodies known as periaqueductal gray (PAG; peri means around). PAG participates in a large and diverse set of functions, including the integrating of autonomic responses, motivated behavior, and defensive responses to threats. PAG appears to play an especially important role in our perception of pain, discussed more fully in Chapter 7. There are large numbers of receptors in the PAG that respond to opioids such as morphine and heroin. Electrical stimulation of this area provides considerable relief from pain. In addition, the PAG participates in the regulation of sleep and coordinates complex motor patterns, including vocalizations, temperature regulation, cardiovascular and respiratory responses, sexual behavior, and urination (Benarroch, 2012). The presence of

Figure 2.11 Structures of the Midbrain Important structures in the midbrain include the superior and inferior colliculi, the cerebral aqueduct, the periaqueductal gray, the substantia nigra, and the red nucleus. Substantia nigra Superior colliculus Tectum

Tegmentum

Inferior colliculus Superior colliculus

mesencephalon Another term for midbrain, the division of the brain lying between the hindbrain and forebrain. tectum The “roof,” or dorsal portion, of the midbrain. tegmentum The “covering,” or ventral, portion of the midbrain. cerebral aqueduct The small channel running along the midline of the midbrain that connects the third and fourth ventricles. periaqueductal gray Gray matter surrounding the cerebral aqueduct of the midbrain that is believed to play roles in sleep, complex movements, the sensation of pain, and parenting behavior.

Cerebral aqueduct Periaqueductal gray Red nucleus Substantia nigra

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Table 2.2 | Important Structures in the Brainstem Brainstem Location

Important Structures

Functions

Medulla

Reticular formation

Arousal, consciousness, movement, pain, attention

Cranial nerve nuclei

Various

Reticular formation (continuing)

Arousal, consciousness, movement, pain, attention

Cranial nerve nuclei

Various

Cochlear nucleus

Audition

Vestibular nucleus

Balance, position

Raphe nucleus

Sleep, mood, appetite, aggression

Locus coeruleus

Sleep, vigilance

Cerebellum

Dentate nucleus

Balance, motor coordination, cognition

Midbrain

Reticular formation (continuing)

Arousal, consciousness, movement, pain, attention

Cranial nerve nuclei

Various

Periaqueductal gray

Pain, sleep, cardiovascular function, sexual behavior, parental behavior, vocalization, temperature control, urination

Red nucleus

Movement

Substantia nigra

Movement, reward seeking

Superior colliculi

Vision

Inferior colliculi

Audition

Pons

large numbers of oxytocin and vasopressin receptors suggests that the PAG is also important to parental behavior (Bartels & Zeki, 2004; refer to Chapters 4 and 10). The midbrain also contains a number of nuclei associated with cranial nerves and the most rostral portion of the reticular formation. Several important motor nuclei are also found at this level of the brainstem, including the red nucleus and the substantia nigra. The red nucleus, which is located within the reticular formation, communicates motor information between the spinal cord and the cerebellum. It gives rise to the rubrospinal tract, which is an alternate pathway for voluntary movement commands that seems more important in other animals than in humans (refer to Chapter 8). The substantia nigra, whose name literally means “black stuff ” due to the pigmentation of the structure, is considered to be part of the basal ganglia of the forebrain (discussed in the next section). Degeneration of the substantia nigra occurs in Parkinson disease, which is characterized by difficulties in initiating movement. The ventral tegmental area, adjacent to the substantia nigra, participates in circuits involved with reward-seeking behaviors (refer to Chapter 9). On the dorsal surface of the midbrain are four prominent bumps. The upper pair is known as the superior colliculi. The superior colliculi receive input from the optic nerves leaving the eye. Although the colliculi are part of the

visual system, they are unable to tell you what you’re seeing. Instead, these structures allow us to make visually guided movements, such as turning the eyes in the direction of a visual stimulus. They also participate in a variety of visual reflexes, including changing the size of the pupils of the eye in response to light conditions (refer to Chapter 6). The other pair of bumps is known as the inferior colliculi. These structures are involved with hearing, or audition. The inferior colliculi are one stop along the pathway from the ear to the auditory cortex. These structures are involved with auditory reflexes such as turning the head in the direction of a loud noise. The inferior colliculi also participate in the localization of sounds in the red nucleus A structure located within the reticular formation that communicates motor information between the spinal cord and the cerebellum; source of the rubrospinal tract. substantia nigra Midbrain nuclei that communicate with the basal ganglia of the forebrain. ventral tegmental area An area adjacent to the substantia nigra of the midbrain that participates in reward-seeking behaviors. superior colliculi A pair of bumps on the dorsal surface of the midbrain that coordinates visually guided movements and visual reflexes. inferior colliculi A pair of bumps on the dorsal surface of the midbrain that processes auditory information.

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environment by comparing the timing of the arrival of sounds at the two ears (refer to Chapter 7).

The Forebrain The forebrain contains many of the most advanced and most recently evolved structures of the brain. Like the hindbrain, the forebrain divides again later in embryological development. The two resulting divisions are the diencephalon and the telencephalon. The diencephalon contains the thalamus and hypothalamus, which are located at the midline just above the mesencephalon or midbrain. The diencephalon is also the embryological source of the retina of the eye (refer to Chapter 6). The telencephalon contains the bulk of the left and right cerebral hemispheres. The Thalamus and Hypothalamus The diencephalon, depicted in Figure 2.12, is located at the rostral end diencephalon A division of the forebrain made up of the hypothalamus, the thalamus, and the retina of the eye. telencephalon The division of the brain comprising the bulk of the cerebral hemispheres. cerebral hemispheres One of the two large, globular structures that make up the telencephalon of the forebrain. thalamus A structure in the diencephalon that processes sensory information, contributes to states of arousal, and participates in learning and memory. hypothalamus A structure found in the diencephalon that participates in the regulation of homeostatic processes like hunger, thirst, sexual behavior, and sleep, and also plays a role in aggression.

of the brainstem. The upper portion of the diencephalon consists of the thalamus, often referred to as the “gateway to the cortex.” We actually have two thalamic nuclei, one on either side of the midline. These structures appear to be just about in the middle of the brain from a midsagittal perspective. The thalamus receives two types of information from other parts of the brain: sensory input and regulatory input. Most of our sensory systems (with the exception of olfaction, or smell) converge initially on the thalamus, which then forwards the information to the cerebral cortex for further processing. It appears that the thalamus does not change the nature of the sensory information as much as it filters the information delivered to the cortex depending on the organism’s state of arousal (Alexander et al., 2006). The reticular formation of the brainstem and the cortex form large numbers of connections with the thalamus that regulate its sensitivity during stages of sleep and wakefulness (refer to Chapter 11). The thalamus receives motivational input from the hypothalamus and other regulatory circuits that is also passed on to the cortex for use in the planning of behavior. The thalamus coordinates the processing of information across different parts of the cortex (Nakajima & Halassa, 2017). Damage to the thalamus typically results in coma, and disturbances in circuits linking the thalamus and cerebral cortex are involved in some seizures (refer to Chapter 15). The thalamus also participates in learning and memory (refer to Chapter 12). Just below the thalamus is the hypothalamus. The name hypothalamus literally means “below the thalamus.” The hypothalamus is a major regulatory center for

Figure 2.12 The Thalamus and Hypothalamus of the Diencephalon The thalamus lies close to the center of the brain, and the hypothalamus is located rostrally and ventrally relative to the thalamus. Directly below the hypothalamus is the pituitary gland, which is an important part of the endocrine system. Parietal lobe Lateral ventricle Thalamus

Thalamus

Hypothalamus

Hypothalamus Pituitary gland

Temporal lobe

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behaviors such as eating, drinkFigure 2.13 The Basal Ganglia ing, sex, biorhythms, and temperature control. Rather than The basal ganglia include the caudate nucleus, putamen, globus pallidus, subthalamic being a single, homogeneous nucleus, and nucleus accumbens. The substantia nigra of the midbrain is usually constructure, the hypothalamus is a sidered to be a part of this system. collection of nuclei. For example, the aforementioned ventromedial nucleus of the hypothalamus (VMH) participates in the regulation of feeding behavior. The suprachiasmatic nucleus receives input from the optic nerve and helps set daily rhythms according to the rising of the sun (refer to Chapter 11). The hypothalamus plays an important role in regulating the endocrine system and is directly connected to the pituSource: Adapted by Karla Freberg from https://www.kenhub.com/en/library/anatomy/basal-ganglia itary gland, from which many important hormones are released (refer to Chapter 10). Finally, the hypothalamus directs the autonomic nervous system, the basal ganglia can be viewed as selecting and enabling the portion of the PNS that controls our glands and organs. execution of motor programs stored by the cortex. Output from the basal ganglia to the thalamus can excite it, which in turn excites the motor cortex via the loops described The Basal Ganglia Several nuclei make up the basal previously, allowing selected motor programs to go forganglia, which participate in motor control. A ganglion ward. Additional output from the basal ganglia to the thal(ganglia is plural) is a general term for a collection of cell amus inhibits competing motor programs. Degeneration bodies. These nuclei, illustrated in Figure 2.13, include of the basal ganglia, which occurs in Parkinson disease the caudate nucleus, the putamen, the globus pallidus, and Huntington disease, produces characteristic disorders the subthalamic nucleus (which gets its name from its of movement (refer to Chapter 8). The basal ganglia have location “sub,” or below, the thalamus), and the nucleus also been implicated in a number of psychological disaccumbens. Despite its location in the midbrain, the orders, including attention deficit hyperactivity disorder substantia nigra is also considered to be part of the basal (ADHD) and obsessive-compulsive disorder (OCD; refer ganglia because of its tight connections with the other to Chapter 16). nuclei. The basal ganglia might perform similar functions We can organize these nuclei into three categoduring cognitive tasks as they do during motor tasks, ries: input nuclei, output nuclei, and intrinsic nuclei namely, selecting and enabling programs that are stored (Lanciego et al., 2012). Input, primarily from the cerebral cortex, thalamus, and substantia nigra, is received by the caudate nucleus, putamen, and the nucleus pituitary gland A gland located just above the roof of the mouth accumbens. This input is processed further within the that is connected to the hypothalamus and serves as a major source intrinsic nuclei, which include parts of the globus palof hormones. lidus and substantia nigra along with the subthalamic basal ganglia A collection of nuclei within the cerebral nucleus before the output travels from adjacent parts of hemispheres that participate in the control of voluntary movement. the globus pallidus and the substantia nigra back to the thalamus. caudate nucleus One of the major input nuclei in the basal ganglia. The basal ganglia receive input from the cortex and putamen One of the input nuclei contained in the basal ganglia. form connections with the motor areas of the thalamus. globus pallidus One of the nuclei making up the basal ganglia that In turn, the thalamus connects back to the cortex, formperforms both intrinsic and output functions. ing complex loops that are essential to movement. Volsubthalamic nucleus An intrinsic nucleus in the basal ganglia, located ventral to the thalamus. untary movement is initiated by the cortex, but without healthy functioning in the basal ganglia, cortical comnucleus accumbens An input nucleus in the basal ganglia known to be important in reward and addiction; also known as the ventral mands do not reach the parts of the motor system that striatum. actually implement these commands. In other words, the

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Figure 2.14 The Limbic System Participates in Learning and Emotion A number of closely connected forebrain structures are included in the limbic system, which participates in many emotional, learning, and motivated behaviors. Hypothalamus Fornix

Figure 2.15 The Hippocampus The hippocampus curves away from the midline out toward the rostral temporal lobe. This structure plays important roles in learning, memory, and stress. Medial surface

Posterior cingulate cortex Mammillary body

Anterior cingulate cortex

Hippocampus Parahippocampal gyrus

Amygdala

Fornix

Deep lateral surface Olfactory bulb

in other locations such as the cortex. The basal ganglia play important roles in operant conditioning, or the association formed between a behavior and its outcomes (Caligiore et al., 2019; refer to Chapter 12). In humans, the basal ganglia are also involved with forming and using implicit, or unconscious, memories (refer to Chapter 12). The Limbic System The limbic system, presented in Figure 2.14, is often referred to as the “limbic” or “sixth lobe” of the cortex, although it is not a true lobe. Limbic means border and describes the location of these structures on the margins of the cerebral cortex. Limbic structures, listed in Table 2.3, play significant roles in learning, motivated behavior, and emotion. The hippocampus, named after the Greek word for “seahorse,” curves around within the cerebral hemispheres from close to the midline out to the tip of the temporal lobe, as presented in Figure 2.15. The hippocampus participates in learning and memory, and it is vulnerable to damage from stress (refer to Chapters 14 and 16). Damage to the hippocampus in both hemispheres produces a syndrome known as anterograde amnesia (refer to Chapter 12). People with this type of memory loss have difficulty forming new long-term declarative memories, which are memories for facts, language, and personal experience. In studies of patients with hippocampal damage, it was found that memories formed prior

Hippocampus

Mammillary body

Mammillothalamic tract

(c) Skirmantas Janusonis, Gregory Lieberman & Andrew Bender

Skirmantas Janusonis/University of California/Santa Barbara

Septal area

to the damage remained relatively intact. In addition, the patients were still able to learn and remember procedures for solving a puzzle requiring multiple steps (refer to Chapter 12). Structures near and connected to the hippocampus are also included in the limbic system. The parahippocampal gyrus is a fold of tissue near the hippocampus. The fornix is a fiber pathway connecting the hippocampus with the mammillary bodies of the diencephalon. Like the hippocampus itself, these structures participate in the processing of memory.

limbic system A collection of forebrain structures that participate in emotional behavior, motivated behavior, and learning. hippocampus A structure deep within the cerebral hemispheres that is involved with the formation of long-term declarative memories and responses to stress; part of the limbic system. parahippocampal gyrus A fold of tissue near the hippocampus that also participates in memory. fornix A fiber pathway connecting the hippocampus and mammillary bodies. mammillary body One of two bumps on the ventral surface of the brain that participates in memory.

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Table 2.3 | Structures of the Limbic System Structure

Function

Hippocampus

Declarative memory formation, stress

Amygdala

Connecting stimuli and their emotional meanings; fear, aggression, reward, memory, motivation

Hypothalamus

Aggression; regulation of hunger, thirst, sex, temperature, circadian rhythms, hormones

Anterior cingulate cortex (ACC)

Decision making, error detection, cognitive control of emotion, anticipation of reward, pain, autonomic control

Posterior cingulate cortex (PCC)

Emotion and cognition; participates in default mode network (DMN)

Septal area

Reward, pleasure

Parahippocampal gyrus

Memory

Mammillary bodies

Part of the hypothalamus; memory

Fornix

Connects the hippocampus to mammillary bodies and other parts of the brain, memory

Figure 2.16 Amygdala Abnormalities Can Lead to Irrational Violence

Shutterstock.com

In 1966, Charles Whitman opened fire from the University of Texas clock tower, killing 14 people before he was killed by police. During an autopsy, Dr. Coleman de Chenar (in the photo below) found a cancerous tumor that experts believe might have been pressing on Whitman’s amygdala, possibly leading to his uncharacteristically violent behavior.

The amygdala, located at the anterior end of the hippocampus, plays an important role in connecting stimuli to their emotional meanings, both positive and negative (Putnam & Chang, 2021; refer to Figure 2.16). Although processing fear appears to be a central role of the amygdala, this structure also responds to the presence of rewards (Baxter & Murray, 2002). The amygdala receives input about the external world from sensory systems via connections with the thalamus. In turn, the amygdala sends information to other limbic structures and to the cerebral cortex. Electrical stimulation of the amygdala usually produces intense fear (Davis & Whalen, 2001). Damage to the amygdala leads to an abnormal emotional calmness and specifically interferes with an organism’s ability to respond appropriately to dangerous situations. In laboratory studies, rats with damaged amygdalae were unable to learn to fear tones that reliably predicted electric shock (LeDoux, 2000). Rhesus monkeys with damaged amygdalae were overly friendly with unfamiliar monkeys, a potentially dangerous way to behave in a species that enforces strict social hierarchies (Emery et al., 2001). Stimuli that normally elicit fear in monkeys, such as rubber snakes or unfamiliar humans, failed to do so in monkeys with lesions in their amygdalae (Mason et al., 2006). Abnormalities in both the

amygdala An almond-shaped structure in the rostral temporal lobes that is part of the limbic system.

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structure and connections of the amygdala might underlie some symptoms of autism spectrum disorder (refer to Chapter 16). The cingulate cortex is a fold of cortical tissue on the inner surface of the cerebral hemispheres. Cingulum means “belt” in Latin. The cingulate cortex is further divided into anterior and posterior sections. The anterior cingulate cortex (ACC) is involved in a number of higherorder cognitive functions, including decision-making, impulse control, and emotion. In particular, the ACC guides behavior in rapidly changing and uncertain situations (Monosov et al., 2020). The posterior cingulate cortex (PCC) is believed to participate in cognition and emotion, but its exact role remains unclear (Leech & Sharp, 2014). The PCC plays a central role in the default mode network (DMN; refer to Chapter 11) and thus participates in the management of consciousness (Buckner et al., 2008). The septal area is located anterior to the thalamus and hypothalamus and participates in reward (refer to Chapter 9). Electrical stimulation of this area is usually experienced as pleasurable, while lesions in this area produce uncontrollable rage and attack behaviors. On one unforgettable occasion, a rat with a septal lesion jumped at

cingulate cortex A segment of older cortex just dorsal to the corpus callosum that is part of the limbic system. septal area An area anterior to the thalamus and hypothalamus that participates in reward and is often included as part of the limbic system. gyrus/gyri One of the “hills” on the convoluted surface of the cerebral cortex. sulcus/sulci A “valley” in the convoluted surface of the cerebral cortex. fissure A large sulcus.

my face when I leaned over to pick it up (my apologies to those of you who are phobic about rodents). The Cortex The outer covering of the cerebral hemispheres is known as the cortex, from the Latin word for “bark.” Like the bark of a tree, the cerebral cortex is a thin layer of gray matter that varies from 1.5 mm to 4 mm in thickness in different parts of the brain, or about the thickness of a stack of one to four credit cards. Unlike the spinal cord, the cerebral hemispheres are organized with gray matter on the outside and white matter on the inside. Below the thin layers of cortical cell bodies are vast fiber pathways that connect the cortex with the rest of the nervous system. The average 20-year-old human brain features about 100,000 miles (162,500 km) of fiber pathways (Marner et al., 2003). The cerebral cortex has a wrinkled appearance somewhat like the outside of a walnut. The hills of the cortex are referred to as gyri (plural of gyrus), and the valleys are known as sulci (plural of sulcus). A particularly large sulcus is usually called a fissure. Why is the cerebral cortex so wrinkled? This feature of the cortex provides more surface area for cortical cells. We have limited space within the skull for brain tissue, and the wrinkled surface of the cortex allows us to pack in more neurons than we could otherwise. If stretched out flat, the human cortex would cover an area of about 2½ square feet. Just as we ball up a piece of paper to save space in our wastebasket, the sulci and gyri of the brain allow us to fit more tissue into our heads. The degree of wrinkling, or convolution, is related to how advanced a species is. Figure 2.17 shows that human brains are much more convoluted than a sheep’s brain, for example, and the sheep’s brain is more convoluted than a rat’s brain. The cells of the cerebral cortex are organized in layers, as presented in Figure 2.18. The number, organization, and

Figure 2.17 Comparative Convolutions of the Cortex The relative degree of cortical convolution is positively correlated with the cognitive abilities of a species.

Cerebral cortex

Sulci Gyrus Fissure

Rat

Sheep

Human

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Figure 2.18 The Layers of the Cerebral Cortex The cerebral cortex covers the outer surface of the brain. Six distinct layers are apparent in most areas of the cortex. Three different views of these layers are shown here (below, right). The Golgi stain highlights entire neurons (left), and the Nissl stain highlights cell bodies (middle). Note the large pyramidal cells shown by the Nissl stain in layer V. The Weigert stain highlights pathways formed by myelinated axons through the cortex (right). Outer surface of cortex Complete single cells (Golgi stain)

Cell bodies (Nissl stain)

Myelin (Weigert stain)

Corpus callosum White matter Gray matter

Layer II

Layer III

Layer IV

Layer V

Layer VI

Inner surface of cortex

size of the layers vary somewhat throughout the cortex. In most parts of the cortex, there are six distinct layers, which are numbered from the outermost layer toward the center of the brain. Layer I has no cell bodies at all. Instead, it is made up of the nerve fibers of cells forming connections with other layers. Layers II and IV contain large numbers of small cells known as granule cells. Layers III and V are characterized by large numbers of triangular-shaped pyramidal cells. These layers usually provide most of the output from an area of cortex to other parts of the nervous system. Layer VI has many types of neurons, which merge into the white matter that lies below the cortical layers. There are a number of systems for dividing the cerebral cortex. As demonstrated in Figure 2.19, Korbinian Brodmann used the distribution of cell bodies within the six layers of the cortex to distinguish between 52 separate areas (Brodmann, 1909). A simpler approach divides the cortex into four sections known as lobes, as presented in Figure 2.20. The lobes are actually named after the skull bones that lie above them. The most rostral of the lobes is the frontal

Cacioppo et al. (2022)

Cortex

From L. Heimer,The Human Brain and Spinal Cord: Functional Neuroanatomy and Dissection Guide, second ed., Springer, 1995 (after Brodmann).

Layer I

lobe. The caudal boundary of the frontal lobe is marked by the central sulcus. On the other side of the central sulcus, we find the parietal lobe. In the ventral direction, the frontal lobe is separated from the temporal lobe by the granule cell A small type of cell found in layers II and IV of the cerebral cortex. pyramidal cell A large, triangular cell found in layers III and V of the cerebral cortex. lobe One of the four major areas of the cerebral cortex: frontal, parietal, temporal, and occipital. frontal lobe The most rostral lobe of the cerebral cortex, separated from the parietal lobe by the central sulcus and from the temporal lobe by the lateral sulcus. central sulcus The fissure separating the frontal and parietal lobes of the cerebral cortex. parietal lobe One of the four lobes of the cerebral cortex; located between the frontal and occipital lobes. temporal lobe The lobe of the cerebral cortex lying ventral and lateral to the frontal and parietal lobes and rostral to the occipital lobe.

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Figure 2.19 Brodmann’s Map of the Brain Early twentieth-century German neurologist Korbinian Brodmann divided the cerebral cortex into 52 different areas based on the distribution of cell bodies in each area. One hundred years after Brodmann’s system was first published, it remains the most widely used system for describing cortical architecture. 31

4

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5 7

9

19 46 40

10 45 44 47

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39

43 41 42 22

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21 38

37

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20 4

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8 9 32

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3 1

31 23

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lateral sulcus The fissure separating the temporal and frontal lobes of the cortex. occipital lobe The most caudal lobe of the cortex; location of primary visual cortex. insula The cortex located within the lateral sulcus between the frontal/parietal and temporal lobes. Referred to as “the fifth lobe.” longitudinal fissure The major fissure dividing the two cerebral hemispheres on the dorsal side of the brain. sensory cortex An area of the cortex that is devoted to the processing of sensory information. motor cortex An area of the cortex that is devoted to the processing of movement. association cortex An area of the cortex that does not process sensory or motor information directly but rather serves as a bridge between areas that do process these functions. primary visual cortex An area of the sensory cortex located within the occipital lobe that provides the initial cortical processing of visual information. primary auditory cortex An area of the sensory cortex located within the temporal lobe that provides the initial cortical processing of sound information. postcentral gyrus The fold of parietal lobe tissue just caudal to the central sulcus; the location of the primary somatosensory cortex. primary somatosensory cortex An area of the sensory cortex located within the parietal lobe that processes body senses such as touch, position, skin temperature, and pain.

19

33

10 12

26 29 30 25 27 34 35

18

lateral sulcus. At the very back of the cortex is the occipital lobe. Within the lateral sulcus, which separates the fron36 18 38 tal and temporal lobes, we find an area known as the 19 37 insula, which is sometimes referred to as the insula lobe 20 or “fifth lobe.” Separating the two cerebral hemispheres along the dorsal midline is the longitudinal fissure. Figure 2.20 The Lobes of the Cerebral Cortex These areas of the cortex are so large that many differThe cortex is traditionally divided into the frontal, parietal, temporal, and occipital lobes. ent functions are located in Precentral gyrus each lobe. In general, we can Central (Primary motor divide the functional areas of sulcus cortex) Postcentral gyrus Dorsolateral the cortex into three catego(Primary somatosensory prefrontal ries: sensory cortex, motor cortex) cortex (DLPC) cortex, and association cortex. The sensory cortex processes Parietal lobe incoming information from the sensory systems. Different areas Occipital lobe of the sensory cortex are found Frontal in the occipital, temporal, and lobe parietal lobes. The occipital lobe Primary visual cortex contains the primary visual Orbitofrontal cortex. The primary auditory cortex cortex is located in the tempoLateral sulcus ral lobe. The postcentral gyrus of the parietal lobe contains the primary somatosensory cortex, which processes information Primary Temporal lobe about touch, pain, position, and auditory skin temperature. The postcencortex tral gyrus gets its name from 11

28

17

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in executive functions such as attention and working memory and in the planning of behavior (refer to Chapter 12), and the Two fiber bundles, the very large corpus callosum and the much smaller anterior orbitofrontal cortex is involved commissure, connect the right and left cerebral hemispheres. in impulse control and delayed gratification. Corpus callosum One of the classical methods for identifying brain functions is to consider cases in which the area of interest has been damaged. Possibly the most dramatic case of frontal lobe damage is that of the unfortunate Phineas Gage, a railroad worker in the mid-1800s. While Gage was preparing to blow up Anterior some rock, a spark set off his commissure gunpowder and blew an iron tamping rod through his head, entering below his left eye and exiting through the top of its location directly caudal (post means after) to the cenhis skull (refer to Figure 2.22). Miraculously, Gage survived tral sulcus, which divides the frontal and parietal lobes. the accident. He was not the same man, however, accordThe motor areas of the cortex provide the highest level of ing to his friends. Prior to his accident, Gage appears to command for voluntary movements. The primary motor have been responsible, friendly, and polite. After his accicortex is located in the precentral gyrus (pre means dent, Gage had difficulty holding a job and was profane before) of the frontal lobe. and irritable. His memory and reason were intact, but his Some areas of the cortex have neither specific motor personality was greatly changed for the worse. nor specific sensory functions. These areas are known as Gage’s results are consistent with modern findings association cortex and are located primarily in the frontal, of frontal lobe damage. People with damage to the DLPC temporal, and inferior parietal lobes. Association means experience apathy, personality change, and the lack of connection. In other words, these are the areas we have ability to plan. People with damage to the orbitofrontal available for connecting and integrating sensory and cortex experience emotional disturbances and impulmotor functions. sivity. As we will note in our discussion of mental disorThe right and left cerebral hemispheres are linked by ders (Chapter 16), several psychological disorders involve two major pathways, the corpus callosum and the much the frontal lobes. Some people with schizophrenia show smaller anterior commissure. These pathways are prelower than normal activity in the frontal lobe. Because sented in Figure 2.21. children with attention deficit hyperactivity disorder are usually very impulsive and have short attention spans, it Localization of Function in the Cortex In addition has been suggested that they, too, experience underactivity to the sensory and motor functions identified earlier, we can localize a number of specific functions in areas of the cerebral cortex. In many cases, these functions appear primary motor cortex An area of the cortex located within the to be managed by the cortex on either the left or right frontal lobe that provides the highest level of command to the hemisphere. motor systems. In addition to being the location of the primary motor precentral gyrus The fold of frontal lobe tissue just rostral to the cortex, the frontal lobe participates in a number of highercentral sulcus; the location of the primary motor cortex. level cognitive processes such as the planning of behavcorpus callosum A wide band of axons connecting the right and left cerebral hemispheres. ior, attention, and judgment (Stuss & Knight, 2013). Two important areas within the frontal lobes are the dorsolatanterior commissure A small bundle of axons that connects structures in the right and left cerebral hemispheres. eral prefrontal cortex (DLPC), located to the top and side dorsolateral prefrontal cortex (DLPC) An area located at the top of the frontal lobes, and the orbitofrontal cortex, located and sides of the frontal lobe that participates in executive functions above and behind the eyes. These areas of the frontal such as attention and the planning of behavior. lobes, illustrated in Figure 2.20, maintain extensive, reciporbitofrontal cortex An area of the frontal lobe located just rocal connections with the limbic system, the basal ganbehind the eyes involved in impulse control; damage to this area is associated with antisocial behavior. glia, and other parts of the cortex. The DLPC is involved

Figure 2.21 The Corpus Callosum and the Anterior Commissure

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Functional Neuroanatomy and the Evolution of the Nervous System

Figure 2.22 The Case of Phineas Gage

(a)

(b)

© Plos One

Mid-nineteenth-century railroad worker Phineas Gage suffered an accident in which an iron rod was shot through the frontal lobe of his brain. Although Gage survived, he was described by his friends as a “changed man.” Gage’s case illustrates the localization of higher-order cognitive functions in the frontal lobe.

of the frontal lobes. Finally, people who exhibit extreme antisocial behavior, including murderers, frequently show reduced volume in the orbitofrontal cortex (Sajous-Turner et al., 2020). Further evidence of the importance of the frontal lobes comes from the unfortunate experiment in frontal lobotomies during the mid-twentieth century (Valenstein, 1986). In 1935, Yale researchers Carlyle Jacobsen and John Fulton reported evidence indicating that chimpanzees with frontal lobe damage experienced a reduction in negative emotions. After listening to a presentation by Fulton, Portuguese neurologist Egaz Moniz advocated the use of frontal lobotomies with human patients to reduce negative outbursts. During the 1940s and 1950s, more than 10,000 frontal lobotomies were performed to reduce fear and anxiety in mental patients and in some people without major disorders. The lobotomy, discussed in greater detail in Chapter 14, consisted of a surgical separation of the most rostral parts of the frontal lobe from the rest of the brain. Without any remaining connections, the functions of this area of cortex would be lost. Moniz received the Nobel Prize in 1949 for advocating the procedure. Walter Freeman, an American doctor, performed many such operations, either in his office or even in his car, which he nicknamed his “lobotomobile.” Initially, the operation frontal lobotomy A surgical procedure in which a large portion of the frontal lobe is separated from the rest of the brain. Broca’s area An area near the primary motor cortex in the frontal lobe that participates in speech production.

was restricted to psychotic patients, but by the 1950s in the United States, depressed housewives and other people without major disorders were victims of the procedure. I would like to be able to say that physicians stopped doing lobotomies because they recognized the tremendous negative side effects of the procedure, but that would not be entirely accurate. Lobotomies were largely discontinued when the major antipsychotic medications were discovered. With the new drugs, the lobotomies were no longer considered necessary. The frontal lobe is also home to an important area of the motor cortex known as Broca’s area. Broca’s area is necessary for speech production. Damage to this area produces difficulty speaking but has relatively less effect on a person’s understanding or comprehension of speech (refer to Chapter 13). For most people, language functions appear to be controlled by cortex on the left hemisphere rather than on the right hemisphere. In addition to speech, other cognitive functions appear to show lateralization to one hemisphere or the other. Overall, the left hemisphere manages behavior in familiar circumstances while the right hemisphere responds to novelty and potentially dangerous environmental changes (Bartolomeo & Seidel Malkinson, 2019). For the vast majority of people, the left hemisphere manages logical thought and basic mathematical computation. You might think of the left hemisphere as the rational, school side of your brain. In contrast, the right hemisphere appears to be more emotional and intuitive. Our appreciation for art and music, as well as our ability to think three-dimensionally, are typically processed in the right hemisphere. Please try to forget any pop psychology you have read previously about accessing your right brain to become a better artist. With the corpus callosum constantly relaying messages from one hemisphere to the other, you are already using your right hemisphere as much as you can. We will explore the lateralization of functions in more detail in Chapter 13. Brain Networks Before we leave the discussion of the CNS to explore the PNS, we need to ensure that our discussion of the functions of certain parts of the brain has not led to a misunderstanding about the nature of neural processing. Neurons and structures do not behave in isolation but rather participate in circuits and networks. Parts of the brain, such as the ventromedial hypothalamus, do not “control” a function like satiety but rather participate in circuits that influence satiety. Technological advances, along with improved computational methods for managing “big data,” have provided neuroscientists new insights into functional relationships among molecules, neurons, brain areas, and even social systems (Bassett & Sporns, 2017). Eventually, improved network analysis might help us intervene to produce better health and to understand dynamic, changing network activity during social interactions.

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Figure 2.23 A Network Analysis of Social Pain Neuroscientists increasingly look to networks rather than isolated structures for behavioral correlates. In this study, the experience of social exclusion increased (indicated by red lines) connectivity in a mentalizing/default mode network (blue dots). Exclusion did not change connectivity within a social pain network (green dots). L L

R

R

Source: Schmälzle, R., O’Donnell, M. B., Garcia, J. O., Cascio, C. N., Bayer, J., Bassett, D. S., . . . Falk, E. B. (2017). Brain connectivity dynamics during social interaction reflect social network structure. Proceedings of the National Academy of Sciences of the United States of America, 114(20), 5153–5158. doi:10.1073/pnas.1616130114

Behavioral Neuroscience Goes to Work So You Want to Be a Neurosurgeon? When people think of the most complicated type of medicine possible, neurosurgery is high on the list. All medical specialties can be challenging, but operating on the body’s most complex organ is especially so. How do people prepare for this career? Becoming a neurosurgeon begins with the standard 4 years of medical school. Unlike students aiming for other specialties, medical students interested in neurosurgery typically engage in extensive research during medical school, resulting in the attainment of both the M.D. and Ph.D. degrees. They also participate in sub-internships toward the end of medical school in preparation for the highly selective seven-year residencies that come next. Residency is followed by 1–2 years of fellowship, required for pediatric neurosurgery and optional, but expected,

for other neurosurgeons wishing to combine practice and an academic career. If you haven’t noticed already, becoming a neurosurgeon requires passion and commitment. The long period of training is only the beginning. Work-life balance is very difficult because the neurosurgeon’s hours are usually long and inflexible compared to physicians in other specialties. The emotional toll of working with some of the sickest patients also should not be underestimated. But if this does not deter you, you might have what it takes for this profession. If you are a woman, we would especially love to see you consider this path as women make up only 10 percent of neurosurgeons in the United States. You can learn more about the history of women neurosurgeons through the organization Women in Neurosurgery (WINS; Women in Neurosurgery, 2022).

Thinking Ethically Predicting “Dangerousness” The field of forensic neuroscience is an application of neuroscience principles to the understanding and management of criminal behavior. One of the challenges faced by our legal systems is the prediction of future violence. These predictions inform decisions about bail, sentencing, probation, and court-ordered treatments.

Traditionally, such predictions are made on the basis of expert assessments by psychologists and psychiatrists using interviews and standardized tests. Can behavioral neuroscience increase the accuracy of these predictions? An interesting demonstration of neuroprediction was reported by Aharoni et al. (2013). These researchers (continued)

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Thinking Ethically Predicting “Dangerousness” (Continued) used mobile fMRI equipment to assess brain activity in 96 inmates about to be released from prison and followed their record of arrest for the next 4 years. Inmates with higher levels of ACC activity during a test of inhibitory control were substantially less likely to be rearrested than those with lower ACC activity. While promising, this approach is far from perfect (Poldrack et al., 2018). Neuroprediction suffers from the same group-to-individual (G2i) problem that plagues many applications. Knowing what “most” people do is

useful, but it does not guarantee that we know what a particular individual will do. Is it fair to apply group data like the results from Aharoni et al. to one person? Imaging also requires a cooperative participant. An inmate fearing negative results could easily disrupt the scanning process or learn to adopt countermeasures. Existing methods of predicting dangerousness have their own set of flaws, but neuroprediction is not a magic solution. We need more work and more validation before routinely deploying this method.

Summary Table 2.2: Major Structures of the Brain Division

Major Structures

Functions

Hindbrain

Medulla

Breathing, heart rate, and blood pressure; contains nuclei serving several cranial nerves

Reticular formation (extends into midbrain)

Consciousness, arousal, movement, pain, and attention

Pons

Sleep/waking cycles, mood, arousal, aggression, appetite; contains nuclei serving several cranial nerves

Cerebellum

Motor control, balance, cognition, learning

Superior colliculi

Visual reflexes

Inferior colliculi

Auditory reflexes

Substantia nigra

Motor control

Red nucleus

Motor control

Periaqueductal gray

Pain, sleep, cardiovascular function, sexual behavior, urination, parental behavior, vocalizations, temperature control

Thalamus

Sensory processing, states of arousal, attention, consciousness, learning, and memory

Hypothalamus

Regulation of hunger, thirst, aggression, sexual behavior, and the autonomic nervous system

Basal ganglia

Selection and enabling of motor programs stored in the cortex

Amygdala

Connecting stimuli to their emotional meanings, especially fear but also reward

Hippocampus

Memory formation, stress

Cingulate cortex

Control of autonomic functions, exertion of cognitive control over emotion, eye movements, spatial orientation, memory, consciousness

Septal area

Reward

Cerebral cortex

Highest level of sensory and motor processing; highest cognitive activity

Corpus callosum

Connects the two cerebral hemispheres

Midbrain

Forebrain

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The Peripheral Nervous System

Interim Summary 2.2 Summary Points 2.2 1. The spinal cord is divided into cervical, thoracic, lumbar, sacral, and coccygeal segments. In addition to carrying messages to and from the brain, the spinal cord provides a variety of protective and motor reflexes. (LO3) 2. The hindbrain consists of the medulla, pons, and cerebellum. Running through the medulla and pons at the midline is the reticular formation. The midbrain contains the remaining section of the reticular formation, the periaqueductal gray, the red nucleus, the superior colliculi, the inferior colliculi, and the substantia nigra. The forebrain is divided into the diencephalon and the telencephalon. The diencephalon contains the thalamus and hypothalamus. The telencephalon contains the cerebral cortex, basal ganglia, and limbic system structures. (LO4) 3. The cerebral cortex is made up of six layers that cover the outer surface of the cerebral hemispheres. The hills of the cortex are referred to as gyri, and the valleys are referred to as sulci or fissures. (LO5) 4. The cerebral cortex is divided into four lobes: the frontal lobe, the parietal lobe, the temporal lobe, and the occipital lobe. (LO5) 5. The two cerebral hemispheres are connected by the corpus callosum and the anterior commissure. Some functions, such as language, appear to be localized on one hemisphere or the other. (LO5) 6. The cortex can be divided into sensory, motor, or association cortex. (LO5) Review Questions 2.2 1. What are the major structures and functions found in the hindbrain, midbrain, and forebrain? 2. What functions can be localized in particular areas of cortex?

The Peripheral Nervous System For all its power, the brain still depends on the PNS to enable it to perceive the outside world and tell the body to carry out its commands. The role of the PNS is to carry sensory information from the body to the spinal cord and brain and bring back to the body commands for appropriate responses. The PNS contains three structural divisions: the cranial nerves, the spinal nerves, and the autonomic nervous system.

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Together, the cranial nerves and spinal nerves make up the somatic nervous system. The somatic nervous system brings sensory input to the brain and spinal cord and returns commands to the muscles. The autonomic nervous system controls the actions of smooth muscles and many glands and organs. The glands of the endocrine system coordinate arousal, metabolism, growth, and sex by releasing chemical messengers directly into the bloodstream.

The Cranial Nerves As presented in Figure 2.24, 12 pairs of cranial nerves enter and exit the brain directly. Three of the cranial nerves carry only sensory information. These are the olfactory nerve (I), the optic nerve (II), and the auditory nerve (VIII). Five of the nerves carry only motor information. The muscles of the eyes are controlled by the oculomotor nerve (III), the trochlear nerve (IV), and the abducens nerve (VI). The spinal accessory nerve (XI) controls the muscles of the neck, and the hypoglossal nerve (XII) controls the movement of the tongue. The remaining nerves have mixed sensory and motor functions. The trigeminal nerve (V) controls chewing movements and also provides some feedback regarding facial expression. The facial nerve (VII) produces facial expressions and carries the sensation

somatic nervous system The peripheral nervous system (PNS) division that brings sensory input to the brain and spinal cord and returns commands to the muscles. autonomic nervous system The division of the peripheral nervous system (PNS) that directs the activity of the glands, organs, and smooth muscles of the body. endocrine system Glands that secrete hormones directly into the blood supply. cranial nerves Twelve pairs of nerves that exit the brain as part of the peripheral nervous system (PNS). olfactory nerve (I) A cranial nerve carrying information about smell to the brain. optic nerve (II) A cranial nerve carrying information from the eyes to the brain. auditory nerve (VIII) A cranial nerve that carries information from the inner ear to the brain. oculomotor nerve (III) A cranial nerve that controls muscles of the eye. trochlear nerve (IV) A cranial nerve that controls the muscles of the eye. abducens nerve (VI) A cranial nerve that controls the muscles of the eye. spinal accessory nerve (XI) A cranial nerve that controls the muscles of the neck. hypoglossal nerve (XII) A cranial nerve responsible for movement of the tongue. trigeminal nerve (V) A cranial nerve that controls chewing movements and provides feedback regarding facial expression. facial nerve (VII) A cranial nerve that produces muscle movement in facial expressions and that carries taste information back to the brain.

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Figure 2.24 The Twelve Pairs of Cranial Nerves Twelve pairs of cranial nerves leave the brain directly to carry sensory and motor information to and from the head and neck areas and internal organs. The red lines represent sensory functions, and the blue lines show motor control. Some cranial nerves are sensory only (in red), some are motor only (in blue), and some are mixed (red for sensation, blue for motor control).

I. Olfactory

III. Occulomotor IV. Trochlear VI. Abducens

II. Optic

V. Trigeminal Vision Smell

Touch, pain

of taste. The glossopharyngeal nerve (IX) performs both sensory and motor functions for the throat. Finally, the long-distance fibers of the vagus nerve (X) (vagus comes from the same Latin root as vagabond) provide input and receive sensation from the heart, liver, and digestive tract.

The Spinal Nerves

As mentioned earlier, 31 pairs of spinal nerves exit Eye the spinal cord to provide movements sensory and motor pathJaw ways to the torso, arms, and muscles legs. Each spinal nerve is VII. Facial XII. Hypoglossal also known as a mixed nerve because it contains a senTongue sory, or afferent, nerve (the movements “a” means toward the CNS Face muscles in this case, as in access) and a motor, or efferent, nerve Taste (the “e” means away from the CNS, as in exit). The mixed nerves travel together to the XI. Spinal Neck part of the body they serve. VIII. Auditory accesory muscles This makes a great deal of practical sense. The nerves X. Vagus that are bringing you sensory Hearing information from your hand 9. Glossopharyngeal IX. Glossopharyngeal Balance are adjacent to the nerves that tell your hand to move. Damage to a mixed nerve is likely to reduce both sensation and motor control for a particular part of the body. Taste Internal organs Figure 2.25 shows spinal Muscles of nerves exiting a segment throat and of the spinal cord. Afferent larynx roots arise from the dorsal part of the spinal cord, while efferent roots arise from the ventral part. Once outside glossopharyngeal nerve (IX) A cranial nerve that manages both the cord, the dorsal afferent root swells into the dorsal sensory and motor functions in the throat. root ganglion, which contains the cell bodies of the affervagus nerve (X) A cranial nerve that serves the heart, liver, and ent nerves that process information about touch, skin digestive tract. temperature, and other body senses from the periphery. mixed nerve Spinal nerves that carry both sensory and motor information. Beyond the dorsal root ganglion, the dorsal and ventral afferent nerve A nerve that carries sensory information to the CNS. roots join to form a mixed nerve. efferent nerve A nerve that carries motor commands away from Afferent (sensory) nerves contain both myelinated the CNS. and unmyelinated fibers, while efferent (motor) nerves are dorsal root ganglion A collection of cell bodies of afferent nerves all myelinated in the adult human. As discussed further located just outside the spinal cord. in Chapter 3, myelin is a substance that insulates nerve

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voluntary control of autonomic functions. We do this all the time, but it takes attention. For examThis cross-section of the spinal cord shows a number of important anatomical features. ple, breathing normally conThree layers of meninges surround the cord. The gray matter of the cord is located in tinues whether we are awake or a butterfly shape near the central canal, which contains cerebrospinal fluid (CSF). The asleep. However, when we swim, dorsal afferent (sensory) nerves join the ventral efferent (motor) nerves beyond the dorsal root ganglion to form a mixed nerve. it’s vital that we take conscious control of our breathing patDorsal root Ventral Ventral root Central canal terns, or we’ll end up swallowing (afferent or (efferent or a lot of water. Through specialWhite matter sensory input) motor output) ized training in biofeedback, Gray matter Dorsal root people can learn to control a ganglion number of autonomic processes, such as lowering blood pressure Mixed nerve and reducing blood flow to the brain to avoid migraine headPia mater aches. Once they shift attention, Subarachnoid however, the effect may not last. space The brain structure that plays the greatest role in manArachnoid aging the autonomic nervous membrane system is the hypothalamus. The Dura mater pathways to and from the hypothalamus are exceedingly complex. Many structures involved with emotion have the potential to affect the hypothalamus and, indirectly, the autonomic Dorsal nervous system. As a result, the responses of our internal organs are tightly connected with our fibers and increases the speed with which they can transemotional behaviors, leading to the many common physmit messages. Myelinated fibers in both systems tend to ical symptoms we experience as a result of our emotions, be very large and very fast. Among the sensations carried such as feeling like you have butterflies in your stomach. by myelinated afferent fibers is the first, sharp experience The hypothalamus, in turn, connects with the midof pain. Small unmyelinated afferent fibers are responsible brain tegmentum and to the reticular formation in parfor that dull, achy feeling that follows injury. ticular. Damage to the midbrain in the vicinity of the red nucleus produces a wide variety of autonomic disturThe Autonomic Nervous System (ANS) bances, probably due to interruptions to large fiber pathways that descend from these areas to the autonomic neuThe autonomic nervous system was first described as cells rons of the lower brainstem and spinal cord. and fibers that pass to tissues other than the skeletal muscle The autonomic nervous system is divided into three (Langley, 1921). Your heart, lungs, digestive system, and main parts: the sympathetic and parasympathetic nervous other organs are commanded by the autonomic nervous systems and the enteric nervous system. The sympasystem. The autonomic nervous system participates in a thetic and parasympathetic systems transmit commands large number of critical regulatory functions, including

Figure 2.25 The Structure of the Spinal Cord

blood circulation, secretion, digestion, urination, and defecation. In addition, many reflexive behaviors are carried out with the assistance of autonomic neurons. These reflexes include respiration, pupil dilation, sneezing, coughing, swallowing, vomiting, and genital responses. You might think of this system as the automatic, or “cruise control,” nervous system. It manages many vital functions without conscious effort or awareness. You wouldn’t have much of a social life if you had to consciously command your lungs to inhale and exhale and your heart to beat. This doesn’t mean that you are incapable of taking

biofeedback A set of techniques that enable people to control typically unconscious or involuntary functions such as blood pressure. sympathetic nervous system The division of the autonomic nervous system that coordinates arousal. parasympathetic nervous systems The division of the autonomic nervous system responsible for rest and energy storage. enteric nervous system A division of the autonomic nervous system consisting of neurons embedded in the lining of the gastrointestinal system.

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to the glands and organs from the CNS. The enteric nervous system consists of neurons embedded in the lining of the gastrointestinal system, extending its entire length from the esophagus to the anus. Although the organs of the gastrointestinal system receive sympathetic and parasympathetic input as well, the enteric nervous system can act independently to control the functions of the gastrointestinal tract. The parasympathetic division is typically activated by internal stimuli such as the arrival of food in the digestive system. In contrast, the sympathetic nervous system is activated by external environmental cues such as the sensing of danger. The action of the sympathetic and parasympathetic systems on their target organs is presented in Figure 2.26. These two systems usually have opposite effects on the same set of organs, so we traditionally view them as working like a toggle switch. Turning one system on can inhibit the other. It’s difficult to imagine being aroused and resting at the same time. Nonetheless, it is overly simplistic to view these systems as mutually exclusive. There are many instances in which both systems operate cooperatively and simultaneously. A good example of the cooperation between the systems is sexual behavior. The parasympathetic system stimulates erection of the penis, and the sympathetic system stimulates ejaculation. A healthy balance between the two systems can be assessed using the heart rate variability (HRV) measure described in Chapter 1. If the system is working properly, the variability in heart rate is higher. Lower variability indicates a preponderance of sympathetic activity. Faster heart beats leave less room for variability. Low HRV is often due to stress and/or a number of health and psychological conditions, including cardiac disease and depression. The Sympathetic Nervous System The sympathetic nervous system manages arousal and copes with emergencies by preparing the body for action. Human beings have two basic ways of dealing with an emergency. We can run, or we can fight. As a result, the sympathetic nervous system is known as our fight-or-flight system. You probably know all too well what this feels like because you probably have had a close call or two while driving your car. In this type of emergency, our hearts race, our breathing is rapid, the palms of our hands get sweaty, our faces are pale, and we are mentally alert and focused. These behaviors have been refined through millions of years of evolution to keep you alive when faced with an emergency. The sympathetic nervous system prepares the body for fighting or fleeing by shutting down low-priority systems and putting blood and oxygen into the most necessary parts of the body. Salivation and digestion are put on sympathetic chain A string of cell bodies outside the spinal cord that receive input from sympathetic neurons in the central nervous system (CNS) and that communicate with target organs.

standby. If you are facing a hungry lion on the Serengeti Plain, you don’t need to worry about digesting your lunch unless you survive the encounter. Your heart and lungs operate to provide extra oxygen, which is fed to the large muscle groups. Blood vessels near the skin’s surface are constricted to channel blood to the large muscle groups. Aside from giving you that pale look, you enjoy the added benefit of not bleeding very badly should you be cut. With the increased blood flow to the brain, mental alertness is at a peak. The sympathetic nervous system is configured for a simultaneous, coordinated response to emergencies. Axons from neurons in the thoracic and lumbar segments of the spinal cord communicate with a series of ganglia just outside the cord known as the sympathetic chain. Fibers from cells in the sympathetic chain then communicate with target organs. Because the messages from the spinal neurons reach the sympathetic chain through fibers of equal length, they arrive at about the same time. Consequently, input from the sympathetic chain arrives at all of the target organs simultaneously. This coordinated response is essential for survival. It wouldn’t be efficient for the heart to get a delayed message in the case of an emergency. Because the same organs receive input from both the sympathetic and parasympathetic systems, it is important for the organs to have a way to identify the source of the input. This is accomplished through the types of chemical messengers used by the two systems. Both the sympathetic and parasympathetic systems communicate with cells in ganglia outside the spinal cord, which then form a second connection with a target organ. Both systems use the chemical messenger acetylcholine (ACh) to communicate with their ganglia (refer to Chapter 4). At the target organ, the parasympathetic nervous system continues to use ACh. The sympathetic nervous system, however, switches to another chemical messenger, norepinephrine, to communicate with target organs. The only exception is the connection between the sympathetic nerves and the sweat glands, where ACh is still used. This system of two chemical messengers provides a clear method of action at the target organ. If the heart, for instance, is stimulated by ACh, it will react by slowing. If it receives stimulation from norepinephrine, it will speed up. Survival depends on not having any ambiguities, mixed messages, or possibilities of error. The Parasympathetic Nervous System During times of sympathetic nervous system activity, the body is expending rather than storing energy. Obviously, the sympathetic nervous system can’t run continuously, or the body would run out of resources. The job of the parasympathetic nervous system is to provide rest, repair, and energy storage. After a period of arousal, the parasympathetic nervous system works to return functions like heart rate to baseline. While the neurons for the sympathetic nervous system are found in the thoracic and lumbar regions of the spinal cord, the neurons for the parasympathetic nervous system

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The Peripheral Nervous System

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Figure 2.26 The Autonomic Nervous System The sympathetic and parasympathetic divisions of the autonomic nervous system often have opposite effects on target organs. To carry out their respective tasks, sympathetic neurons form their first synapse in the sympathetic chain, while parasympathetic neurons synapse on ganglia close to the target organs. In addition, the systems use different neurotransmitters at the target organ.

Dilates pupil

Contracts pupil

Inhibits salivation

Stimulates

Oculomotor nerve (cranial nerve III) Facial nerve (cranial nerve VII)

salivation

Glossopharyngeal nerve (cranial nerve IX) Heart Accelerates heartbeat Relaxes airway

Slows heartbeat

Constricts airway

Cranial

Cervical

Thoracic

Lumbar

Cranial

Lungs

Liver

T1 2 3 4 5 6 7 8 9 10 11 12 L1 2

Stimulates digestion

Inhibits digestion

Vagus nerve (cranial nerve X)

Cervical

Gallbladder Stomach

Constricts blood vessels

Stimulates

Thoracic

digestion

Inhibits digestion

Spleen Stimulates

Inhibits urination

digestion Pancreas

Lumbar

Large intestine Stimulates digestion Small intestine

S2

Rectum

4

Sacral

3

Sacral

Adrenal gland

Coccygeal

Coccygeal Sympathetic chain ganglion

Kidney

Sympathetic Nervous System

Promotes urination Stimulates orgasm

Parasympathetic Nervous System

Stimulates penile erection and labial engorgement

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Chapter 2

Functional Neuroanatomy and the Evolution of the Nervous System

are found above and below these regions, in the brain and sacral divisions of the spinal cord, specifically. This is the origin of the name parasympathetic. Para means around, and the neurons of the parasympathetic nervous system are around those of the sympathetic nervous system, like brackets or parentheses. After exiting the brain and sacral spinal cord, parasympathetic axons do not synapse with a chain, as is the case with the sympathetic axons. Instead, they travel some distance to locations near their target organs, where the parasympathetic ganglia are located. Because timing is not as important to parasympathetic activity as it is to sympathetic activity, the coordination provided by a chain is not necessary. The Enteric Nervous System Because of the number of neurons it contains along with its relative autonomy, the enteric nervous system, shown in Figure 2.27, has been referred to as “a second brain.” The number of neurons in this system is roughly equivalent to the number found in the spinal cord. Some functions of the enteric nervous system contribute to conscious sensations, such as pain, hunger, and satiety, while much of its work remains below the level of conscious awareness. The enteric nervous system forms a two-way communication system with the brain known as the gut–brain axis (GBA). The GBA influences and is influenced by the endocrine system, the immune system, and the parasympathetic and sympathetic nervous systems. The population of bacteria inhabiting the gut, known as the microbiome, plays an important role in GBA functions. Disruptions to the microbiome have been implicated in allergies, autoimmune disorders, metabolic disease, and some psychological disorders.

The Endocrine System The hypothalamus directly controls the release of hormones by the glands making up the endocrine system, including the pineal gland, the pituitary gland, the thyroid gland, the adrenal glands, the islets of Langerhans in the pancreas, and the ovaries and testes.

Figure 2.27 The Enteric Nervous System The enteric nervous system serves the gastrointestinal tract. Activity in this system is related to digestion, hunger, and satiety. Neuroscientists have been increasingly interested in the gut–brain axis and the influence of the gut microbiota on brain function and behavior. Esophagus

A cutaway of the small intestine Enteric nervous system

Stomach Large intestines Small intestines

Nerve signals travel to the brain Muscle Contractions that move food along are controlled by the enteric nervous system.

The pineal gland plays an important role in the maintenance of our sleep–waking cycles, discussed in greater detail in Chapter 11. The pituitary gland is often referred to as the body’s “master gland” because the hormones it releases activate many other glands. Pituitary activity can stimulate the release of sex hormones by the gut–brain axis (GBA) A two-way communication system between the enteric nervous system and the brain.

Neuroscience in Everyday Life Can I Improve My Heart Rate Variability (HRV)? We have described heart rate variability (HRV) as one measure of how well your autonomic nervous system is functioning. Higher scores indicate better balance between the sympathetic and parasympathetic divisions. Lower scores indicate a preponderance of sympathetic activity. A “good” score depends on many variables, including age. Many technologies, such as the Apple Watch or WHOOP, provide HRV data. Following good basic health habits, such as exercising regularly, eating well, and having a steady sleep

routine, are likely to promote a better HRV. Alcohol consumption can suppress HRV significantly for up to four days, so avoiding alcohol is an easy way to improve an otherwise low HRV. Formal HRV biofeedback (HRVB), which consists of moment-to-moment feedback and paced breathing, is an effective procedure for reducing stress, anxiety, and depression (Lehrer & Gevirtz, 2014; Pizzoli et al., 2021).

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The Evolution of the Human Nervous System

ovaries and testes (refer to Chapter 10) or the release of cortisol by the adrenal glands in times of stress (refer to Chapter 14). Other pituitary products include oxytocin and vasopressin, which contribute to bonding and parenting (refer to Chapter 10), and growth hormone. Hormones released by the thyroid gland regulate metabolism. The islets of Langerhans produce a number of hormones essential to digestion, including insulin (refer to Chapter 9).

The Evolution of the Human Nervous System Brains are a relatively recent addition among living things, and our modern Homo sapiens brain may be only 100,000 to 200,000 years old (refer to Figure 2.28).

Natural Selection and Evolution As outlined in his 1859 book On the Origin of the Species, Charles Darwin proposed that species evolve, or change from one version to the next, in an orderly manner. Modern biologists define evolution as “descent with modification from a common ancestor.” Darwin was well aware of the artificial selection procedures used by farmers to develop animals and plants with particular desirable traits. If a farmer’s goal was to raise the strongest oxen, it was advisable to breed the strongest available oxen with each other. In these cases, the farmer makes the determination of which individuals

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have the opportunity to produce offspring. In natural selection, Darwin suggested that the pressures of survival and reproduction in the wild would take the place of the farmer. Natural selection favors the organism with the highest degree of fitness, or likelihood of reproducing successfully compared with others of the same species. Fitness is not some static characteristic, such as being strongest or fastest. Instead, fitness describes the successful interaction between an organism’s characteristics and the environment in which it exists. An organism that succeeds during an ice age might be at a significant disadvantage during more temperate times. Combining our modern understanding of genetics (refer to Chapter 5) with Darwin’s work provides a basis for understanding the progression of species and their behavior. As Richard Dawkins (1982) reminds us, genes can replicate themselves but not without a lot of help from their friends. All genes in a single individual share the same fate. When individuals survive and reproduce, their genes will become more frequent in the next generation. At the same time, the ability to survive and reproduce will be a function of the characteristics encoded by an individual’s genes. natural selection The process by which favorable traits would become more common and unfavorable traits would become less common in subsequent generations due to differences among organisms in their ability to reproduce successfully. fitness The ability of an organism with one genetic makeup to reproduce more successfully than organisms with other types of genetic makeup.

Figure 2.28 Timeline for the Evolution of the Brain

Left to Right: SciePro/Getty Images; Pandemin/Getty Images; blickwinkel/Alamy Stock Photo; Schreiter/Alamy Stock Photo; The Natural History Museum, London/Science Source

When the time scale of the 4.5-billion-year evolution of the Earth is expressed as a 24-hour day, we can appreciate how recently brains appeared. 18 hours ago

3 hours 45 minutes ago

23 00 1

2 22 3 0 21 55 5 20 50 10 19 15 18 45 17 40 20 16 25 35 30 9 15 10 14 13 12 11

23 00 1

4 5 6 7 8

Single-cell organism

2 22 3 0 21 55 5 20 50 10 19 15 18 45 17 40 20 16 25 35 30 9 15 10 14 13 12 11

2 hours 40 minutes ago 23 00 1

4 5 6 7 8

Jellyfish (first nervous systems)

2 22 3 0 21 55 5 20 50 10 19 15 18 45 17 40 20 16 25 35 30 9 15 10 14 13 12 11

2.5 minutes ago

3 seconds ago

23 00 1

4 5 6 7 8

Lamprey (first brains)

2 22 3 0 21 55 5 20 50 10 19 15 18 45 17 40 20 16 25 35 30 9 15 10 14 13 12 11

First hominins

4 5 6 7 8

23 00 1 2 22 3 0 21 55 5 20 50 10 19 15 18 45 17 40 20 16 25 35 30 9 15 10 14 13 12 11

Homo sapiens

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4 5 6 7 8

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Chapter 2

Functional Neuroanatomy and the Evolution of the Nervous System

Evolution of the Nervous System Nervous systems are a rather recent development belonging only to animals. To begin our evolution timeline, illustrated in Figure 2.28, current estimates place the origin of Earth at about 4.5 billion years ago. Single-cell organisms appeared about 3.5 billion years ago, and animals with simple nerve nets first developed about 700 million years ago. More complex animals, with the first rudimentary brains, appeared about 250 million years ago, and the first hominin brain probably appeared about 7 million years ago (Calvin, 2004). The neural networks that developed early, such as those found in snails, consist of collections of cells, or ganglia, that control certain aspects of the animal’s behavior in a particular region of the body. Although some of these ganglia are located in the head, they do not perform the central executive functions we normally attribute to a brain. The abdominal ganglia may perform behaviors that are just as crucial to the animal’s survival as behaviors managed by the ganglia in the head. In addition, most of these primitive nervous systems are located in the more vulnerable ventral, or belly, side of the animal where they are easily damaged or attacked. Because they lack a spinal column, such animals are referred to by biologists as invertebrates. Animals with spinal columns and real brains are referred to as vertebrates, or chordates (refer to Figure 2.29). Brains provide a number of advantages for chordates compared with the neural networks found in

hominin A primate in the family Hominidae, of which Homo sapiens is the only surviving member. chordates The phylum of animals that possess true brains and spinal cords. Also known as vertebrates. Homo sapiens The species of modern humans.

more primitive species. Unlike the ganglia of the invertebrate, the brain and spinal cord coordinate all of the animal’s activity. The brain exerts this executive control from its vantage point in the head, close to the major sensory systems that provide information from the eyes, ears, nose, and mouth. With its centralized functions and ability to integrate sensory input, the brain of the first chordates to appear on the scene many millions of years ago enabled those animals to respond consistently and rapidly. The brains and spinal cords of the chordates enjoyed much more protection than the ganglia of the invertebrates. Not only were these important structures now encased in bone but their location on the dorsal, or back, surface of the animal’s body was also easier to defend. As shown in Figure 2.30, the brains of chordates continued to develop, culminating in the very large brains found in mammals and birds. Early brains differ from more advanced brains in both size and degree of convolution, or folding, of the cortex. In addition, the size of the forebrain and cerebellum increased in more advanced chordate species.

Evolution of the Human Brain Human beings are members of the primate order, a biological category that includes some 275 species of apes, monkeys, lemurs, tarsiers, and marmosets. We are further classified as being in the suborder of apes, the family of hominids, and the species of Homo sapiens. The first modern Homo sapiens appeared between 100,000 and 200,000 years ago. By this point, early humans had migrated extensively throughout Europe and Asia. Their tool use appeared quite sophisticated, they hunted efficiently, and their culture, which included the ritual burial of their dead, was cooperative and social. During the 7 million years since the first hominin species appeared, brain development appears to have occurred very quickly (refer to Figure 2.31). The early

Figure 2.29 True Brains Are Found in Chordates Compared with invertebrates, such as the Aplysia californica (a type of sea slug) on the right, chordates have true brains as opposed to ganglia. The chordate nervous system runs near the dorsal rather than the ventral surface of the animal’s body. Brain

Spinal cord

Dorsal

Buccal Cerebral ganglion ganglion

Parietal ganglion

Abdominal ganglion

Ventral Chordate: Rat

Nonchordate: Aplysia

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The Evolution of the Human Nervous System

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Figure 2.30 Chordate Brains Continued to Evolve More complex chordate brains feature increased convolutions and larger cerebrums and cerebellums.

Cerebrum

Olfactory bulb

Cerebellum

Optic tectum

Brainstem

Frog

Goose

Human

Figure 2.31 Human Brain Development Proceeded Swiftly Hominin brains advanced rapidly from those of the early australopithecines, shown on the left, who had brains about the size of modern chimpanzees, to Homo erectus (700 cubic cm; shown in the center), to Homo sapiens (1,400 cubic cm; shown on the far right). Brain development then appears to have leveled off. You are reading this text with essentially the same size brain that has worked for Homo sapiens for the past 200,000 years.

Source: Australian Museum

tool-using australopithecines living about 5 million years ago had brains that were about the same size as that of a modern chimpanzee, around 400 cubic cm. Homo erectus, living about 2 million years ago, had a brain of about 700 cubic cm, and modern human brains are around 1,400 cubic cm. Interactions among multiple factors, including body size, the long period of dependency in children, long life-spans, the need to adapt to changing climates, and the complexity of social life probably contributed to the rapid increase in hominin brain size (Charvet

& Finlay, 2012). However, since the initial appearance of Homo sapiens, brain size has not changed much. What is unclear is why major cultural changes such as agriculture, urbanization, and literacy have not produced additional changes in brain size. Further increases in brain size might simply be too costly in terms of greater difficulties in childbirth and the need for more resources. Unless we experience a reduction in costs or pressure for even greater intelligence, we might have reached a balance between the advantages and disadvantages of large brains.

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Chapter 2

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Interim Summary 2.3

3. The endocrine system consists of glands that release important hormones into the blood that regulate arousal, growth, metabolism, and sex. (LO6)

Summary Points 2.3 1. The PNS includes the cranial nerves, the spinal nerves, and the autonomic nervous system. The 12 pairs of cranial nerves exit the brain and provide sensory and motor functions to the head, neck, and internal organs. The 31 pairs of spinal nerves perform the same functions for the rest of the body. (LO6) 2. The autonomic nervous system processes sensory and motor information to and from glands, organs, and smooth muscle. The sympathetic nervous system operates during times of arousal and prepares the body for fight-or-flight reactions. The parasympathetic nervous system operates during times of rest and restoration. The enteric nervous system moves food through the gut and provides feedback to the CNS. (LO6)

4. True brains evolved relatively recently. Hominin brain evolution featured very rapid increases in brain size. (LO7) Review Questions 2.3 1. How are the spinal nerves organized once they exit the cord? 2. How are the structures of the sympathetic and parasympathetic nervous systems well suited to their functions? 3. Why hasn’t the human brain changed in size in response to more recent changes such as agriculture, urbanization, and literacy?

Summary Table 2.3: Major Structures of the Peripheral Nervous System Structure

Function

Cranial nerves

Carry sensory and motor information between the brain and regions of the head and neck; the vagus nerve communicates with the heart, liver, and digestive tract

Spinal nerves: cervical, thoracic, lumbar, sacral, coccygeal

Carry sensory and motor information between the spinal cord and the torso and limbs

Autonomic nervous system

Provides input to and receives information from the glands and organs

Sympathetic division

Arousal

Parasympathetic division

Rest, digestion, and repair

Enteric system

Moves food through digestive tract and provides feedback from gut to brain

Endocrine system

Releases hormones into the circulation under the direction of the hypothalamus

Chapter Review T h ough t Qu est ion s 1. Given your understanding of the functions of the basal ganglia, why are these structures suspected of playing a role in attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD)? 2. Given your understanding of frontal lobe functions, what objectionable side effects might result from a frontal lobotomy? 3. What types of challenges facing human populations today might result in natural selection?

K e y Te rm s afferent nerve (p. 54) amygdala (p. 45) anterior (p. 29) arachnoid layer (p. 31) association cortex (p. 48) autonomic nervous system (p. 53) basal ganglia (p. 43) biofeedback (p. 55) brainstem (p. 38) caudal (p. 28) caudate nucleus (p. 43) central canal (p. 32)

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Chapter Review

central nervous system (CNS) (p. 35) central sulcus (p. 47) cerebellum (p. 38) cerebral aqueduct (p. 40) cerebral hemisphere (p. 42) cerebrospinal fluid (CSF) (p. 32) cingulate cortex (p. 46) contralateral (p. 29) coronal/frontal section (p. 29) corpus callosum (p. 49) cranial nerve (p. 53) diencephalon (p. 42) distal (p. 29) dorsal (p. 28) dorsolateral prefrontal cortex (DLPC) (p. 49) dura mater (p. 29) efferent nerve (p. 54) endocrine system (p. 53) enteric nervous system (p. 55) fitness (p. 59) forebrain (p. 38) frontal lobe (p. 47) globus pallidus (p. 43) gray matter (p. 37) gut–brain axis (GBA) (p. 58) gyrus/gyri (p. 46) hindbrain (p. 38) hippocampus (p. 44) hominin (p. 60) Homo sapiens (p. 60) horizontal/axial/transverse section (p. 29) hypothalamus (p. 42) inferior (p. 29) inferior colliculi (p. 41) insula (p. 48) ipsilateral (p. 29) lateral (p. 29) lateral sulcus (p. 48) limbic system (p. 44) locus coeruleus (p. 39) longitudinal fissure (p. 48) medial (p. 29) medulla (p. 38) meninges (p. 29) mesencephalon (p. 40)

metencephalon (p. 39) midbrain (p. 38) myelencephalon (p. 38) natural selection (p. 59) nucleus accumbens (p. 43) occipital lobe (p. 48) orbitofrontal cortex (p. 49) parasympathetic nervous system (p. 55) parietal lobe (p. 47) periaqueductal gray (p. 40) peripheral nervous system (PNS) (p. 35) pia mater (p. 31) pituitary gland (p. 43) pons (p. 38) postcentral gyrus (p. 48) posterior (p. 29) precentral gyrus (p. 49) primary auditory cortex (p. 48) primary motor cortex (p. 49) primary somatosensory cortex (p. 48) primary visual cortex (p. 48) proximal (p. 29) putamen (p. 43) raphe nuclei (p. 39) red nucleus (p. 41) reticular formation (p. 39) rostral (p. 28) sagittal section (p. 29) somatic nervous system (p. 53) spinal cord (p. 35) subarachnoid space (p. 31) substantia nigra (p. 41) subthalamic nucleus (p. 43) sulcus/sulci (p. 46) superior colliculi (p. 41) superior (p. 29) sympathetic nervous system (p. 55) tectum (p. 40) tegmentum (p. 40) telencephalon (p. 42) temporal lobe (p. 47) thalamus (p. 42) ventral (p. 28) ventricle (p. 32) white matter (p. 36)

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Chapter 3 Learning Objectives L01

Differentiate between glia and neurons.

L02

Identify the major types, structures, and functions of glia.

L03

Describe the structural features and functions of the cell membrane, cytoskeleton, cell body, axons, and dendrites.

L04

Compare the structural and functional types of neurons.

L05

Explain the processes responsible for electrical and chemical signaling.

L06

L07

Distinguish between excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs), and explain the process of neural integration. Discuss the modulation provided by neurons at axo-axonic synapses.

Neurophysiology: The Structure and Functions of the Cells of the Nervous System Chapter Outline Glia and Neurons

Glia The Structure of Neurons Structural Variations in Neurons Functional Variations in Neurons

Interim Summary 3.1 Generating Action Potentials

The Ionic Composition of the Intracellular and Extracellular Fluids The Movement of Ions

The Resting Potential The Action Potential Propagating Action Potentials Interim Summary 3.2 The Synapse

Gap Junctions Chemical Synapses Axo-Axonic Synapses

Interim Summary 3.3 Chapter Review

Neuroscience in Everyday Life: Should I Take Prebiotics or Probiotics? Thinking Ethically: Lethal Injection Connecting to Research: Are Synapse Size and Strength Related? Behavioral Neuroscience Goes to Work: How Does an EEG Work? 65

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Chapter 3

Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Glia and Neurons The great architect Frank Lloyd Wright was fond of saying that “form follows function.” That same wisdom applies not only to good architecture but also to biology. The entire nervous system, from large structures to the cellular level, has been shaped through the course of evolution to carry out functions essential to survival and reproduction. The nervous system is made up of two types of cells, glia and neurons. The neurons and glia cooperate to carry out nervous system functions. The glia, whose name comes from the Greek word for glue, serve a variety of support functions for neurons. The neuron is specialized to carry out the functions of information processing and communication. First, we will consider the supportive glia, followed by a detailed discussion of the structure and function of neurons.

Glia The approximately 360 billion glial cells make up 80 to 90 percent of all cells found in the central nervous system. Additional glia are found in the peripheral nervous system. Glia are generally categorized by size. The macroglia are large varieties of glial cells, and the microglia are relatively small. Macroglia originate in the ectoderm layer (refer to Chapter 5) during embryonic development along with neurons. Microglia originate instead in the mesoderm layer. There are four primary types of macroglia (summarized in Table 3.1): astrocytes, ependymal cells, oligodendrocytes, and Schwann cells. The astrocytes provide a variety of support functions to neurons. Ependymal cells line the ventricles of the brain and the central canal of the spinal cord. The oligodendrocytes and Schwann cells supply the myelin covering that insulates nerve fibers known as axons. glia Cells in the nervous system that support the activities of neurons. neuron A cell of the nervous system that is specialized for information processing and communication. macroglia Large glial cells, including astrocytes, ependymal cells, oligodendrocytes, and Schwann cells. microglia Tiny, mobile glial cells that migrate to areas of damage and digest debris and participate in synaptic pruning. astrocyte A large, star shaped glial cell of the central nervous system (CNS), responsible for structural support, isolation of the synapse, control of the extracellular chemical environment at the synapse, and communication. ependymal cells Glial cells lining the ventricles and central canal of the spinal cord. oligodendrocyte A glial cell that forms the myelin on central nervous system (CNS) axons. Schwann cell A glial cell that forms the myelin on axons in the peripheral nervous system (PNS). synapse The junction between two neurons at which information is transferred from one to another.

Astrocytes Astrocytes get their name from their starlike shape, which is evident in Figure 3.1. Astrocytes, the most common type of glia in the brain, are essential to maintaining homeostasis in the CNS. There are two types of astrocytes, which can be distinguished by their appearance. Protoplasmic astrocytes feature many fine branches and are found in gray matter (refer to Chapter 2). Fibrous astrocytes feature long, fiber-like branches and are found in white matter. One of the primary functions of the astrocytes is to provide a structural matrix for the neurons. Otherwise, the neurons would be literally floating around in the extracellular fluid. In reality, neurons occupy a cramped space controlled by the adjacent astrocytes. Astrocytes form close connections with the capillary cells of the brain, making what are known as neurovascular units. The close association of astrocytes with the capillary cells allows these glia to transfer glucose and other nutrients to the neurons. Because of their ability to contact both blood vessels and synapses, or points of communication between two cells, astrocytes regulate local blood flow based on synaptic activity. We can observe this relationship between brain activity and blood flow on a larger scale

Figure 3.1 Astrocytes Astrocytes have several support functions. Through their close association with the blood supply, astrocytes help transfer nutrients to neurons and block the movement of some circulating toxins into neural tissue. Astrocytes also provide a structural matrix for neurons, holding them in place. Astrocytes isolate the synapse, regulate levels of chemicals, and communicate with neurons and other cells in their vicinity.

Astrocyte

Capillary

Neuron

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Glia and Neurons

glial scars, or scar tissue that fills the area previously occupied by the now dead neurons, and release chemicals that inhibit neural regrowth (Bradbury & Burnside, 2019). The response of the astrocytes to injury is initially helpful in the overall healing process, protecting cells from harmful chemicals, promoting healing of the blood–brain barrier, and reducing inflammation. However, scarring also interferes with the repair of damaged connections. A major area of glial research is focused on preventing the astrocyte’s interference in repair in cases of brain or spinal injury. Ependymal Cells Cube-shaped ependymal cells, presented in Figure 3.2, line the ventricles of the brain and the central canal of the spinal cord. They play important roles in the homeostasis of the CSF, brain metabolism, and clearance of waste from the brain (MacDonald et al., 2021). Ependymal cells feature fine, hair-like cilia that project into a ventricle or the central canal and move cerebrospinal fluid (CSF) with a whip-like motion. The cilia also absorb some CSF, allowing the ependymal cells to monitor the quality of the CSF and supply underlying brain cells with proteins from the CSF. Special ependymal cells separate the ventricle from a rich network of capillaries known as the choroid plexus. Fluid is filtered from the choroid plexus capillaries through these special ependymal cells to form the CSF.

blood–brain barrier An impediment to the transfer of molecules from the circulation into the brain formed by the astrocytes. reactive astrocyte An astrocyte that changes physically and functionally in response to disease, injury, and aging.

Figure 3.2 Ependymal Cells Ependymal cells line the ventricles of the brain and the central canal of the spinal cord. Their fine cilia move cerebrospinal fluid using a whip-like motion.

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using fMRI (refer to Chapter 1). Astrocytes also contribute to the protective blood–brain barrier. The blood–brain barrier prevents most toxins circulating in the blood from entering the brain. Astrocytes help form the blood–brain barrier by literally covering the outer surface of capillaries with their endfeet, large structures at the end of each of the astrocyte’s branches. Astrocytes surround and isolate the area of the synapse. A single astrocyte in the hippocampus or cortex can envelope as many as 100,000 or more synapses (Sofroniew & Vinters, 2010). Neurochemicals are very active, and it is not in our best interests to have them floating every which way. The astrocytes keep the neurochemicals released at a synapse from moving outside a restricted area. In addition, astrocytes can clear molecules from the synaptic gap. As we will discuss shortly, neurons release potassium ions when they send messages, and the astrocytes have the important task of removing excess potassium from the extracellular fluid. Astrocytes appear to play even more direct roles in the functions taking place at synapses. Neurons grown in Petri dishes along with astrocytes are 10 times more responsive than neurons grown alone (Pfrieger & Barres, 1997). Follow-up research showed that the astrocytes were signaling the neurons to build synapses (Ullian et al., 2001). The astrocytes probably fulfill this role by releasing growth factors and similar molecules. This suggests an important role for astrocytes in the development of the brain and in learning and memory as both processes involve the reorganization of synaptic connections between neurons (Min & Nevian, 2012; refer to Chapter 12). Astrocytes influence adjacent neurons and other astrocytes by releasing several excitatory and inhibitory neurochemicals typically released by neurons (Fellin et al., 2006; Sofroniew & Vinters, 2010). Consequently, astrocytes have the direct ability to excite and suppress the activity of neighboring neurons and other astrocytes. Astrocytes also release neurosteroids, including estradiol and progesterone, which interact with receptors in the brain. Astrocytes that change physically and functionally in response to disease, injury, and aging are known as reactive astrocytes. Reactive astrocytes can be harmful or beneficial (Escartin et al., 2021). Reactive astrocytes might play a role in chronic pain, Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and psychological disorders (Ji et al., 2019; Lee et al., 2022). Damaged astrocytes can release large quantities of glutamate, the brain’s major excitatory neurochemical (refer to Chapter 4). Although glutamate is an important neurochemical, too much glutamate kills neurons (Farber et al., 1998). Medical treatments targeting reactive astrocytes could be beneficial in treating many common brain disorders (Hines & Haydon, 2013; Lee et al., 2022). When central nervous system (CNS) neurons are damaged, nearby astrocytes become reactive. They form

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A reservoir of adult neural stem cells exists below the ependymal cells in the lateral ventricles. These stem cells typically migrate to the olfactory bulbs, where they differentiate into new neurons (refer to Chapter 5). The stem cells make connections with both the blood supply and the CSF through long processes that reach through the ependymal cells, suggesting that activation of the stem cells might require signals from blood, CSF, and the ependymal cells themselves. Finally, the ependymal cells act as a firewall against viruses attacking the central nervous system. The ependymal cells fight off viral infections but are often destroyed in the process. The malfunction of ependymal cells might lead to hydrocephalus (Abdi et al., 2018; refer to Chapter 2).

Oligodendrocytes and Schwann Cells Oligodendrocytes and Schwann cells provide the myelin covering that insulates some nerve fibers or axons (Peters et al., 1991). Oligodendrocytes form myelin in the CNS, and Schwann cells supply the myelin for the peripheral nervous system (PNS). As depicted in Figure 3.3, a single oligodendrocyte puts out a number of branches that wrap themselves around the axons of adjacent neurons. Because a single oligodendrocyte can myelinate axons from an average of 15 different neurons, these macroglia contribute to the structural stability of the brain and spinal cord. In contrast, one Schwann cell provides a single myelin segment on a peripheral axon. It takes large numbers of Schwann cells to myelinate a peripheral nerve.

Figure 3.3 Oligodendrocytes and Schwann Cells (a) Each oligodendrocyte in the central nervous system (CNS) sends out branches that form myelin segments on an average of 15 different axons. (b) The Schwann cells perform a similar function in the peripheral nervous system (PNS), although each Schwann cell forms only one segment of myelin.

Oligodendrocytes Myelin

Myelin Axon

Node of Ranvier

Axon

(a) Oligodendrocyte

Axon

Schwann cells

Myelin Axon Schwann cell nucleus

Myelin Node of Ranvier

(b) Schwann Cell

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Figure 3.4 Regrowth of Peripheral Axons Makes Body Part Transplants Possible

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Volunteer firefighter Patrick Hardison was burned beyond recognition in a house fire in 2001 but received a face transplant in 2015. He is no longer afraid of going out in public.

do die. Rather than leave the debris lying around where it might interfere with neural function, microglia serve as the brain’s cleanup crew (refer to Figure 3.5). They are the brain version of the white blood cells or phagocytes that populate the rest of the body. At rest, the branches of microglia reach out and sample their immediate environments (Nimmerjahn et al., 2005). Should they detect any one of the many types of molecules related to cell damage, whether from head injury, stroke, or other sources, these tiny cells travel to the location of the injury, where they digest the debris. exosome Tiny vesicle that removes debris and transports material.

Figure 3.5 Microglia Microglia, in red, are mobile cells that participate in synaptic pruning and cleaning up debris in the brain.

Microglia You might not particularly like the idea of having “brain debris,” but like any cells, neurons and glia Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

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We can appreciate the importance of myelin by studying conditions in which it is damaged. The disease multiple sclerosis (MS) involves a progressive demyelination of the central nervous system (refer to Chapter 15). The end result is neural signaling that may not work properly, leading to a range of symptoms from mild (increased fatigue) to more severe (vision and mobility problems) to death. Oligodendrocytes and Schwann cells can actually communicate with their nearby axons by releasing little packets of material known as exosomes (Budnik et al., 2016). These tiny vesicles (50–100 nm in diameter) can remove debris from a cell and also appear to deliver substances, including genetic material, to other cells. In the periphery, exosomes released by Schwann cells appear to aid in the regeneration of damaged axons. In the CNS, exosomes released by the oligodendrocytes support transport within neurons and protect neurons from damage. While generally beneficial, especially at times of stress, exosomes might also transport substances that contribute to cancer, prion diseases, and dementia (Isola & Chen, 2017; refer to Chapter 15). Oligodendrocytes and Schwann cells differ in their reactions to injury. Schwann cells help guide the regrowth of damaged axons, while the oligodendrocytes lack this capacity. If axon regrowth were impossible in the PNS, we would not bother to reattach severed fingers or limbs. Surgeons are even transplanting hands and faces from cadavers to living people (refer to Figure 3.4), which would be pointless unless nerve growth eventually provided some sensation and motor control (Petit et al., 2003; Sosin et al., 2016).

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Neuroscience in Everyday Life Should I Take Prebiotics or Probiotics? In this chapter, we have explored the roles of microglia in the development and homeostasis of the brain. Problems with microglia have been implicated in a wide range of neurological disorders. Health behaviors that favor optimum microglia function sound like a promising idea, but how do we know what to do? Although microglia are influenced by their local environment in the brain, they are also extremely sensitive to signals from the gut. In particular, the gut microbiota plays an essential role in the development and functioning of the microglia. Dysbiosis, or imbalances of the gut microbiota, could lead to both microglia dysfunction and neurological problems (Abdel-Haq et al., 2019). Observation of dysbiosis in aging and in a wide range of neurological disorders has led to suggestions that treatments aimed at restoring a healthy gut microbiota might be useful. Treatments could take the form of administering prebiotics, indigestible plant fibers that enhance bacterial growth in the gut, or probiotics, live organisms that add to the healthy population of bacteria in the gut. Prebiotics are obtained naturally by eating fruits

Uncontrolled activation of microglia, though, can damage the brain. Microglia have been observed digesting healthy cells located next to damaged cells (Kim & Joh, 2006). Inflammation caused by microglia activation is under investigation as a contributor to neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and multiple sclerosis (Li & Barres, 2018). The ability to deplete microglia in mice, which surprisingly does not seem to impact their health or behavior, might lead to new therapies for these conditions (Spangenberg et al., 2016). While all of this sounds destructive, the ability to remove neural material is important in refining connections in the healthy brain (refer to Chapter 5). Microglia organelle A small structure within a cell that carries out a specific function. cell body/soma The main mass of a neuron, containing the nucleus and many organelles. axon The branch of a neuron usually responsible for carrying signals to other neurons. dendrite The branch of a neuron that generally receives information from other neurons. intracellular fluid The fluid inside a cell; also known as cytoplasm. extracellular fluid The fluid surrounding a cell; also known as interstitial fluid.

and vegetables, while probiotics are found in fermented foods like yogurt, sauerkraut, and kimchi. Both are also available in a wide variety of dietary supplements. Prebiotic and probiotic supplements, like supplements in general, are not subject to much regulation, so caution regarding their use is warranted. Research into the efficacy of prebiotics and probiotics in treating microglial dysfunction is limited, and most studies are conducted with rodents (Chunchai et al., 2018). Efforts to improve symptoms of conditions believed to involve both dysbiosis and microglial abnormalities, such as autism spectrum disorder (ASD; refer to Chapter 16) have produced isolated success stories but not strong overall evidence. Among children with ASD and gastrointestinal difficulties, treatment with probiotics reduced the symptoms of autism (Santocchi et al., 2020), but much more research is needed in this area. What does this mean for the average person who just wants to be healthy? The best strategy would be to consult with your healthcare provider, who knows you best, before embarking on any effort to maintain a healthy gut microbiota.

play a role in the removal of less active synapses, which is an important part of the wiring of the developing brain (Hong et al., 2016). However, it is also possible that by removing synapses in a dysfunctional way, microglia could contribute to Alzheimer disease, which is characterized by synaptic loss (refer to Chapter 15).

The Structure of Neurons All animal cells, including neurons, have membranes, nuclei, and small internal structures known as organelles. Many of these structures are found within the main mass of the neuron, known as the cell body or soma. Neurons differ structurally from other cells in that they have specialized branches extending from the cell body, known as the axons and dendrites, which they use to communicate with other cells. Neural Membranes The primary task of any cell membrane is to form a boundary between the cell and its external environment. The neural membrane must separate the intracellular fluid or cytoplasm of the cell’s interior from the extracellular fluid surrounding the neuron. As we will discuss later in this chapter, the chemical compositions of these two types of fluids are quite different. Maintaining this difference is essential to the process of generating and sending neural messages.

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Table 3.1 | Types of Glia Type

Location

Functions Structural and nutritional support for neurons

Astrocyte

Isolation of the synapse

Central nervous system

Debris cleanup Blood–brain barrier Participation in chemical signaling Move cerebrospinal fluid

Lining of the ventricles and central canal of the spinal cord

Ependymal Cells

Regulate stem cells Firewall against viruses

Oligodendrocyte

Central nervous system (CNS)

Myelination of axons

Schwann cell

Peripheral nervous system (PNS)

Myelination of axons

Microglia

Central nervous system (CNS)

The neural membrane accomplishes its task by way of its molecular structure. As presented in Figure 3.6, the neural membrane is made up of a double layer of phospholipids, fatty molecules that contain phosphate. Because they are fats, phospholipids do not dissolve in water. As the saying goes, “oil and water do not mix.” Because of its

Debris cleanup Synapse removal

lipid structure, the neural membrane is able to restrain the water-based fluids on either side, maintaining the structural integrity of the cell. Membranes are able to do this despite being only two phospholipid molecules wide, with a resulting thickness of only 5 nanometers (1 nanometer = 1 billionth of a meter or 1029 meters).

Figure 3.6 The Neural Membrane Neural membranes consist of double layers of phospholipid molecules. Embedded within the lipid layers are proteins that serve as ion channels and ion pumps. These structures open and close, controlling the movement of ions across the neural membrane. Dendrites

Cell body or soma Axon

+

+

Extracellular fluid

– +

–

–

+

+

Myelin

Negative ion

+

Positive ion

+

Ion channel

Intracellular fluid Closed ion channel

Axon terminals

–

–

–

– +

–

– –

–

+ +

+

Phospholipid layers of cell membrane

+

Depolarization of cell membrane

+

+ + –

+

–

Open ion channel

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Suspended within this phospholipid membrane are a number of important protein structures that control its permeability, or the movement of substances across the cell membrane. There are two primary types of protein structures of interest in our discussion of neural function, ion channels and ion pumps. These structures provide pores, or channels, through which specific ions, or electrically charged particles, can move into or out of the neuron. Ion channels allow ions to move passively, without the expenditure of energy, while ion pumps require energy. Both channels and pumps show ion selectivity, or the ability to let a particular type of ion pass and not others. The amino acids, or protein building blocks, that make up the ion channel or pump determine which ions will be allowed to pass through the membrane. Ion channels have the ability to open and close in response to stimuli in their immediate vicinity. Some ion channels, known as voltage-dependent channels, open and close in response to the electrical status of adjacent areas of membrane. These channels form an important part of our later discussion of electrical signaling within the neuron. Chemically-gated channels open when they come in contact with specific chemicals. These chemicals are typically our naturally occurring chemical messengers, but they can be drugs from artificial sources as well (refer to Chapter 4). Chemically-gated channels become very important as we discuss events taking place at the synapse, or the junction between two neurons. The two most important ion pumps in neurons are the sodium-potassium pumps and the calcium pumps.

permeability A property of a substance that determines the extent to which other substances may pass through it. ion channel A protein structure embedded in a cell membrane that allows ions to pass without the use of additional energy. ion pump A protein structure embedded in a cell membrane that uses energy to move ions across the membrane. ion An electrically charged particle in solution. voltage-dependent channel An ion channel that opens or closes in response to the local electrical environment. chemically-gated channel An ion channel in the neural membrane that responds to chemical messengers. sodium-potassium pump An ion pump that uses energy to transfer three sodium ions to the extracellular fluid for every two potassium ions retrieved from the extracellular fluid. calcium pump A protein structure embedded in the neural membrane that uses energy to move calcium ions out of the cell. cytoskeleton A network of filaments that provides the internal structure of a neuron. microtubule The largest type of fiber in the cell cytoskeleton, responsible for the transport of neurochemicals and other products to and from the cell body. anterograde transport Movement of materials from the cell body of a neuron to the axon terminal along the microtubules. retrograde transport Movement of material from the axon terminal back to the cell body via the cell’s system of microtubules. tau One type of microtubule-associated protein (MAP).

These pumps help maintain the differences in chemical composition between the intracellular and extracellular fluids. Sodium-potassium pumps do a “prisoner exchange” across the neural membrane by sending three sodium ions out of the cell while collecting two potassium ions from the extracellular environment. This process comes at a high cost to the neuron. Possibly as much as 20 to 40 percent of the energy required by the brain is used to run the sodium-potassium pumps (Sheng, 2000). Calcium pumps perform a similar function, although they do not collect another type of ion in exchange for the calcium they pump out of the cell. When we discuss the release of neurochemicals by a neuron, you will understand further why it is essential to maintain low levels of calcium within the cell. The Neural Cytoskeleton Having a neural membrane without structural support would be like having skin without bones. The structural support that maintains the shape of the neuron is provided by the cytoskeleton. Three types of filament, or fiber, make up the neural cytoskeleton. These structural fibers also move elements within the cell and anchor the various channel and receptor proteins in their appropriate places on the neural membrane. The largest of the three types of cytoskeleton fibers are the microtubules, which are formed in the shape of hollow tubes with a diameter of about 25 nm (nanometers). Microtubules, displayed in Figure 3.7, are responsible for the movement of various materials within the cell, including the vesicles that contain neurochemicals. Movement along the microtubules away from the cell body is known as anterograde transport, and movement toward the cell body from the periphery is known as retrograde transport. The rate of transport can vary from “slow” (less than 8 mm or about half an in per day) to “fast” (approximately 400 mm or nearly 16 in per day), depending on the type of material being moved (McEwen & Grafstein, 1968). Many pathogens that cannot otherwise enter the nervous system due to the blood–brain barrier, such as rabies, polio, herpes simplex, and tetanus toxin, “hitchhike” via the retrograde transport system to travel from the terminal of an axon to the brain and spinal cord, where they do considerable damage. Microtubules have been implicated in the development of Alzheimer disease (refer to Chapter 15). This condition is characterized initially by memory loss, followed by a progressive decline in cognitive and physical functions, eventually leading to death. One of the characteristic symptoms of Alzheimer disease is the presence of neurofibrillary tangles consisting of a protein called tau. Tau is one of several types of microtubule-associated protein (MAP). In a healthy brain, tau connects adjacent microtubules and holds them in place, much like the rungs of a ladder. In Alzheimer disease, tau levels become elevated

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Figure 3.7 Three Fiber Types Compose the Cytoskeleton of Neurons Microtubules provide a means for transporting materials within the neuron. Intermediate filaments provide structural support, while microfilaments may be involved with structural changes associated with development and learning.

Myelin Microtubule Intermediate filament Microfilament

Organelles transported by retrograde transport

(Baas & Qiang, 2005). In response, an affected neuron adds molecules of phosphate to the tau protein, which causes it to disconnect from the microtubules. As presented in Figure 3.8, the disconnected tau begins to form tangles, hindering the cell’s ability to signal and maintain its structure. The neuron folds in on itself and collapses (Brandt, 2001). The middle-sized filaments, known as intermediate filaments, are the most common fiber in the neuron. Intermediate filaments are usually about 10 nm in diameter, or less than half the size of the microtubules. Their structure is similar to that of hair, and they are quite strong for their size. Intermediate filaments run parallel to the length of the axon and provide structural support. The smallest fibers are the microfilaments, which are usually quite short and range from 3 to 5 nm in diameter. Because most of the microfilaments are located in the branches of the neuron, they may participate in changing the shape and length of these structures during development (Dent et al., 2011) and in response to learning (refer to Chapter 12). The Neural Cell Body The neural cell body, or soma, presented in Figure 3.9, contains many of the same small structures and carries out many of the same functions as

Organelles transported by anterograde transport

do other animal cells. In addition, the neural cell body is specialized to participate in the information processing and communication functions of the neuron. The most prominent structure in the cell body is the nucleus, which contains the DNA that directs the cell’s functions. The nucleus contains a substructure, known as the nucleolus, which builds organelles known as ribosomes. The ribosomes produce proteins either on their own or in association with the endoplasmic reticulum, another organelle located in the cell body. The endoplasmic

intermediate filament A neural fiber found in the cell cytoskeleton that is responsible for structural support. microfilament The smallest fiber found in the cell cytoskeleton that may participate in the changing of the length and shape of axons and dendrites. nucleus The substructure within a cell body that contains the cell’s DNA. nucleolus A substructure within a cell nucleus where ribosomes are produced. ribosome An organelle in the cell body involved with protein synthesis. endoplasmic reticulum An organelle in the cell body that participates in protein synthesis.

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Figure 3.8 Tau Phosphorylation Molecules of phosphate added to the tau protein lead to neurofibrillary tangles and structural collapse. 1

Tau (in blue) connects microtubules and holds them in place. P P

2 Due to the action of certain

P

P

P P

enzymes, molecules of phosphate are added to tau.

P

P P P P

P

P

P P P

Disconnected tau forms neurofibrillary tangles.

P

3

P P

P

P

P

P P

P

P P P P

5

P

place, the microtubules separate and collapse.

P

P

4 Without tau to hold them in

Interference caused by the neurofibrillary tangles and the collapsed microtubules leads to cell death.

Figure 3.9 The Cell Body Neurons share a number of features with other body cells. Most cells have a membrane, a nucleus, a nucleolus, mitochondria, ribosomes, smooth and rough endoplasmic reticuli, and Golgi apparati.

Neural membrane Nucleus Nucleolus Golgi apparatus Smooth endoplasmic reticulum

Rough endoplasmic reticulum

Mitochondrion Ribosomes Microtubules

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Glia and Neurons

reticulum may be divided into rough and smooth portions. The rough endoplasmic reticulum has many ribosomes bound to its surface, giving it the bumpy appearance responsible for its name. There are no ribosomes attached to the smooth endoplasmic reticulum. After proteins are constructed by the ribosomes on the rough endoplasmic reticulum, they are moved by the smooth endoplasmic reticulum to a Golgi apparatus. This organelle inserts the completed proteins into vesicles, or small packages made out of membrane material. Mitochondria extract oxygen and pyruvic acid from sugar in the intracellular fluid and construct and release molecules of adenosine triphosphate (ATP), the major energy source for the neuron. The number of mitochondria in a cell is dependent on its energy needs and can range from a single mitochondrion to thousands. A resting cortical neuron requires 4.7 billion ATP molecules per second (Zhu et al., 2012). Mitochondria differ from other organelles because they have their own DNA and reproduce independently from the cell in which they exist. Mitochondria are inherited from the mother in most animal species. Sperm carry mitochondria in their tails, which drop off when they attach to an egg during fertilization. As a result, the only version of mitochondria remaining in the fertilized egg comes from the mother. Because mitochondrial DNA is not “shuffled” like nuclear DNA in each generation, it is particularly useful in tracking the course of evolution (refer to Chapter 2). The complex structure and length of neurons pose special problems for mitochondria, which are synthesized in the cell body but might be needed in an axon terminal several feet away. Disturbances in mitochondrial distribution and transport within neurons are suspected in a number of conditions, including bipolar disorder (refer to Chapter 16), Parkinson disease (refer to Chapter 8), and Alzheimer disease (refer to Chapter 15). Dendrites Most neurons have a large number of branches known as dendrites, from the Greek word for tree. Along with the cell body, the dendrites serve as locations at which information from other neurons is received. The greater the surface area of dendritic membrane a neuron has, the larger the number of connections or synapses it can form with other neurons. An average spinal motor neuron receives information at approximately 10,000 synapses, with about 2,000 of these located on the cell body and the remaining 8,000 on the dendrites. At each synapse on a dendrite, special chemically-gated ion channels serving as receptor sites are embedded in the neural membrane. These receptor sites interact with molecules of neurochemicals released by adjacent neurons that float across the synaptic gap, a fluid-filled space between the transmitting and receiving neurons, or with molecules of neurochemicals that diffuse from other parts of the nervous system.

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Some dendrites form knobs known as dendritic spines. As presented in Figure 3.10, spines provide additional locations for synapses to occur. Spines are able to change their shape based on the amount of activity occurring at the synapse, which contributes to the processes of learning and memory (refer to Chapter 12). Abnormalities in spine density and shape might contribute to autism spectrum disorder (ASD), schizophrenia, and Alzheimer disease (Penzes et al., 2011). The Axon Although a neuron may have large numbers of dendrites, it typically has only one axon, as shown in Figure 3.10. The axon is responsible for carrying messages to other neurons. The cone-shaped segment of axon that lies at the junction of the axon and the cell body is known as the axon hillock. Electrical signals known as action potentials arise in the initial segment, or the portion of axon between the axon hillock and the first segment of myelin and are then reproduced down the length of the axon. Axons vary substantially in diameter. In vertebrates, including humans, axon diameters range from less than 1 micrometer (μm, or 1026 meter) to about 25 micrometers. In invertebrates, such as the squid, axon diameter can be as large as 1 mm, or over 1,000 times larger than the smallest vertebrate axons. Axon diameter is crucial to the speed of signaling. Larger diameter axons are much faster than smaller diameter axons. Does this mean that the squid thinks faster than we do? Not at all. As we mentioned in the section on macroglia, many vertebrate axons are insulated by myelin, a material that allows for rapid signal transmission despite smaller axon diameter. In addition to varying in diameter, axons also vary in length. Some neurons have axons that barely extend from the cell body to communicate with adjacent cells. These

Golgi apparatus An organelle in the cell body that packages proteins in vesicles. mitochondria Organelles that provide energy to the cell by transforming pyruvic acid and oxygen into molecules of adenosine triphosphate (ATP). neurochemical A small organic molecule that participates in neural activity. synaptic gap The tiny fluid-filled space between neurons at a synapse. dendritic spine A knob on the dendrite that provides additional membrane area for the formation of synapses with other neurons. axon hillock The cone-shaped segment of axon located at the junction of the axon and cell body. action potential The nerve impulse arising in an axon. initial segment The portion of axon between the axon hillock and the first segment of myelin. myelin The fatty insulating material covering some axons that boosts the speed and efficiency of electrical signaling.

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Figure 3.10 Axons and Dendrites Action potentials originate in the initial segment between the axon hillock and the first myelin sheath and then travel the length of the axon to the axon terminal. The arrival of action potentials at the axon terminal signals the release of neurochemicals from the synaptic vesicles. Molecules of neurochemical diffuse across the synaptic gap, where they interact with receptors embedded in the dendrite of the adjacent neuron. Axon hillock

Initial Myelin segment sheath

Node of Ranvier

Collaterals

Axon terminals

Dendrite Presynaptic axon terminal

Postsynaptic dendrite Synaptic gap

Axon from another neuron

Postsynaptic receptors Synaptic vesicle Mitochondrion Neurochemicals Dendritic spine

neurons are referred to as local circuit neurons. Other neurons, known as projection neurons, have very long axons. Consider for a moment that you have neural cell bodies in your spinal cord with axons that extend as far as

local circuit neuron A neuron that communicates with neurons in its immediate vicinity. projection neuron A neuron with a very long axon that communicates with neurons in distant areas of the nervous system. collateral One of the branches near the end of the axon closest to its targets. axon terminal The swelling at the tip of an axon collateral specialized for the release of neurochemicals. axonal varicosity A swelling in an unmyelinated segment of axon containing mitochondria and, in some cases, synaptic vesicles. synaptic vesicle Small structure in the axon terminal that contains neurochemicals.

your big toe. Depending on your height, these axons can be 3 ft long or more. A neuron with only one axon can still communicate with a large number of other cells. The ends of many axons are divided into branches, known as collaterals. At the very end of each axon collateral is a swelling known as the axon terminal. Additional swellings, or axonal varicosities, occur at intervals along the length of unmyelinated segments of axon. Axon terminals and axonal varicosities contain both mitochondria and synaptic vesicles from which neurochemicals can be released. Synaptic vesicles are made from the same double-lipid molecule structure as the cell membrane and are approximately 40 nm in diameter. Many, but not all, axons in vertebrate nervous systems are covered by myelin. In the adult human, the vast majority of CNS neurons and peripheral motor neurons are myelinated. Peripheral sensory nerves may or may

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Glia and Neurons

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not be myelinated, with the smallest diameter fibers less likely to be so (refer to Chapter 7). Myelin does not cover the entire length of an axon. The axon hillock and initial segment are completely uncovered, and between each myelin segment, there is a bare space of axon membrane known as a node of Ranvier. Nodes of Ranvier are about 1 μm long (1 millionth of a meter) and occur somewhere between 0.2 mm and 2.0 mm apart down the length of the axon, depending on both the diameter and length of the axon. Large diameter axons have thicker myelin and greater distances between nodes of Ranvier. There are a number of important advantages to myelin. First of all, as mentioned earlier, myelin allows human axons to be smaller in diameter without sacrificing transmission speed. Space is a precious commodity in the nervous system. The smaller the diameter of our axons, the more neural tissue we can pack into our skulls and the more information we can process. In addition, myelin reduces the energy requirements of neurons by decreasing the amount of work done by sodium-potassium pumps. Myelin segments wrap so tightly around axons that there is little to no extracellular fluid between the myelin and the axon membrane. As a result, there is no need for ion channels under a myelin sheath. The only places on a myelinated axon that have large numbers of ion channels are the axon hillock, the initial segment, and the nodes of Ranvier. In contrast, an unmyelinated axon has ion channels along its entire length. During signaling, therefore, fewer ions move through the ion channels of a myelinated axon membrane than through an unmyelinated axon membrane of the same length. Because the sodium-potassium pumps work to restore ions to their presignaling locations, less of this work needs to be done in a myelinated axon.

with one part extending back toward the CNS and the other part extending toward the skin and muscle. Signals begin at the peripheral end near skin and muscle, travel past the cell body, and proceed toward the spinal cord or brain. A second structural type is the bipolar neuron. These cells have two branches extending from the neural cell body: one axon and one dendrite. Bipolar neurons play important roles in sensory systems, including in the retina of the eye (refer to Chapter 6). A special type of bipolar cell is known as a spindle or von Economo neuron (VEN), named after one of its discoverers (von Economo & Koskinas, 1929). These cells feature a large spindle-shaped cell body and are found in the anterior cingulate cortex (ACC), in the junction of the frontal lobe and insula area of the temporal lobe, and in the dorsolateral prefrontal cortex in humans, great apes, elephants, and members of the whale family. Although their exact function is not well understood, the VENs appear to be specifically designed to provide fast, intuitive assessments of complex situations (Allman et al., 2005). It is possible that these cells are particularly important to assessing and performing the complex social behaviors that characterize the very intelligent species that possess them. The loss of VENs in frontotemporal dementia (refer to Chapter 15) might result in the relative lack of empathy, social awareness, and self-control associated with this condition. The most common structural type of neuron in the vertebrate nervous system is the multipolar neuron. Multipolar neurons have many branches extending from the cell body. Usually, this means that the cell has one axon and numerous dendrites. Multipolar neurons may be further classified according to shape. For example, pyramidal cells in the cerebral cortex and the hippocampus have cell bodies that are shaped like pyramids. The Purkinje cells of the cerebellum have dramatic dendritic trees that allow a single cell to form as many as 150,000 synapses.

Structural Variations in Neurons

Functional Variations in Neurons

There are a number of ways we can categorize neurons. We have already classified neurons as either local circuit or projection neurons based on the length of their axons. Another strategy is to classify neurons according to other structural features. Specifically, we will look at the number of branches extending from the neural cell body. As we said earlier, form usually does follow function, so understanding the form of a neuron provides insight into the possible roles it plays in the nervous system. A sample of different structural types of neurons and their associated functions are presented in Figure 3.11. Unipolar neurons have a single branch extending from the cell body, as indicated by the name. These neurons are typical of invertebrate nervous systems. In vertebrates like us, unipolar cells are found in the sensory systems. For example, unipolar cells are involved with the somatosenses (touch, temperature, and pain; refer to Chapter 7). Just beyond the cell body of a unipolar neuron in the somatosensory system, the single branch divides in two,

Neurons can be classified according to the roles they play within the nervous system. Sensory neurons are specialized to receive information from the outside world and from within our bodies. Our senses of vision, hearing, touch, taste, smell, and pain all depend on specialized receptor neurons. These neurons can translate many types node of Ranvier The uncovered section of axon membrane between two adjacent segments of myelin. unipolar neuron A neuron with one branch that extends a short distance from the cell body and then splits into two branches. bipolar neuron A neuron with two branches extending from the cell body: one axon and one dendrite. multipolar neuron A neuron that has multiple branches extending from the cell body, usually one axon and numerous dendrites. sensory neuron A specialized neuron that translates incoming sensory information into electrical signals.

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Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Figure 3.11 Structural and Functional Classification of Neurons Unipolar and bipolar neurons are usually found in vertebrate sensory systems, where they encode and transmit information from the outside world or from within the body. Multipolar neurons typically serve as motor neurons, carrying commands to glands and muscles, or interneurons, serving as bridges between sensory and motor neurons. Type

Appearance

Unipolar neuron

Branch to the central nervous system Branch to the periphery

Bipolar neuron

Dendrite Axon

Dendrite

Axon

Location

Examples of Some Functions

Near spinal cord, with processes extending to skin, muscle, organs, and glands

Transmits information about touch, skin temperature, and pain

Retina Cochlea Olfactory bulb Tongue

Transmits information in several sensory systems

Anterior cingulate cortex (ACC) Fronto-insular cortex Dorsolateral prefrontal cortex

Provides fast, intuitive assessments of complex situations

Von Economo neuron (VEN) Multipolar Dendrites Cerebral cortex

Participates in movement and cognition

Cerebellum

Participates in movement

Axon Pyramidal cell

Dendrites

Axon Purkinje cell Dendrites

Spinal cord, with axons extending to muscles and glands

Carries commands to muscles and glands

Axon Motor neuron

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Generating Action Potentials

of information, such as light or sound waves, into neural signals that the nervous system can process. Motor neurons transmit commands from the CNS directly to muscles and glands. The vast majority of neurons are known as interneurons. Interneurons are not specialized for either sensory or motor functions but act as bridges between the sensory and motor systems.

Interim Summary 3.1 Summary Points 3.1 1. The nervous system is made up of two types of cells, glia and neurons. Glia perform a variety of support functions, and neurons are responsible for processing and communicating information. (LO1) 2. Macroglia provide a variety of support functions to neurons, including the formation of myelin. Microglia remove weak synapses and debris resulting from damage to neurons. (LO2) 3. The neural membrane is composed of a twomolecule-thick layer of phospholipids. Embedded within the phospholipid membrane are ion channels and pumps, which are specialized proteins that allow chemicals to pass into and out of the neuron. The neural cytoskeleton provides structural support and the ability to transport substances within the neuron. (LO3) 4. The cell body contains important organelles that participate in the basic metabolism and protein synthesis of the cell. In addition, the cell body is a site of synapses with other neurons. (LO3) 5. Neurons communicate with other cells through special branches known as axons and dendrites. (LO3) 6. Neurons may be classified according to the number of branches extending from their cell bodies and by their sensory, motor, or interneuron functions. (LO4) Review Questions 3.1 1. What are the different functions carried out by the macroglia and microglia? 2. What are the roles of the dendrites and dendritic spines, and what structural features enable them to carry out these functions?

Generating Action Potentials The first step in neural communication is the development of an electrical signal, the action potential. This signal is generated first in the initial segment of the neuron that is sending information, known as the presynaptic neuron. Next, the signal must be propagated, or duplicated, down

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the length of the axon, somewhat like a spark traveling the length of a fuse. When the action potential arrives at the axon terminal, the process switches from electrical to chemical signaling. The presynaptic neuron releases molecules of neurochemical from its terminal. The neurochemical molecules float across the synaptic gap to the waiting postsynaptic, or receiving, neuron, or diffuse to other locations to interact with more distant neurons. It is then up to the postsynaptic neuron to determine whether to send the message along.

The Ionic Composition of the Intracellular and Extracellular Fluids Electrical signals require a source of energy, like a battery. In our discussion of the neural membrane, we found that one of the important responsibilities of the membrane is to keep the intracellular and extracellular fluids apart. In addition, the sodium-potassium pumps discussed earlier also work to maintain the differences between these two fluids. It is the difference between these two types of fluid that provides the neuron with a source of energy for electrical signaling. The intracellular and extracellular fluids share a common ingredient, water, but differ from each other in the relative concentrations of ions they contain. When certain chemicals are dissolved in water, they take the form of ions. For example, table salt (sodium chloride, or NaCl) dissolves in water, forming separate sodium ions (Na+) and chloride ions (Cl−). The ions remain separate rather than rejoining to form salt because their attraction to water is stronger than their attraction to each other. The plus and minus signs associated with each type of ion indicate its electrical charge. This, in turn, is a function of the ion’s relative numbers of protons and electrons. A negatively charged ion has more electrons than protons, and a positively charged ion has fewer electrons than protons. As shown in Figure 3.12, extracellular fluid is characterized by large concentrations of sodium and chloride ions and a relatively small concentration of potassium (K+) ions. If you have difficulty remembering which ions go where, keep in mind that extracellular fluid is very similar to seawater. Single cell organisms interacted directly with seawater. As organisms became more complex, they essentially packaged some seawater within their bodies so their individual cells remained in the same environment as before. Intracellular fluid is quite different from extracellular fluid. The intracellular fluid of the resting neuron contains large numbers of potassium ions and relatively few sodium and chloride ions. In addition, the intracellular motor neuron A specialized neuron that communicates with muscles and glands. interneuron A neuron that serves as a bridge between sensory and motor neurons.

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Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Figure 3.12 The Composition of Intracellular and Extracellular Fluids Extracellular fluid is similar to seawater, with large concentrations of sodium and chloride but small concentrations of potassium. Intracellular fluid has a large concentration of potassium but relatively little sodium and chloride. 600

Concentration (millimoles)

500

400

Sodium ions (Na+) Chloride ions (Cl –) Potassium ions (K+)

the inside and outside of a neuron is approximately 70 millivolts (mV), although this can range from 40 to 80mV depending on the exact type of cell. A millivolt is one one-thousandth of a volt, so neurons definitely work on a different scale of electricity than that of a car. It is conventional to assign the extracellular environment a value of 0; thus, we speak of this 70mV difference across the membrane as negative, or 270mV. Because this difference is measured when the cell is not processing a message, it is known as the resting potential of the cell.

The Movement of Ions

Electrical signals in an axon, or action potentials, result from the movement of ions across the mem300 brane. To understand the development of these signals, we need to review the forces that cause ions to move. 200 Diffusion is the tendency for molecules to distribute themselves equally within a medium such as air or water. In other words, like city 100 dwellers seeking the quiet countryside, molecules will move from a crowded location to a 0 less crowded location. In more formal terms, Seawater Extracellular Intracellular diffusion pressure moves molecules along a fluid fluid concentration gradient from areas of high conSource: Data from Smock (1999). centration to areas of low concentration. Another important cause of the movement of molecules is electrostatic pressure. As you may already know from playing with magnets, opposite signs attract and fluid contains some large proteins in ion form that are neglike signs repel. Ions work the same way. Table salt forms atively charged. readily when it dries out because the positively charged Because of the distribution of ions and other charged sodium is highly attracted to the negatively charged particles, particularly the large, negatively charged proteins, chloride. Two positively charged ions will repel each the electrical environment inside the neuron is more negaother, as will two negatively charged ions. Ions respond tive than it is on the outside. How do we know? As demonnot only to other ions but also to the overall charge in strated in Figure 3.13, we can actually record the difference their vicinity as well. between the two environments by inserting a tiny glass With diffusion and electrostatic pressure in mind, let’s microelectrode through the membrane of the neuron itself. revisit the distribution of ions on either side of the neural We can use a voltmeter to measure the difference between membrane in the resting cell, presented in Figure 3.14. the microelectrode and a wire placed in the extracellular For the purposes of this exercise, assume that the neural fluid adjacent to our cell. We use a similar process when membrane allows ions to move freely back and forth measuring the amount of charge left in a battery. The dif(which it doesn’t do in the real world). Potassium is ference between the positive and negative terminals in a found in larger concentrations on the inside of the cell car battery is 12 volts. In contrast, the difference between than on the outside. Diffusion would move the potassium ions along their concentration gradient from the inside (the area of higher concentration) to the outside resting potential The measurement of the electrical charge across (the area of lower concentration). However, diffusion is the neural membrane when the cell is not processing information. balanced by electrostatic pressure in this case. Potassium diffusion The force that moves molecules from areas of high is a positively charged ion. As such, it is content to stay concentration to areas of low concentration. in the negative environment on the inside of the cell and concentration gradient An unequal distribution in the concentration of molecules across a cell membrane. reluctant to venture into the relatively positive environelectrostatic pressure The force that moves molecules with like ment outside the cell. The net distribution of potassium electrical charges apart and molecules with opposite electrical reflects a balance, or equilibrium, between diffusion charges together. pressure and electrostatic pressure.

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Generating Action Potentials

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Figure 3.13 Measuring the Resting Potential of Neurons Axons from invertebrates like the squid can be dissected and maintained in a culture dish for study. Because these axons are so large in diameter, electrodes can be inserted into the intracellular fluid. If we compare the recordings from two electrodes, one located in the intracellular fluid of the axon and the other in the extracellular fluid, our recording shows that the inside of the cell is negatively charged relative to the outside. The relatively larger number of negatively charged molecules in the intracellular fluid compared with the extracellular fluid is responsible for this difference. Squid axon

1 mm

40

Voltmeter mV

Reference electrode

Recording microelectrode

Squid axon

–70 1 Voltmeter records zero difference when both electrodes are in seawater.

Seawater

40 mV

Voltmeter

Seawater + + + + + + + – – – – – – – Inside axon

0

0

–70 2 Voltmeter records –70mV difference between intracellular fluid and seawater.

– – – – – – – + + + + + + +

Chloride is the mirror image of potassium. Chloride, a negatively charged ion, is more concentrated outside the cell than inside it. Therefore, diffusion works to push chloride into the cell. Once again, diffusion is counteracted by electrostatic pressure. The negative interior of the cell repels the negatively charged chloride ions, while the relatively positive exterior attracts them. Chloride finds its equilibrium.

Now we come to the interesting case of sodium. Sodium is found in greater concentration on the outside of the cell. By now, you know that means that diffusion will work to push sodium into the cell. But unlike the cases of potassium and chloride, electrostatic pressure is not working against diffusion but rather in the same direction. The positive sodium ions should be very attracted to the negative interior of the cell. With both diffusion pressure and

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Figure 3.14 Diffusion and Electrostatic Pressure Diffusion will push molecules in the direction of their concentration gradient, or from areas of higher to lower concentration. Electrostatic pressure refers to the attraction of opposite charges and the repulsion of like charges. In a resting neuron, diffusion and electrostatic pressure balance each other to determine an equilibrium for potassium and chloride. In contrast, both diffusion and electrostatic pressure act to push sodium into the neuron. The large protein molecules found in the intracellular fluid cannot move through the membrane due to their size. Because of their negative charge, they contribute to the relative negativity of the intracellular fluid. Na+

Ion concentration gradients K+

Cl–

(a) Extracellular fluid (positively charged relative to the intracellular fluid)

Intracellular fluid (negatively charged relative to the extracellular fluid)

Ion channel

Negatively charged protein molecule Too large to pass through ion channel.

–

Neural cell membrane

– –

–

+

+

+

+

+

Potassium ion (K+) Diffusion pushes K+ out. + Electrostatic pressure Electrostatic attracts K+ in. pressure +

+

K+

+

+

Diffusion

+

–

–

–

–

Cl–

–

–

–

–

Na+

–

–

Diffusion

Electrostatic pressure

–

+

Chloride ion (Cl–) Diffusion pushes Cl– in. Electrostatic pressure attracts Cl– out. –

+

+

–

+

–

–

–

–

+

–

–

+

+

+ +

+

–

+

+ + +

+

+

+

+

+

+

Diffusion

Electrostatic pressure

+

Sodium ion (Na+) Diffusion pushes Na+ in. Electrostatic pressure attracts Na+ in.

(b)

electrostatic pressure pushing sodium into the cell, how do we account for the fact that most of the sodium is found on the outside? The answer lies in the nature of our very important neural membrane. So far, we have assumed that the neural membrane allows ions to move freely. In the real world, it does not.

Although the membrane contains sodium channels, most of these are closed when the cell is at rest. Some sodium leaks into the cell, but most is removed by the sodium-potassium pumps. The net result is that sodium concentrations within the neuron are maintained at low levels despite the actions of diffusion and electrostatic pressure.

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Generating Action Potentials

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Thinking Ethically Lethal Injection would also produce death alone, but not for one half hour or so. The muscle paralysis agent is much more controversial, as it plays no essential role in the death of the condemned prisoner. Instead, it prevents any movements in response to the effects of the potassium chloride. As such, it is administered more for the benefit of those who must witness the procedure and who might be upset by the prisoner’s involuntary movements occurring during the dying process. Lethal injection remains a highly controversial issue, above and beyond capital punishment itself, due to concerns about the training of prison personnel, the possibility of conscious awareness that cannot be expressed due to paralysis, and other humane concerns. Autopsies demonstrating fluid in the lungs suggest that individuals might have experienced a sense of drowning before death. Manufacturers have periodically stopped providing drugs used in lethal injection, leading to shortages and substitutions. Regardless of your thoughts on capital punishment itself, what is your position on the use of lethal injection? What further information do you need to inform your opinions? What recommendations would you make for further research? Are there other methods that you believe are more humane? Why or why not?

Powerphotos/Shutterstock.com

Understanding the methods used to perform lethal injections for use in capital punishment is important because we are called on as members of a democracy to participate thoughtfully in ethical decisions. Lethal injection is now the most common form of capital punishment used in the United States. As shown in Figure 3.15, the procedure typically uses a combination of three drugs, administered intravenously: a barbiturate that induces coma, a muscle paralysis agent, and potassium chloride (Human Rights Watch, 2006). It is the potassium chloride that actually produces death by stopping the heart, typically within 1 minute of administration. As we mentioned in this chapter, the distribution of potassium across the neural membranes (and the membranes of heart cells, too) is essential for electrical signaling. By increasing the concentration of potassium in the extracellular fluid, the resting potential of cells is increased. This depolarization inactivates sodium channels. The cell is unable to signal again until its normal resting potential is regained. The effects of potassium chloride alone would be extremely painful, so it is never given without other anesthesia. The barbiturate provides this pain relief, and it is given before the other drugs and in doses that far exceed those normally used in surgery. These doses

The Resting Potential The resting neural membrane allows potassium to cross freely. In other words, we would say that the membrane is permeable to potassium. If the membrane were permeable to potassium and no other ions, the resting potential of the cell would be about 293mV rather than the actual measurement of 270mV. The difference between these figures is the result of some sodium leaking into the cell. Because sodium is positively charged, the interior of the cell moves in a positive direction from 293mV to about 270mV.

Figure 3.15 Three Drugs Are Combined in Lethal Injection The current standard approach to lethal injection is to administer sodium thiopental, a barbiturate anesthetic; pancuronium bromide, a curare derivative that causes muscle paralysis and respiratory arrest; and potassium chloride, which blocks electrical signaling in the heart, causing cardiac arrest. In 2014, the use of another combination, the sedative midazolam and the painkiller hydromorphone, took more than 25 minutes to kill convicted Ohio murderer Dennis McGuire, raising new challenges to the idea of lethal injection as well as concerns about the methods used.

Because the resting potential in a neuron is so dependent on potassium, the importance of controlling the concentration of potassium in the extracellular fluid becomes quite clear. We mentioned earlier that astrocytes have the important task of collecting excess potassium in the vicinity of neurons. If the concentration of potassium increases in the extracellular fluid, the resting potential is wiped out. The neuron would act like a battery that had lost its charge, and no signaling would occur.

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Chapter 3

Neurophysiology: The Structure and Functions of the Cells of the Nervous System

The Action Potential Our next step is to describe the changes that take place when the cell signals by producing an action potential. We will explore the technique used by Nobel Laureates Alan Hodgkin and Andrew Huxley (1952) to identify the ionic basis of action potentials. To understand the sequence of events responsible for the action potential, we need first to clarify how one is measured. The giant axon of the squid, which controls the animal’s escape behavior, was used by Hodgkin and Huxley for their investigations of action potentials. The squid giant axon can be as much as 1 mm in diameter, allowing it to be seen easily with the naked eye and to be perforated by recording and stimulating electrodes without curbing its activity. An axon dissected out of a squid will remain active for many hours when placed in a trough containing seawater, which substitutes for the extracellular fluid due to its similar ionic composition. During this time, researchers can stimulate the axon and record its activity. To measure action potentials, we insert a recording electrode into the intracellular fluid of the squid axon and another into the extracellular fluid (or its experimental equivalent). We should now be able to read a resting potential of approximately 270mV. Threshold Because there is no natural input to the disembodied squid axon we are studying, we need to employ a stimulating electrode in addition to the recording electrodes. Normally, a neuron reacts either to sensory input (pressure, light, etc.) or to chemical messages from other neurons. In the squid axon experiment, we duplicate the effects of these natural inputs with a tiny, depolarizing electrical shock. Whether we’re discussing politics or electricity, polarization means that we’re on opposite ends of a continuum. Conversely, depolarization means that we’re moving closer together. In response to a depolarizing shock to the squid axon, the interior of the cell will become more similar to the exterior of the cell; that is, it will become more positive. Shocks that produce a depolarization of less than 5mV to 10mV have no further effects on the axon, which quickly returns to the resting potential. However, if we apply a shock that results in a depolarization of at least 5mV to 10mV, we begin a chain of events that will lead to the production of an action potential. In other words, when our recording reaches about 265mV to 260mV, we have reached the cell’s threshold for producing an action

depolarization A change in a membrane potential in a more positive direction. threshold The level of depolarization at which an action potential is initiated. hyperpolarization A change in membrane potential in a more negative direction.

potential. Reaching the threshold for an action potential is similar to lighting a candle. If your heat source (a match or lighter) is not hot enough, nothing happens. A heat source at threshold will light the candle. An even stronger heat source (perhaps a blowtorch) will still light the candle, but the candle flame will not be hotter or brighter than with the threshold level heat source. The sequence of events that characterizes an action potential is shown in Figure 3.16. Channels Open and Close During an Action Potential The first consequence of reaching a cell’s threshold is the opening of voltage-dependent sodium channels. Once the sodium gates open, sodium is free to move into the cell, and both diffusion and electrostatic pressure ensure that it does so rapidly. The rush of sodium ions into the neuron is reflected in the recording, which rises from a threshold of around 265mV up to a peak of about +40mV. In other words, at the peak of the action potential, the inside of the axon is now positively charged relative to the extracellular fluid, a complete reversal of the resting state. The peak of the action potential is similar to sodium’s equilibrium of about +60mV. In other words, if the membrane allowed sodium to move freely, the inside of the cell would be positive relative to the extracellular fluid. Voltage-dependent potassium channels are also triggered at threshold, but their response is much slower than the sodium channels. Toward the peak of the action potential, potassium begins to leave the cell, and the recording drops back to resting levels. Why does potassium move out of the cell toward the peak of the action potential? Recall that potassium is positively charged. In the resting cell, potassium is attracted to the negatively charged interior of the cell and relatively repulsed by the positive exterior. At the peak of the action potential, however, the positive potassium ions find themselves in a more positive environment within the neuron. The exterior looks relatively attractive. As a result, potassium diffuses outside due to both diffusion and electrostatic pressure. As these positively charged ions leave the neuron, the interior of the cell becomes negative again, as shown in the downward slope of the recording. Once the cell returns to the resting level, it actually hyperpolarizes, or overshoots its target and becomes even more negative than when at rest. The cell slowly returns to its normal resting level. Throughout the process, the sodium-potassium pumps are hard at work to return sodium ions to the extracellular fluid. There are several important differences between the sodium and potassium voltage-dependent channels that are involved with action potentials. First of all, the sodium channels open very rapidly, but the potassium channels open slowly. This difference accounts for the rapid rise in our recording of the action potential. Second, the sodium channels remain open only briefly and are then inactivated

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Generating Action Potentials

85

Figure 3.16 The Action Potential

Resting

Once a cell’s threshold is reached, an action potential will be generated by a sequential opening and closing of ion channels in the neural membrane. Voltage-dependent sodium and potassium channels are triggered at the threshold. The sodium channels open and close very rapidly, allowing sodium to rush into the cell. As a result, the cell is depolarized. The potassium channels open near the peak of the action potential and close more slowly than the sodium channels. Potassium leaves the now positive intracellular environment, which brings the cell back to its original negative state. Because the sodium channels will not open again until the cell is close to its negative resting state, there is an absolute refractory period in which the cell cannot fire again. Due to remaining hyperpolarization during the relative refractory period, a larger than normal stimulus is necessary for the production of an action potential. Absolute refractory period

Relative refractory period

Resting

3 Sodium channels become inactive.

40 2 Potassium channels open; K+ starts to leave cell. Action potential

mV

0

4 Potassium channels close. Sodium channels gradually regain ability to open again.

1 Sodium channels open; Na+ rushes in. Depolarization Threshold Resting potential

– 65 – 70

Hyperpolarization 0 Depolarizing stimulus applied

until the cell nearly reaches its resting potential again. The potassium channels remain open for a longer period of time, leading to the hyperpolarization mentioned previously that occurs at the end of the action potential. Understanding the importance of the sodium channels in electrical signaling helps to explain the dangers of consuming puffer fish sushi, or fugu (refer to Figure 3.17). The fugu toxin (tetrodotoxin, or TTX), produced by bacteria and found in other forms of sea life, specifically blocks the voltage-dependent sodium channels responsible for the rising phase of the action potential. Without the movement of sodium at this point, there is no signaling. With no signaling, of course, life-sustaining processes stop. Refractory Periods The frequency with which neurons can fire is limited. Once the voltage-dependent sodium channels have been activated, they cannot be opened a

1

2 Time (in msec)

3

second time until the membrane is repolarized to nearly resting levels. This interval, in which no stimulus whatsoever can produce another action potential, is known as the absolute refractory period. When the cell is relatively hyperpolarized following an action potential, it can respond, but only to larger than normal input. We refer to this period as the relative refractory period. When the membrane potential is repolarized to at least 250mV, the sodium channels

absolute refractory period The period in which an action potential will not occur in a particular location of an axon regardless of input. relative refractory period The period following an action potential in which larger than normal input will produce a second action potential but in which normal input will be insufficient.

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Chapter 3

Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Figure 3.17 Puffer Fish Poisoning

gradually regain the ability to open again. However, due to the hyperpolarized state of the membrane following an action potential and the relatively smaller numbers of active sodium channels, more depolarization than normal (10 to 15mV as opposed to 5mV or so) is needed to reach threshold. The Action Potential Is All-or-None We do not encode information by producing fat or thin or tall or short action potentials. An action potential is either produced or it is not. Consequently, we speak of action potentials as being all-or-none. If our neurons can make this one type of signal, how do we respond to different levels of stimulation? The rate of neural firing can vary to reflect stimulus intensity. Large amounts of stimulation produce rapid neural firing, while less intense input produces slower rates of firing. Firing rate does have physical limits, however. Because each action potential lasts about 1 msec, the maximum theoretical neural firing rate is about 1,000 action potentials per second (in reality, about 800 per second). In addition to firing rate, the number of active neurons can vary with stimulus intensity. Intense input will recruit action

propagation The replication of the action potential down the length of the axon.

Funny face/Shutterstock.com

Beth Swanson/Shutterstock.com

In spite of their intimidating appearance, hundreds of thousands of pounds of puffer fish, or fugu, are consumed each year in Japan. Unfortunately, certain species of puffer contain tetrodotoxin. In very small amounts, tetrodotoxin can cause death by blocking voltage-dependent sodium channels in axon membranes. When sodium is unable to enter the neuron, no signaling can occur, and death soon follows.

potentials from many neurons, and lower levels of stimulation will activate fewer neurons.

Propagating Action Potentials The process discussed so far takes place at a very small area of axon membrane in the initial segment, and we still need to get the message to an axon terminal that can be feet away. The next step is propagation, the process by which the signal reproduces itself down the length of an axon. This ability to reproduce the original signal ensures that the signal reaching the end of the axon is as strong as the signal formed at the initial segment. Earlier, we measured an action potential by using one recording electrode toward one end of the squid axon and another in the extracellular environment. To follow the traveling signal, we now add more electrodes and record action potentials as they pass electrodes down the length of the axon as shown in Figure 3.18. As presented in Figure 3.19, the movement of an action potential along an axon is influenced by whether the axon is myelinated. When we last saw our unmyelinated squid axon, the generation of an action potential at the initial segment resulted in the entry of sodium ions into the cell. Now that they are inside, these ions will behave like water in a leaky hose. Some of these sodium ions will exit the cell through the sodium-potassium pumps and other ion channels, and others will remain inside the cell membrane, or hose. Where are the remaining sodium ions likely to go?

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Generating Action Potentials

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Figure 3.18 Action Potentials Propagate Down the Length of the Axon Once formed in the initial segment, the action potential propagates, or reproduces, along successive segments of the axon membrane until it reaches the axon terminal. With additional recording electrodes, we can observe action potentials being formed at different points along the axon. Stimulus

+40 mV

Amplifier

A

0

–70 +40 mV

Amplifier

Recording electrodes

–70 Amplifier

A

B

C

+40 mV

Stimulating electrode

B

0

C

0

–70 Squid axon

Action potential

0

1

2

3 4 5 6 7 Time (in msec)

8

9

Source: Adapted from Rosenzweig et al. (1999).

Due to the same diffusion pressure and electrostatic pressure that brought them into the cell, the sodium ions will drift to the adjacent segment of axon, where there are many additional sodium channels. At the same time, incoming positive sodium ions will also push positive potassium ions ahead into adjacent axon segments due to their like electrical charges. The arrival of these positively charged sodium and potassium ions depolarizes the next segment. If this depolarization is sufficient to reach threshold, the events leading to an action potential will be reproduced. A recording electrode in this segment will indicate another action potential identical to the one we recorded at the initial segment. Can the action potential move backward toward the cell body, too? Technically, if an action potential were produced for the first time in the middle of an axon as a result of an experimental shock, there’s no reason why it couldn’t go in either or both directions. In reality, however, the prior segment will still be in the refractory period and won’t be able to fire. Because refractory periods prevent an immediate reoccurrence of an action potential in previous segments, action potentials move

in one direction, from cell body to axon terminal. At the initial segment, the site of the first action potential, there is no previous segment in refractory period. As a result, current does appear to flow backward into the cell body and dendrites. The significance of this backward current remains unknown. Once the initial segment has regained its resting potential, it can initiate a second action potential that will follow the first down the length of the axon. If an axon couldn’t have multiple action potentials following one another in this manner, a neural firing rate of up to 800 times per second would be impossible. Now we are ready to consider the propagation of action potentials in myelinated axons. To produce action potentials, we need ion channels. Numerous channels are located along the length of the unmyelinated axon, but in the myelinated axon, channels appear only at the initial segment and at the nodes of Ranvier, the bare spaces of axon membrane between adjacent segments of myelin. Under the myelin segment itself, there is no contact between the membrane and extracellular fluid at all.

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Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Figure 3.19 Propagation in Unmyelinated and Myelinated Axons In conduction in unmyelinated axons (a), the action potential must be replicated at each successive segment. Saltatory conduction in myelinated axons (b) is much faster because action potentials occur only at the nodes of Ranvier. (a) Conduction in Unmyelinated Axons (Relatively Slow) 1 Stimulus

1 Stimulus

+ ++ + + + + + + + + + + + -- - - - - - - - - - - - --- - - - - - - - - - - ++ + + + + + + + + + + + +

2 1 msec after stimulus + +++ +++ +

-

(b) Conduction in Myelinated Axons (Relatively Fast)

- - - - - - - - - + + + + + + + + + +

4 3 msec after stimulus + + + + + + -++++ ++++ -+ + + + + +

+++

Node of Ranvier

+++

+++

-- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - --- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

+++

+++

+++

+++

+++

+++

+++

2 1 msec after stimulus

+ + + + + + + + + + - - - - - - - - - -

3 2 msec after stimulus ++ + + + + - - - -++++ ++++ -- - - + + + + ++

Myelin

--

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - +++ + +++ + - - - - - - - - - - - - - - - - - - - - -

3 2 msec after stimulus + + + + + - - - - -

--

- - - - + + + + +

--

+ + - - -

- - - - - - - - - - - - - - - - - - - - - - -

+++

- - - - - - - - - - - - - - - - - +++ + +++ + - - - - - - - - - - - - - - - - - -

+++

+ +

4 3 msec after stimulus

+++

+++

+ + + + + - - - - -

-- - - - - - - - - - - - - - -

- - - - + + + + +

--- - - - - - - - - - - - - -

+++

How does myelin produce the faster, more efficient propagation of action potentials? The myelinated axon is like a leaky hose that has been patched. The patches, or myelin, prevent leakage of the sodium ions, at least until they reach a node of Ranvier. Just as water moves faster through the patched hose, so do the sodium ions move faster in the myelinated axon. Once the sodium ions reach a node of Ranvier, they produce another action potential due to the presence of voltage-dependent channels in that area. The nodes are especially rich in these channels. The density of channels at a node of Ranvier is about 10 times greater than the density of channels at any comparable location on an unmyelinated axon (Rasband & Shrager, 2000).

saltatory conduction The movement of an action potential from node of Ranvier to node of Ranvier down the length of a myelinated axon.

-----

- - - - - - - - - - - - - - - - - - - - - - -

+++ +++

- - - - - - -

+++

Because the signal appears to jump from node to node down the length of the axon, we refer to propagation in the myelinated axon as saltatory conduction. Saltatory comes from the Latin word for “leaping” or “dancing.” The action potential essentially passes through the segments of axon covered by myelin, just as an express train skips all but the most important stops. In contrast, propagation in the unmyelinated axon is like the local train that makes every single stop along its route. In a typical invertebrate unmyelinated axon, the action potential will be conducted at a rate of about 5 meters per second (about 11 miles per hour). In contrast, a typical human myelinated fiber can conduct action potentials at about 120 meters per second (268 miles per hour), or 24 times faster. Not only are myelinated fibers faster, but they are also faster despite having a smaller diameter. As fast as propagation is, however, the nervous system does not communicate anywhere near the speed of light, as was once believed. Part of the delay in communication occurs between neurons, at the synapse.

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The Synapse

89

Interim Summary 3.2

The Synapse

Summary Points 3.2

The birth and propagation of the action potential within the presynaptic neuron makes up the first half of our story of neural communication. The second half begins when the action potential reaches the axon terminal, and the message must cross the synaptic gap to the adjacent postsynaptic neuron (refer to Figure 3.20). The human brain contains about 86 billion neurons, and each neuron in the brain forms hundreds to thousands of synapses, suggesting that our brains have at least 10 trillion or more. Despite these large numbers, synapses take one of only two forms. At gap junctions, cells directly stimulate adjacent cells through a shared cytoplasm connected by channels that actually touch. At chemical synapses, neurons stimulate other cells by releasing neurochemicals that interact with postsynaptic receptors.

1. The intracellular fluid contains large amounts of potassium and smaller amounts of sodium and chloride. The extracellular fluid contains large amounts of sodium and chloride and smaller amounts of potassium. (LO5) 2. The resting potential of neurons averages about 270mV. In other words, the interior of the cell is negatively charged relative to the exterior. An action potential is a reversal of this polarity. (LO5) 3. Absolute and relative refractory periods, during which further action potentials are either impossible or less likely, result from the nature of the sodium and potassium channels. (LO5) 4. Action potentials move much more rapidly down the length of myelinated axons than in unmyelinated axons due to the process of saltatory conduction. (LO5) Review Questions 3.2 1. How do diffusion and electrostatic pressure account for the chemical composition of intracellular and extracellular fluids when the neuron is at rest? 2. How do neurons signal stimulus intensity given that the action potential is all-or-none?

gap junction A type of synapse in which a neuron directly affects an adjacent neuron through the movement of ions from one cell to the other. chemical synapse A type of synapse in which messages are transmitted from one neuron to another by neurochemicals.

Summary Table 3.2: Major Features of Electrical Signaling Event

Location

Mechanisms of Action ●

Resting potential

Action potential

Inactive segments of axon

Begins at the initial segment and propagates down the length of the axon

●

Na1 is actively prevented from entering the neuron.

●

Depolarization to threshold triggers opening of Na1 channels.

●

Entering Na1 ions make voltage inside neuron more positive.

●

●

Absolute refractory period

Segments of axon during an action potential

Relative refractory period

Segments of axon that have just experienced an absolute refractory period

Propagation of action potential

Entire length of axon, beginning at the initial segment

Equilibrium between diffusion and electrostatic pressure exists for K1 and Cl2.

●

●

●

●

Opening of K1 channels near peak of action potential allows K1 to leave the neuron. Loss of K1 returns neuron to the resting potential. Na+ channels are unable to open a second time until neuron nearly reaches the resting potential. Return to resting potential resets Na1 channels. Hyperpolarization makes an action potential less likely. Drift of Na1 and K1 ions to adjacent segments of axon causes segments to reach threshold, triggering replication of the action potential. Existence of refractory period in the preceding segment prevents backward propagation.

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Chapter 3

Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Figure 3.20 Neurons Communicate at the Synapse

OMIKRON/Science Source

This colored electron micrograph shows the axon terminals from many neurons forming synapses on a cell body.

Gap Junctions Gap junctions, presented in Figure 3.21, are found joining virtually all cells in solid tissue, not just in animals but in plants as well (Goodenough & Paul, 2009). This ubiquitous nature of gap junctions suggests that they have a very long evolutionary history. In mammals, gap junctions between glia and neurons play significant roles in brain development (refer to Chapter 5). Gap junctions are involved with the synchronization of the hippocampus and cortex that is necessary for learning and memory (refer to Chapter 12). Gap junctions also synchronize the release of hormones in response to activity in the hypothalamus. Disturbances in gap junction functioning contribute to a large number of pathological conditions, including epilepsy (refer to Chapter 15; Dere & Zlomuzica, 2012). In contrast to chemical synapses, the distance between two cells at a gap junction is quite small. The average distance between the presynaptic and postsynaptic neurons at a chemical synapse is about 20 nm, while the distance between cells at a gap junction is only 3.5 nm. Because of this tiny distance, the two cells can be connected by special protein channels extending across the gap. These channels make it possible for dissolved substances, including ions, to move directly from one cell to the next. Larger excitation A neural message that increases the likelihood that a receiving cell will produce an action potential. inhibition A neural message that decreases the likelihood that a receiving cell will produce an action potential.

organelles such as mitochondria, though, are too large to pass through the channels. Gap junctions provide several advantages, including speed. Transmission of a message from one cell to another is nearly instantaneous. In contrast, chemical synapses take anywhere from 0.3 msec to several msec to complete the series of steps involved with transmitting the message from one cell to the next. Consequently, gap junctions are often found in circuits responsible for escape behaviors, particularly in invertebrates (Bennett & Zukin, 2004). Although gap junctions are fast, chemical synapses have the advantage of providing a much greater variety of messages. The only type of message that can be sent at a gap junction between two neurons or muscle cells is an excitatory one. Excitation means that one cell can tell the next cell to produce an action potential. In contrast, chemical synapses allow for both excitatory and inhibitory messages to be sent. In inhibition, the next cell is told not to produce an action potential. Another major advantage of chemical synapses over gap junctions is that a very small presynaptic neuron using chemical messengers can still influence a very large postsynaptic neuron. In the case of a gap junction, it takes a very large presynaptic neuron to influence a tiny postsynaptic neuron because the strength of the signal decreases as it moves from one cell to the next.

Chemical Synapses Intercellular chemical communication in the central nervous system takes two forms: wiring and volume transmission (Agnati & Fuxe, 2014). Our focus will be on chemical

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The Synapse

91

Figure 3.21 The Gap Junction In gap junctions, or electrical synapses, channels connecting the two neurons across a synaptic gap of only 3.5 nm allow for the direct movement of ions from one cell to the other. Gap junctions have the advantage of nearly instantaneous communication between neurons.

Intracellular fluid

Presynaptic Cell A

Ions Cell A +

+

Cell B +

+

Extracellular fluid Synaptic gap: 3.5 nm

+

+

+

+

Protein channels

Postsynaptic Cell B

Table 3.2 | A Comparison of Gap Junctions and Chemical Synapses Type of Synapse

Width of Synaptic Gap

Speed of Transmission

Method of Transmission

Type of Message

Gap junction

3.5 nm

Nearly instantaneous

Direct movement of ions from one cell to the other

Excitatory only

Requires large presynaptic neuron to influence small postsynaptic neurons

Chemical

20 nm

Up to several msec

Release of neurochemicals

Excitatory or inhibitory

Small presynaptic neurons can influence large postsynaptic neurons

communication between neurons, but these modes of communication can involve any type of cell in the nervous system as the source or target (Agnati et al., 1995). Wiring transmission features the diffusion of chemicals from one cell to impact an adjacent cell or cells through private, highly localized channels. The classic chemical synapse, in which a presynaptic axon terminal releases neurochemical molecules that cross the synaptic gap and bind with postsynaptic receptors, is the primary

Impact of Cell Size

mechanism through which neurons exchange information and control behavior (refer to Figure 3.22). This classic synapse will be the main model of neural communication featured in this discussion. A gap junction also uses wiring transmission to share ions and neurochemicals. wiring transmission Process in which chemicals diffuse from one cell to impact an adjacent cell or cells through private, highly localized channels.

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Chapter 3

Neurophysiology: The Structure and Functions of the Cells of the Nervous System

Figure 3.22 The Chemical Synapse

Dennis Kunkel Microscopy/Science Source

In chemical synapses, neurochemicals released by the presynaptic neuron float across the synaptic gap (the horizontal line) to receptor molecules embedded in the membrane of the postsynaptic cell at the bottom of the image. Although this takes more time than transmission at a gap junction, it allows neurons to send a much greater variety of information. This image shows an electron microscopic image of a synapse.

Volume transmission involves the three-dimensional diffusion of neurochemicals through the extracellular fluid and CSF to influence cells located farther away from the releasing cell than the width of a synaptic gap. We will discuss both types of communication further in Chapter 4 in the context of the particular types of neurochemicals released during the two processes. Signaling at chemical synapses occurs in two steps. The first step is the release of neurochemicals by a presynaptic cell. The second step is the reaction of a postsynaptic cell to neurochemicals. Neurochemical Release In response to the arrival of an action potential at an axon terminal, a new type of voltagedependent channel will open. This time, voltage-dependent calcium (Ca21) channels will play the major role in the cell’s activities. The amount of neurochemical released is a direct reflection of the amount of calcium that enters the volume transmission Process in which neurochemicals diffuse through the extracellular fluid and CSF to influence cells located some distance away from the releasing cell. exocytosis The process in which vesicles fuse with the membrane of the axon terminal and release neurochemicals into the synaptic gap.

presynaptic neuron (Barclay et al., 2005). A large influx of calcium triggers a large release of neurochemical. Calcium is a positively charged ion (Ca21) that is more abundant in the extracellular fluid than in the intracellular fluid. Therefore, its situation is similar to sodium, and it will move under the same circumstances that cause sodium to move. Calcium channels are rare along the length of the axon, but there are a large number located in the axon terminal membrane. Calcium channels open in response to the arrival of the depolarizing action potential. Calcium does not move immediately, however, because it is a positively charged ion and the intracellular fluid is positively charged during the action potential. As the action potential recedes in the axon terminal, however, calcium is attracted by the relatively negative interior. Once calcium enters the presynaptic cell, it triggers the release of neurochemicals within about 0.2 msec. Prior to release, neurochemicals are stored in synaptic vesicles. Each vesicle contains about 10,000 molecules of neurochemical. Vesicles are anchored by special proteins near release sites on the presynaptic membrane. The process by which these vesicles release their contents is known as exocytosis, presented in Figure 3.23. Calcium entering the cell frees the vesicles from their protein anchors, which

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The Synapse

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Figure 3.23 Exocytosis Results in the Release of Neurochemicals Once calcium enters the presynaptic cell, it triggers the release of neurochemicals within about 0.2 msec. Microtubules

1 Action potential reaches axon terminal.

2 Calcium ion channels open, allowing Ca2+ ions in.

Extracellular fluid

7 Vesicles either return to neuron cell body via retrograde transport or are refilled at axon terminal.

Synaptic vesicles

6 Vesicle material is recycled.

Neurochemical molecules

Ca2+ ions

Presynaptic axon terminal

3 Ca2+ causes synaptic vesicles to release from microtubules.

Synaptic gap

4 Synaptic vesicles fuse with axon membrane at release sites.

5 Vesicles open, releasing neurochemicals into synaptic gap.

allows them to migrate toward the release sites. At the release site, calcium stimulates the fusion between the membrane of the vesicle and the membrane of the axon terminal, forming a channel through which the neurochemicals escape. Exocytosis can occur in one of two ways. First, a synaptic vesicle can completely merge with the axon terminal membrane, releasing its entire contents into the synaptic gap. Second, vesicles can release some of their content in a process known as “kiss and run” (Ceccarelli et al., 1973). In kiss and run, vesicles are only partially emptied of neurochemical molecules before closing up again. Instead of reconstructing vesicles and filling them from scratch after each use, the same vesicles can be re-used. This process can be especially efficient at synapses experiencing sustained release, such as the photoreceptors in the retina (refer to Chapter 6). Following exocytosis, the neuron must engage in several housekeeping duties to prepare for the arrival of the next action potential. Calcium pumps return calcium to the extracellular fluid. Otherwise, neurochemicals would be released constantly rather than in response to the arrival of an action potential. When the vesicle membrane fuses with the presynaptic membrane, something must be done to prevent a gradual thickening of the membrane that would interfere with neurochemical release. The solution

Postsynaptic membrane

to this unwanted thickening is endocytosis, or the recycling of the vesicle material. Before we leave the presynaptic neuron, we need to consider one of the feedback loops the presynaptic neuron uses to monitor its own activity. Embedded within the presynaptic membrane are special protein structures known as autoreceptors. Autoreceptors bind some of the neurochemicals released by the presynaptic neuron, providing feedback to the presynaptic neuron about its own level of activity. This information influences the neuron’s rate of neurochemical synthesis and release (Parnas et al., 2000). Neurochemicals Bind to Postsynaptic Receptor Sites Moving to the postsynaptic side of chemical communication, we find protein structures embedded in the postsynaptic cell membrane known as receptors. The receptors control ion channels, directly or indirectly, and feature binding sites that interact only with certain types of neurochemicals. Binding sites extend into the extracellular autoreceptor Receptor site located on the presynaptic neuron that provides information about the cell’s own activity levels. receptor A special protein structure embedded in a neural membrane that responds to chemical messengers.

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fluid of the synaptic gap, where they come into contact with neurochemical molecules. These function as keys that fit into the locks made by the binding sites. Two major types of receptors are presented in Figure 3.24. Once the neurochemicals interact with binding sites, ion channels will open either directly (fast) or ionotropic receptor A receptor protein in the postsynaptic membrane in which the binding site is located on the same structure as the ion channel; also known as a ligand-gated receptor. metabotropic receptor A protein structure embedded in the postsynaptic membrane containing a binding site and a G protein. Neurochemicals binding to these receptors do not directly open ion channels. G protein A protein found on the intracellular side of a metabotropic receptor that separates in response to the binding of a neurochemical and travels to adjacent areas of the cell to affect ion channels or second messengers.

indirectly (slowly). In the direct, or fast, case, known as a ligand-gated or ionotropic receptor, the binding site is located on an ion channel. As soon as the receptor binds molecules of neurochemical (the ligands), the ion channel changes its configuration and opens to allow ions through the membrane. These one-step receptors are capable of very fast reactions to neurochemicals. In other cases, however, the binding site does not have direct control over an ion channel (Birnbaumer et al., 1990). These receptors, known as metabotropic receptors, have a binding site that extends into the extracellular fluid and a special protein called a G protein located on the receptor’s intracellular side. When molecules of neurochemical interact with the binding site, the G protein separates from the receptor complex and moves to a different part of the interior of the postsynaptic cell. G proteins can open ion channels in the nearby membrane or activate additional

Figure 3.24 Ionotropic and Metabotropic Receptors Ionotropic receptors, shown in (a), feature a binding site for molecules of neurochemical located on an ion channel. These one-step receptors provide a fast response to the presence of neurochemicals. Metabotropic receptors, shown in (b), require additional steps. Neurochemical molecules are bound by the receptor, which in turn releases internal messengers known as G proteins. G proteins initiate a wide variety of functions within the cell, including opening adjacent ion channels and changing gene expression. Ions Neurochemical

Extracellular fluid

Ion channel

Intracellular fluid 1 Neurochemical molecules bind to an ion channel.

Ions 2 Channel opens and ions pass through.

(a) Ionotropic Receptor Neurochemical

Ions

Ion Receptor G Protein channel 1 A neurochemical binds to a receptor.

G Protein 2 The receptor releases a G protein, which binds to an ion channel.

Ions 3 The G protein causes the ion channel to open, and ions pass through.

(b) Metabotropic Receptor

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The Synapse

chemical messengers within the postsynaptic cell known as second messengers. (The extracellular neurochemicals bound by the metabotropic receptors are the first messengers.) Because of the multiple steps involved, the metabotropic receptors respond more slowly, in hundreds of msec to seconds, than the ionotropic receptors, which respond in msec. In addition, the effects of metabotropic activation can last much longer than those produced by the activation of ionotropic receptors. What is the advantage to an organism of evolving a slower, more complicated receptor system? The answer is that the metabotropic receptor provides the possibility of a much greater variety of responses to the binding of neurochemicals. The activation of metabotropic receptors can result not only in the opening of ion channels but also in a number of additional functions. Different types of metabotropic receptors influence the amount of neurochemicals released, help maintain the resting potential, and initiate changes in gene expression. Unlike the ionotropic receptor, which briefly affects a small, local part of a cell,

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a metabotropic receptor can have wide-ranging, longerlasting, and multiple influences within a cell due to its ability to activate a variety of second messengers. Termination of the Chemical Signal Before we can make a second phone call, we need to end the first call. If we want to send a second message across a synapse, it’s necessary to have some way of ending the first message. Neurochemicals bind very briefly to receptors, after which they are released back into the synaptic gap. In the gap, neurochemicals are deactivated in three different ways, demonstrated in Figure 3.25. The particular method used depends on the type of neurochemical involved (refer to Chapter 4). The first method is simple diffusion away from the synapse. Like any other molecule, neurochemicals diffuse away from areas of high concentration to areas of low second messenger A chemical within the postsynaptic neuron that is indirectly activated by synaptic activity and interacts with intracellular enzymes or receptors.

Figure 3.25 Methods for Deactivating Neurochemicals Neurochemicals released into the synaptic gap must be deactivated before additional signals are sent by the presynaptic neuron. Deactivation may occur through (a) diffusion away from the synapse, (b) the action of special enzymes, or (c) reuptake. Deactivating enzymes break the neurochemical molecules into their components. The presynaptic neuron collects these components and then synthesizes and packages more neurochemical molecules. In reuptake, presynaptic transporters “recapture” released neurochemicals and repackage them in vesicles. Synaptic vesicle Neurochemicals

Enzyme

Post-synaptic receptors (a) Diffusion

(b) Deactivating Enzymes

Transporters

(c) Reuptake

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Connecting to Research Are Synapse Size and Strength Related? Neuroscientists evaluating neural circuits have traditionally used the number of synapses to estimate the strength of connectivity within the circuit. Electron microscopy (refer to Chapter 1) had allowed neuroscientists to view each synapse in fine detail. However, the relationship between the physical size of a synapse and the functional strength of its signaling had not been identified previously until the publication of a study by Holler et al. (2021). The Question: How does the physical size of a

synapse relate to its signaling strength?

Methods The researchers used a combination of electrical recordings, light microscope examination, and electron

concentration. Recall, however, that the astrocytes surrounding the synapse influence the diffusion of neurochemicals away from the synapse, so there are limits to this process. In the second method for ending chemical transmission, neurochemical molecules are deactivated by enzymes in the synaptic gap. In the third process, reuptake, the presynaptic membrane uses its own set of receptors known as transporters to recapture molecules of neurochemical and return them to the interior of the axon terminal. In the terminal, the neurochemicals can be repackaged in vesicles for subsequent release. Unlike the cases in which enzymes deactivate neurochemicals, reuptake spares the cell the extra step of reconstructing the molecules out of component parts. Postsynaptic Potentials When molecules of neurochemical bind to postsynaptic receptors, they can produce one of two outcomes One outcome, excitation, increases the likelihood that the postsynaptic cell will generate an action potential. The other outcome, inhibition, decreases reuptake A process for ending the action of neurochemicals in the synaptic gap in which the presynaptic neuron recaptures the molecules of neurochemical. transporter A receptor in the presynaptic membrane that recaptures released molecules of neurochemical in the process of reuptake. excitatory postsynaptic potential (EPSP) A small depolarization produced in the postsynaptic cell as a result of input from the presynaptic cell. graded potentials An electrical signal that can vary in size and shape. inhibitory postsynaptic potential (IPSP) A small hyperpolarization produced in the postsynaptic cell as a result of input from the presynaptic cell.

microscope examination to evaluate all synapses on a set of pyramidal neurons in the cortex of a mouse.

Results The researchers found a positive linear correlation between the size of a synapse and its signaling strength. In other words, larger volume of a dendritic spine head and postsynaptic structures predicted the measurement of larger excitatory postsynaptic potentials (EPSPs).

Conclusions Being able to quantify the strength of a synapse by examining its size adds an important dimension to neural circuit models. Previous models were forced to use a binary connected-or-not-connected judgment at each synapse. The current results allow the analysis of a circuit to be more nuanced and realistic.

the likelihood that the postsynaptic cell will fire. As we will discuss in Chapter 4, some neurochemicals reliably produce one outcome or the other, while other neurochemicals are excitatory or inhibitory depending on the type of receptor with which they interact. Excitation results from the depolarization of the postsynaptic membrane, known as an excitatory postsynaptic potential, or EPSP. EPSPs result from the opening of chemically-gated (ionotropic or metabotropic) rather than voltage-dependent sodium channels in the postsynaptic membrane. The inward movement of positive sodium ions produces the slight depolarization of the EPSP. In addition to opening a different type of channel, EPSPs differ from action potentials in other ways. We have described action potentials as being all-or-none. In contrast, EPSPs are known as graded potentials, referring to their varying size and shape. Action potentials last about 1 msec, but EPSPs can last up to 5 to 10 msec. The second possible outcome of the binding of neurochemicals to a postsynaptic receptor is the production of an inhibitory postsynaptic potential, or IPSP. The IPSP reduces the likelihood that the postsynaptic cell will produce an action potential. Like the EPSP, the IPSP is a graded potential that can last 5 to 10 msec. IPSPs are produced by the opening of chemically-gated channels that allow for the inward movement of chloride (Cl2) or the outward movement of potassium (K1). The movement of negatively charged chloride ions into the postsynaptic cell would add to the cell’s negative charge. The loss of positively charged potassium cells would also increase a cell’s negative charge. Thus, IPSPs usually produce a hyperpolarizing current. To be completely accurate, however, we must note that IPSPs can also have depolarizing effects in

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The Synapse

some less typical situations. The effects of these depolarizing IPSPs remain inhibitory. A complete explanation of these odd circumstances is beyond the scope of this textbook, but we can say that the outcomes depend on the relationship between a neurochemical’s effects and the particular cell’s threshold for producing an action potential.

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Neural Integration Neurons in the human brain can receive input from thousands of other neurons. Some of that input will be in the form of EPSPs and some in the form of IPSPs. The task faced by the neuron receiving this input is to determine whether to produce an action potential. You may have had the experience of asking friends

Behavioral Neuroscience Goes to Work How Does an EEG Work? If your career path is leading you toward neurology, neuropsychology, or research psychology, you might find yourself working with electroencephalography (EEG). As we discussed in Chapter 1, EEG provides a snapshot of current levels of brain activity useful in the assessments of seizure disorders and states of consciousness. But what exactly are we measuring? While it is likely that your main focus will be whether an individual recording is normal, understanding the underlying logic of the technology will help prepare you for the inevitable improvements that will occur during your career. This chapter provides further insight into the workings of EEG. A single EEG scalp electrode is assessing the

activity of thousands of nearby cortical neurons as they fire together (refer to Figure 3.26). Most of the neurons contributing to the signal are large pyramidal output cells in layers three and five of the cortex (refer to Chapter 2). The EEG is NOT recording current associated with action potentials. Action potentials do not last long enough (about 1 msec) to influence the recording. Instead, the recording sums the excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) generated by cortical neurons. Recall that EPSPs and IPSPs can last at least five to ten times longer than action potentials. These postsynaptic potentials generate extracellular currents, or field potentials, which can be detected by the scalp electrodes.

Figure 3.26 EEG Records Cortical Field Potentials The primary source of information recorded by an EEG electrode is the extracellular currents known as field potentials generated by large pyramidal output cells in layers three and five of the cerebral cortex. Source: Karla Freberg

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Table 3.3 | A Comparison of the Characteristics of Action Potentials, EPSPs, and IPSPs Action Potential

EPSPs

IPSPs

Location

Presynaptic cell

Postsynaptic cell

Postsynaptic cell

Duration

1 to 2 msec

5 to 10 msec up to 100 msec

5 to 10 msec up to 100 msec

Size

About 100mV

Up to 20mV

Up to 15mV

Character

All-or-none

Graded depolarization

Graded hyperpolarization or depolarization

Channels involved

Voltage-dependent sodium and potassium channels

Chemically-gated sodium channels

Chemically-gated potassium or chloride channels

and family members for help with a decision. Some of your advisors give you an excitatory “go for it” message, and others give you an inhibitory “don’t even think about neural integration The determination of whether to fire an action potential based on the summation of inputs to a neuron.

it” message. After reviewing the input, it is your task, like the neuron’s, to consider all of the advice you’ve received and decide whether to go forward (although you have the luxury of disagreeing with your input, and the neuron does not). This decision-making process on the part of the neuron is known as neural integration, presented in Figure 3.27.

Figure 3.27 Neural Integration Combines Excitatory and Inhibitory Input These graphs demonstrate the effects of excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) alone and together on the overall response by the postsynaptic neuron. In (a), the EPSP alone depolarizes the postsynaptic cell to threshold and initiates an action potential. In (b), the IPSP alone hyperpolarizes the postsynaptic neuron. In (c), the EPSP and IPSP essentially cancel each other out, and no action potential occurs.

Excitatory input Axon + ++ ++

Excitatory input

Inhibitory input

–– – ––

++

Inhibitory input –– – –– + + +++

––

–+ – +

Dendrite Axon hillock

Action potential

40

40

0

0

mV

mV

0

Neuron’s response: Action potential generated

40

mV

Cell body

–65 –70 –75

EPSP

(a) Effects of EPSP Alone

Neuron’s response: No action potential –65 –70 –75

–65 –70 –75 (b) Effects of IPSP Alone

(c) Effects of EPSP and IPSP

Source: Data from Kandel and Siegelbaum (1995).

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The Synapse

In vertebrates, cells receive their excitatory and inhibitory advice in different locations. Excitatory input is more common at the dendritic spines and the dendritic shafts farther from the cell body. Inhibitory input is more common at the cell body and the dendritic shafts closer to the cell body (Villa & Nedivi, 2016). Because the dendrites and cell body contain few voltage-dependent channels, they do not typically produce action potentials. Instead, the EPSPs and IPSPs spread passively but very rapidly until they reach the axon hillock. The only time the cell will produce an action potential is when the axon’s initial segment is depolarized to threshold. This may occur as a result of spatial summation, in which inputs from all over the cell converge at the initial segment (refer to Figure 3.28). The cell adds up all the excitatory inputs and subtracts all the inhibitory inputs. If the end result is 5 to 10mV in favor of depolarization, the cell will fire. Spatial summation is analogous to adding up all of your friends’ votes and following the will of the majority. Because EPSPs and IPSPs last longer than action potentials, they can build on one another at a very active synapse, leading to temporal summation. Although it typically takes substantial excitatory input to produce an action potential in the postsynaptic cell, temporal summation provides a means for a single, very active synapse to trigger the postsynaptic cell. One particularly persistent (and noisy) friend can definitely influence our decisions.

Axo-Axonic Synapses The synapses we have discussed so far involve an axon terminal or axonal varicosity as the presynaptic element

and either a dendrite or a cell body as the postsynaptic element. In addition, we can observe synapses between an axon terminal and another axon fiber, as presented in Figure 3.29. These axo-axonic synapses have a modulating effect on the release of neurochemical by the target axon. If the presynaptic neuron increases the amount of neurochemical released, presynaptic facilitation has occurred. If the presynaptic neuron decreases the amount of neurochemical released by the target axon, we say that presynaptic inhibition has occurred. This type of modulation occurs quite frequently in sensory systems and during some types of learning (refer to Chapter 12).

spatial summation Neural integration in which the combined inputs from many synapses converge on the initial segment, where an action potential will result if threshold is reached. temporal summation Neural integration in which excitation from one active synapse is sufficient to initiate the formation of an action potential. axo-axonic synapse A synapse in which both the presynaptic and postsynaptic elements are axons. presynaptic facilitation At a synapse between two axons, the increase of neurochemical release by the postsynaptic axon as a result of input from the presynaptic axon. presynaptic inhibition At a synapse between two axons, the decrease of neurochemical release by the postsynaptic axon as a result of input from the presynaptic axon.

Figure 3.28 Spatial and Temporal Summation In spatial summation, input from all over the cell converges at the axon hillock, possibly initiating an action potential. In temporal summation, repeated stimulation of one synapse can produce an action potential. Simultaneous stimulation from many presynaptic terminals

Repeated stimulation by one presynaptic terminal

Action potential in initial segment of postsynaptic neuron

Spatial summation

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Action potential in initial segment of postsynaptic neuron

Temporal summation

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Figure 3.29 Synapses Between Two Axons Modulate the Amount of Neurochemical Released In presynaptic facilitation (a), input from neuron C will increase the amount of neurochemical released by neuron A onto neuron B. In presynaptic inhibition (b), input from neuron D will decrease the amount of neurochemical released by neuron A onto neuron B. Axon of Neuron C

Dendrite of Neuron B

Neuron D

Neuron B

Axon of Neuron A

Neuron A (b) Presynaptic Inhibition

(a) Presynaptic Facilitation

Interim Summary 3.3 Summary Points 3.3 1. Chemical synapses involve the release of neurochemicals by the presynaptic cell. Gap junctions are characterized by very tiny synaptic gaps crossed by ion channels from the presynaptic and postsynaptic neurons. (LO5) 2. Receptor proteins on the postsynaptic cell can be either ionotropic or metabotropic. (LO5) 3. The action of neurochemicals in the synaptic gap may be terminated through diffusion away from the gap, by deactivation by enzymes, or by reuptake by the presynaptic neuron. (LO5) 4. Postsynaptic potentials are small, local, graded potentials that can last 5–10 msec or more. Excitatory postsynaptic potentials (EPSPs) produce slight depolarizations by opening channels that allow

sodium to enter the cell. Inhibitory postsynaptic potentials (IPSPs) produce slight hyperpolarizations by opening channels that allow either chloride to enter or potassium to exit the cell. (LO6) 5. In spatial summation, the input from many synapses is added together to determine whether an action potential will be produced. In temporal summation, a single, very active synapse may provide sufficient input to produce an action potential. (LO6) 6. The release of neurochemicals at a synapse can be facilitated or inhibited by the activity at axo-axonic synapses. (LO7) Review Questions 3.3 1. Why would presynaptic neurons benefit from having autoreceptors? 2. What are the advantages of presynaptic inhibition and facilitation?

Summary Table 3.3: Communication at the Synapse Event

Location

Exocytosis

Postsynaptic receptors bind neurochemical molecules

Axon terminal or axonal varicosity

Postsynaptic membrane

Mechanisms of Action ●

Ca21 enters the cell.

●

Vesicles fuse with the axon terminal membrane.

●

Neurochemicals are released.

●

Vesicles are returned to the terminal interior and refilled.

●

Receptors bind available neurochemical molecules in the gap.

●

Ion channels are directly opened in ionotropic receptors.

●

G proteins are released by metabotropic receptors, opening nearby ion channels. (continued)

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Chapter Review

Event

Location

Neurochemical deactivation

Synaptic gap

Mechanisms of Action ●

●

Postsynaptic potentials

Postsynaptic membrane

Integration or summation

Initial segment of postsynaptic cell

●

●

●

Chapter Review Tho u g h t Q u e st ion s 1. Which feature of neurons described in this chapter do you think had the biggest impact on the development of more intelligent animals? 2. If two equally active synapses are located on a distant dendrite and on the cell body, which will have the greatest effect on the initial segment and why? What is the likelihood that this cell will produce an action potential? 3. In multiple sclerosis, axons that were meant to be myelinated lose their myelin. In what ways would signaling in these axons be even less effective than in axons designed to be unmyelinated?

Key Ter ms absolute refractory period (p. 85) action potential (p. 75) astrocyte (p. 66) autoreceptor (p. 93) axon (p. 70) axon hillock (p. 75) axon terminal (p. 76) axonal varicosity (p. 76) bipolar neuron (p. 77) blood–brain barrier (p. 66) cell body/soma (p. 70) chemically-gated channel (p. 72) cytoskeleton (p. 72) dendrite (p. 70) dendritic spine (p. 75) depolarization (p. 84) diffusion (p. 80) electrostatic pressure (p. 80) ependymal cells (p. 66)

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Neurochemicals may diffuse away from the synapse, be deactivated by enzymes, or be transported back across the presynaptic membrane. EPSPs result from the opening of chemically-gated Na1 channels. IPSPs result from the opening of chemically-gated K1 or Cl2 channels. Drifting positive and negative currents converge at the initial segment. If sufficient depolarization occurs at the initial segment the postsynaptic cell will generate an action potential.

excitation (p. 90) excitatory postsynaptic potential (EPSP) (p. 96) exocytosis (p. 92) extracellular fluid (p. 70) G protein (p. 94) gap junction (p. 89) glia (p. 66) hyperpolarization (p. 84) inhibition (p. 90) inhibitory postsynaptic potential (IPSP) (p. 96) initial segment (p. 75) intermediate filament (p. 73) interneuron (p. 79) intracellular fluid (p. 70) ion (p. 72) ion channel (p. 72) ion pump (p. 72) ionotropic receptor (p. 94) macroglia (p. 66) metabotropic receptor (p. 94) microfilament (p. 73) microglia (p. 66) microtubule (p. 72) motor neuron (p. 79) multipolar neuron (p. 77) myelin (p. 75) neural integration (p. 98) neurochemical (p. 75) neuron (p. 66) node of Ranvier (p. 77) oligodendrocyte (p. 66) presynaptic facilitation (p. 99) presynaptic inhibition (p. 99) relative refractory period (p. 85) resting potential (p. 80) reuptake (p. 96) saltatory conduction (p. 88) Schwann cell (p. 66) sensory neuron (p. 77)

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sodium-potassium pump (p. 72) spatial summation (p. 99) synapse (p. 66) synaptic gap (p. 75) synaptic vesicle (p. 76) temporal summation (p. 99)

threshold (p. 84) transporter (p. 96) unipolar neuron (p. 77) voltage-dependent channel (p. 72) volume transmission (p. 92) wiring transmission (p. 91)

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Chapter 4 Learning Objectives L01

Differentiate among neurotransmitters, neuromodulators, and neurohormones.

L02

Identify the major locations, functions, synthesis pathways, receptor characteristics, and processes of deactivation for acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, histamine, glutamate, GABA, glycine, and adenosine triphosphate.

L03

Distinguish among small molecules, neuropeptides, and gasotransmitters.

L04

Differentiate between agonists and antagonists.

L05

Propose examples of drugs that produce effects by influencing neurochemical production, neurochemical storage, neurochemical release, receptor activity, reuptake, and enzymatic degradation.

L06

Review the major principles of drug effects, including the mode of administration, sources of individual differences in reactions to drugs, placebo effects, tolerance, withdrawal, and addiction.

L07

Identify the major features and modes of action of stimulants, opioids, marijuana, hallucinogens, and alcohol.

Psychopharmacology

Chapter Outline Neurotransmitters, Neuromodulators, and Neurohormones Types of Neurochemicals

The Small Molecules Neuropeptides Gasotransmitters

Interim Summary 4.1 Mechanisms of Neuropharmacology

Agonists and Antagonists Drugs Influence the Production of Neurochemicals Drug Effects on Neurochemical Storage Drugs Affect Neurochemical Release Drugs Interact With Receptors Drugs Affect Reuptake and Enzymatic Degradation

Interim Summary 4.2 Basic Principles of Drug Effects

Administration of Drugs Individual Differences in Responses to Drugs Placebo Effects Tolerance and Withdrawal Addiction

Effects of Selected Psychoactive Drugs

Stimulants Opioids Cannabis Hallucinogens Alcohol

Interim Summary 4.3 Chapter Review

Connecting to Research: Otto Loewi and “Vagus Stuff” Behavioral Neuroscience Goes to Work: Addiction Counselors Neuroscience in Everyday Life: Should Psychedelics Be Used in Therapy? Thinking Ethically: Drug Use Affects Future Generations 103

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Chapter 4

Psychopharmacology

Neurotransmitters, Neuromodulators, and Neurohormones Neurochemicals can act as neurotransmitters, neuromodulators, or neurohormones. Many of the same chemicals take on these different roles depending on the mode of their release and the type of receptors with which they interact. Scientists still disagree about the boundaries of these definitions, with some still preferring to use the term neurotransmitter in all cases. As we mentioned in Chapter 3, chemical synapses use wiring or volume transmission. As presented in Figure 4.1, neurotransmitters engage in wiring transmission by acting on single or small numbers of other neurons in their own immediate vicinity, generally at a synapse. Neurotransmitters are typically released from an axon terminal and cross a synaptic gap. On the postsynaptic membrane, ion channels open when molecules of neurotransmitter interact with either very fast ionotropic or somewhat slower metabotropic receptors. At ionotropic receptors, the neurotransmitter performs rapid communication on a scale of milliseconds. At metabotropic receptors, neurotransmitter effects might last as long as several hours. Neuromodulators engage in volume transmission and differ from classical neurotransmitters in several ways. Rather than influencing one or two postsynaptic neurons, neuromodulators influence whole populations of other neurons. Instead of merely crossing a synaptic gap, neuromodulators diffuse away from the site of release to influence diverse groups of neurons located at some distance from the releasing cell. Neuromodulators can remain in the cerebrospinal fluid for extended periods of time, during which they can continue to influence the activity of the central nervous system (CNS). As a result, neuromodulators influence more global functions, including attention and assessments of threat, saliency, novelty, and reward (Sabatini & Tian, 2020). While neurotransmitters interact with both ionotropic and metabotropic receptors, neuromodulators are restricted to interactions with metabotropic receptors. They produce slower and longer-lasting changes in a postsynaptic neuron’s metabolic processing for

neurotransmitter A chemical messenger that communicates across a synapse. neuromodulator A chemical messenger that communicates with target cells more distant than the synapse by diffusing away from the point of release. neurohormone A chemical messenger that communicates with target cells at a great distance by traveling through the circulation.

Figure 4.1 Neurotransmitters, Neuromodulators, and Neurohormones Neurotransmitters typically influence cells across a synaptic gap, as presented here, while neuromodulators diffuse away after being released to affect cells at a distance. Neurohormones are often released into the bloodstream to travel to their ultimate destinations.

iStock.com/nobeastsofierce

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periods of up to several weeks. While classic neurotransmitters travel one way from presynaptic to postsynaptic cells, neuromodulators can interact with both pre- and postsynaptic cells. In response to neuromodulators, presynaptic cells might alter their rate of synthesizing, releasing, reuptake, or enzyme-initiated breakdown of neurochemicals. Affected postsynaptic cells might change enzyme activity or protein synthesis, allowing them to install more receptors to adjust sensitivity to neurochemicals. Neuromodulators are released within systems that have several features in common. In each system, relatively small groups of subcortical neurons capable of releasing a single neurochemical communicate with widespread regions of the brain. Neuromodulator systems form complex reciprocal connections with the prefrontal cortex and parts of the limbic system. The major neuromodulator systems to be discussed further in this chapter involve dopamine, norepinephrine, serotonin, histamine, acetylcholine, endogenous cannabinoids, and several neuropeptides. Neurohormones are secreted by special neurons into the blood supply. Regardless of the distance traveled, these chemical messengers will interact only with other cells that have specialized receptor sites to receive them. Many cells that produce neurohormones are located in the hypothalamus, the adrenal glands, and the enteric nervous system (refer to Chapter 2).

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Types of Neurochemicals

Types of Neurochemicals As displayed in Figure 4.2, neurochemicals can be classified as small molecules, neuropeptides, or gasotransmitters. The small molecules can be further divided into amino acids and amines, which are derived from amino acids. Neuropeptides are chains of amino acids. Gases known as gasotransmitters have been shown to influence adjacent neurons in ways similar to more classical chemical messengers (Sen & Snyder, 2010). Small molecules and neuropeptides differ in several important ways. Small molecules are typically synthesized in the axon terminal, while neuropeptides are synthesized in the cell body and must be transported the length of the axon. Vesicles containing neuropeptides are used only once, in contrast to the recycling of vesicles possible with small molecules. Compared to the release of small molecules, the release of neuropeptide vesicles requires higher levels of calcium, which, in turn, requires a higher rate of action potentials reaching the axon terminal (Fulop &

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Smith, 2006). Finally, neuropeptides diffuse away from the synapse or are broken down by enzymes, but unlike the small molecules, they are not deactivated by reuptake (review Chapter 3). The major features of small molecules and neuropeptides are summarized in Table 4.1. Early pharmacological pioneer Henry Dale referred to different neurons according to the neurochemicals they release, such as a dopaminergic neuron that releases dopamine. This practice was misinterpreted by some to mean that a single neuron released one and only one type of chemical messenger. Instead, many neurons release a small molecule along with a neuropeptide or a gasotransmitter. small molecule One of a group of neurochemicals that includes amino acids and amines. neuropeptide A peptide that acts as a neurotransmitter, a neuromodulator, or a neurohormone. amino acid An essential component of proteins. gasotransmitter A gas such as nitric oxide (NO) that performs a signaling function.

Figure 4.2 Categories of Neurochemicals Acetylcholine (ACh) Catecholamines • Dopamine • Norepinephrine • Epinephrine

Monoamines Small molecules

Indoleamines • Serotonin • Melatonin

Amino acids

Neurochemicals

Histamine

• Glutamate • GABA • Glycine • 5 others ATP and its by-products

Neuropeptides

Gasotransmitters

• Endorphins • Substance P • Cholecystokinin • Insulin • Vasopressin • Oxytocin • More than 40 others • Nitric oxide • Carbon monoxide • Hydrogen sulfide

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Connecting to Research Otto Loewi and “Vagus Stuff” Early physiologists realized that if electrical signaling was the only mode of communication in the nervous system, messages would be sent and received much faster than their observations were indicating. There must be another step involved, but what form did that step take? German physiologist Otto Loewi (1873–1961) suspected, like many others, that some form of chemical communication was involved. In 1921, he succeeded in demonstrating he was correct. The Question: In addition to electricity, what else is involved with neural signaling?

Methods To test his hypothesis, Loewi dissected hearts from two frogs and placed them in separate containers. Inserting a small cannula of saline solution maintained normal heart activity for several hours. Loewi electrically stimulated the vagus nerve attached to one of the hearts and then removed some of the liquid from the cannula inserted in this heart and applied it to the second heart.

Results

The second, revolutionary observation occurred when he also saw the second heart slow as well.

Conclusions Loewi concluded correctly that a substance released by the vagus nerve was responsible for slowing the heart. He referred to the substance as “Vagusstoff” or “vagus stuff,” but we know this substance today by the name of acetylcholine. Loewi’s discovery earned him the Nobel Prize in 1932, but he is almost more famous for his recollections of how his experiment came to mind (Loewi, 1953). After struggling with his research question, Loewi came up with the perfect design while asleep, but not necessarily while “dreaming” as is often reported (refer to Chapter 11). He wrote notes on paper on his nightstand and, much to his dismay, could not read the notes the next morning. While asleep the next night, Loewi once again thought of his design. This time, instead of writing it down, he went to his laboratory at 3 o’clock in the morning and immediately performed his experiment.

Electrical stimulation of the vagus nerve was already known to slow the heart, and this is what Loewi observed.

Further, studies of motor neurons show that the same neuron can release two small molecules in different locations. Motor neurons release acetylcholine onto muscle fibers and other neurons in the spinal cord but release glutamate in the spinal cord and not onto muscle fibers (Nishimaru et al., 2005).

The Small Molecules A number of small molecules play vital roles in neural signaling: acetylcholine, six monoamines, several amino acetylcholine (ACh) A major small-molecule neurochemical used at the neuromuscular junction, in the autonomic nervous system, and in the central nervous system (CNS).

acids, and the energy molecule adenosine triphosphate (ATP) and its by-products. Acetylcholine Acetylcholine (ACh) was the first chemical messenger to be discovered. Neurons that use ACh as their major neurochemical are referred to as cholinergic neurons. The cholinergic neuron obtains the building block choline from dietary fats and from the breakdown of existing ACh. A second building block, acetyl coenzyme A (acetyl CoA), results from the metabolic activities of mitochondria, so it is abundantly present in most cells. The enzyme choline acetyltransferase (ChAT) acts on these two building blocks, or precursors, to produce ACh. The presence of the enzyme ChAT provides a useful marker for identifying cholinergic neurons

Table 4.1 | Features of Small Molecules and Neuropeptides Small molecules

Neuropeptides

Synthesis

In axon terminal

In cell body; requires transport

Recycling of Vesicles

Yes

No

Activation

Moderate action potential frequency

High action potential frequency

Deactivation

Reuptake or enzymatic degradation

Diffusion away from the synapse or enzymatic degradation

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acetylcholinesterase (AChE) An enzyme that breaks down acetylcholine (ACh). nicotinic receptor A postsynaptic receptor that responds to nicotine and acetylcholine (ACh). muscarinic receptor A postsynaptic receptor that responds to both acetylcholine (ACh) and muscarine.

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because ChAT is found only in neurons that Figure 4.3 The Distribution of Cholinergic produce ACh. Cholinergic neurons also manufacture the Systems in the Brain enzyme acetylcholinesterase (AChE). AChE is In addition to playing important roles at the neuromuscular junction and released into the synaptic gap, where it breaks in the autonomic nervous system, cholinergic neurons are widely disdown any ACh in that location. The choline tributed in the brain. Important systems originate in the basal forebrain resulting from the breakdown of ACh can then and brainstem and form projections to the limbic system and cerebral be recaptured by the presynaptic neuron and cortex. These systems participate in learning and memory and deterioresynthesized into more ACh. rate in patients diagnosed with Alzheimer disease. ACh is the primary neurotransmitter at the Cerebral cortex Thalamus neuromuscular junction, the synapse between a neuron and a muscle fiber (refer to Chapter 8). ACh is also essential to the operation of the autonomic nervous system. All preganglionic synapses in the autonomic nervous system are cholinergic. Postganglionic synapses in the parasympathetic division of the autonomic nervous system are also cholinergic (review Chapter 2). In addition to their role in the peripheral nervous system (PNS), cholinergic neurons form an important neuromodulation system in the brain. As presented in Figure 4.3, major groups of choBasal forebrain linergic neurons located in the basal forebrain, septal area, and brainstem influence the cerebral Hippocampus Amygdala cortex, hippocampus, and amygdala. As we will discuss in Chapter 15, cholinergic neurons in the Cholinergic nuclei basal forebrain deteriorate as a result of Alzheiof the pons and mer disease (Ferreira-Vieira et al., 2016). Not too midbrain surprisingly, given the memory loss associated Projections of cholinergic neurons with Alzheimer disease, these cholinergic systems appear to participate in attention, wakefulness, learning, and memory. Two major subtypes of cholinergic receptors, nicotinic Figure 4.4 Amanita muscaria receptors and muscarinic receptors, are found in the nervous system (Dani, 2001). These receptors take their names Muscarinic cholinergic receptors get their name in recogfrom the substances other than ACh to which they also nition of their response to both acetylcholine (ACh) and muscarine, derived from the deadly Amanita muscaria react. In other words, a nicotinic receptor responds to both mushroom. ACh and to nicotine, found in all tobacco products, and the muscarinic receptor responds to both ACh and muscarine, a substance derived from the hallucinogenic (and highly poisonous) mushroom Amanita muscaria, presented in Figure 4.4. Nicotinic and muscarinic receptors differ in their mechanisms of action and locations within the nervous system. As we observed in Chapter 3, receptors are either single-step ionotropic or multiple-step metabotropic in structure. Nicotinic receptors are fast ionotropic receptors.

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In contrast, muscarinic receptors are slower metabotropic receptors. Nicotinic receptors are found at the neuromuscular junction, which is logical given the need for speed in muscular responses. Muscarinic receptors are found in the heart muscle and other smooth muscles (refer to Chapter 8). The CNS contains both nicotinic and muscarinic receptors, but the muscarinic are more common (Ehlert et al., 1995). Both types of receptors are found in the autonomic nervous system. Monoamines The six monoamines are further divided into subgroups, the catecholamines (dopamine, norepinephrine, and epinephrine), the indoleamines (serotonin and melatonin), and histamine. All of the monoamines are subject to reuptake from the synaptic gap following release. Within the axon terminal, monoamines that are not encased in vesicles are broken down by the action of the enzyme monoamine oxidase (MAO). In the extracellular fluid, catecholamines are broken down by the enzyme catechol-O-methyl-transferase (COMT). Catecholamine synthesis begins with the amino acid tyrosine, as displayed in Figure 4.5. All neurons containing a catecholamine also contain the enzyme tyrosine hydroxylase (TH). When TH acts on tyrosine, the end product is L-dopa (L-dihydroxyphenylalanine). The production of dopamine requires an additional step following the synthesis of L-dopa. The enzyme dopa decarboxylase acts on L-dopa to produce dopamine. Dopamine is converted to norepinephrine by the action of the enzyme dopamine β-hydroxylase (DBH). This last step takes place within the synaptic vesicles. Finally, the catecholamine epinephrine is produced by the reaction between norepinephrine and the enzyme phenylethanolamine N-methyl-transferase (PNMT). The synthesis of epinephrine is complicated. PNMT exists in the intracellular fluid of the axon terminal of neurons that use epinephrine. Once norepinephrine is monoamines One of a major group of biogenic amine neurochemicals, including dopamine, norepinephrine, epinephrine, and serotonin. catecholamines A member of a group of related biogenic amines that includes dopamine, epinephrine, and norepinephrine. indoleamines One of a subgroup of monoamines, including serotonin and melatonin. monoamine oxidase (MAO) An enzyme that breaks down monoamines. catechol-O-methyl-transferase (COMT) An enzyme that breaks down catecholamines in the synaptic gap. L-dopa A substance produced during the synthesis of catecholamines that is also administered as a treatment for Parkinson disease. dopamine A major monoamine and catecholamine neurochemical implicated in motor control, reward, and psychosis. norepinephrine A major monoamine and catecholamine neurochemical. epinephrine One of the monoamine/catecholamine neurochemicals; also known as adrenaline.

Figure 4.5 Catecholamines Share a Common Synthesis Pathway The catecholamines, including dopamine, norepinephrine, and epinephrine, are synthesized from the substrate tyrosine. Tyrosine is converted into L-dopa by the action of tyrosine hydroxylase. L-dopa is converted into dopamine by dopa decarboxylase. The action of dopamine b-hydroxylase on dopamine produces norepinephrine. When norepinephrine reacts with phenylethanolamine N-methyl-transferase, epinephrine is produced. Tyrosine Tyrosine hydroxylase (TH) L-dihydroxyphenylalanine (L-dopa) Dopa decarboxylase Dopamine (DA) Dopamine b-hydroxylase (DBH) Norepinephrine Phenylethanolamine N-methyl-transferase (PNMT) Epinephrine

synthesized within synaptic vesicles, it must be released back into the intracellular fluid, where it is converted by PNMT into epinephrine. The epinephrine is then transported back into vesicles. Dopamine systems are involved with movement as well as with motivated behaviors and the processing of reward. As we will discuss later in the chapter, addiction to drugs (and also to some behaviors, such as gambling) is especially influenced by activity in circuits using dopamine. In addition, disruptions in dopamine function are suspected of playing a role in schizophrenia and attention deficit hyperactivity disorder (ADHD; refer to Chapter 16). As presented in Figure 4.6, cells releasing dopamine are located primarily in the ventral midbrain and connect with other parts of the brain along several major pathways. Together, these pathways form one of the brain’s most

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dopaminergic neurons projecting from the midbrain to the cortex, might be responsible for some of the symptoms observed in this psychological Dopaminergic neurons in the midbrain project to the basal ganglia, disorder. the limbic system, and the frontal lobes of the cerebral cortex. These Two other dopaminergic pathways originate systems appear to participate in motor control, reward, and the planin the hypothalamus. The paraventricular dopaning of behavior. mine system connects the hypothalamus to the Frontal lobe Basal ganglia thalamus and to sympathetic neurons in the spinal cord, helping coordinate motivated behaviors such as appetite, sex, and thirst. A second hypothalamic dopaminergic pathway connects to the pituitary gland and controls milk production in mammals. As we saw in the case of ACh receptors, multiple receptor subtypes also exist for dopamine, labeled D1 through D5 in order of their discovery. The receptors are grouped into two categories. One class includes the D1 and D5 receptors, and the other class includes the remaining D2, D3, and D4 receptors. All of these receptors are of the slow metabotropic variety. The first class proNucleus accumbens duces excitation, and the second class produces inhibition. Both classes of receptors are found in Amygdala Hippocampus the basal ganglia, nucleus accumbens, and olfactory cortex. The first-class receptors are also found Ventral Substantia in the hippocampus and hypothalamus, while the tegmental nigra second-class receptors are found in the frontal lobes area of the cortex, the thalamus, and the brain stem. Projections of dopaminergic neurons Epinephrine and norepinephrine were formerly referred to as adrenalin and noradrenalin, respectively. We continue to refer to neurons important neuromodulating systems. To make learning the releasing epinephrine as adrenergic and those releasing names of neural pathways easier, remember that the order norepinephrine as noradrenergic. of the terms in a pathway name allows you to follow the Epinephrine is an important neurohormone but plays pathway from its origin to any intermediary stops and to its a limited role as a CNS neurochemical. Two areas in the final destination. medulla contain cells that release epinephrine and particThe first pathway, known as the mesostriatal pathipate in such basic functions as the coordination of eating way or nigrostriatal pathway, originates in the substantia and regulation of blood pressure. The “adrenalin rush” we nigra of the midbrain and proceeds in a dorsal direction associate with stress actually results from the release of epito communicate with the caudate nucleus and putamen nephrine into the blood supply from the adrenal glands of the basal ganglia. This system contains approximately located above the kidneys in the lower back. 80 percent of the brain’s dopamine and participates in Neurons that secrete norepinephrine are found in the motor planning and voluntary motor activity. Damage pons, medulla, and hypothalamus. The most significant to this system in cases of Parkinson disease is associated source of norepinephrine is the locus coeruleus of the pons, with great difficulties in initiating movement (refer to depicted in Figure 4.7, despite the fact that this structure Chapter 8). might contain as few as 4,000 cells. These cells make up A second major dopaminergic pathway, the mesolimfor their small numbers, however, by having axons with as bic pathway, arises in the ventral tegmentum of the midbrain and projects to the nucleus accumbens. As we will mesostriatal pathway or nigrostriatal pathway A dopaminergic discuss in Chapter 9, this pathway responds to many types pathway originating in the substantia nigra and projecting to the of reward. A mesocortical pathway connects the ventral basal ganglia. tegmentum of the midbrain to areas of the prefrontal cortex mesolimbic pathway A dopaminergic pathway originating in the and participates in executive functions and planning. As ventral tegmentum of the midbrain and projecting to the nucleus accumbens. we will discuss in Chapter 16, disruption of these systems mesocortical pathway A dopaminergic pathway originating in the appears to be involved in schizophrenia. Increased activventral tegmentum of the midbrain and projecting to the prefrontal ity in dopaminergic neurons projecting from the midbrain cortex. to the limbic system, coupled with a decrease in activity in

Figure 4.6 Dopaminergic Systems in the Brain

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to share the umbrella term of monoamine yet are different enough to warrant their own subheading. The synthesis of serotonin begins with the Neurons releasing norepinephrine are found in the pons, medulla, and amino acid tryptophan. Tryptophan is obtained hypothalamus. Released norepinephrine goes to nearly every major from dietary sources, including grains, meat, part of the brain and spinal cord, producing arousal and vigilance. and dairy products. As shown in Figure 4.8, two Cerebral cortex Thalamus chemical reactions are required to convert tryptophan into serotonin. The first is the action of the enzyme tryptophan hydroxylase, which converts tryptophan to 5-hydroxytryptophan (5-HTP). Second, the 5-HTP is converted to serotonin by the action of the enzyme 5-HTP decarboxylase. As we have observed in other neuromodulating systems, serotonergic neurons in the CNS carry out global functions yet are surprisingly few in number. We noted in Chapter 2 that 95 percent of the body’s serotonergic neurons are located in the enteric nervous system. In contrast, estimates suggest there might be as few Hypothalamus as 200,000 serotonergic neurons in the human brain (Baker et al., 1991). Some serotonergic Temporal Locus neurons are located in the medulla and cerelobe coeruleus bellum, but most are located in the raphe nuclei Pons Cerebellum of the brainstem, presented in Figure 4.9. The more rostral serotonergic neurons project to Medulla To spinal cord the forebrain, and the more caudal serotonergic neurons project to the spinal cord. At least Projections of noradrenergic neurons 15 subtypes of serotonergic receptors have been identified, and all but one of these function as metabotropic receptors (Leonard, 1992). Several serve as autoreceptors. many as 100,000 collaterals each. Projections from the locus Serotonergic activity has been implicated in a variety of coeruleus go to the spinal cord and nearly every major part behaviors, including appetite, sleep, mood, dominance, and of the brain, forming another important neuromodulating aggression. Serotonin pathways influence our motivation system. The primary result of activity in these circuits is increased arousal and vigilance. In the PNS, norepinephrine is found at the postganglionic synapses of the sympathetic nervous system, which is also involved in arousal. Figure 4.8 The Synthesis of Serotonin Receptor types that respond to either norepinephrine Serotonin synthesis begins with dietary tryptophan, which or epinephrine are referred to as adrenergic α (alpha) or is converted into 5-HTP by the action of tryptophan β (beta) receptors. These receptors are found in both the hydroxylase. 5-HTP is converted into serotonin by the CNS and target organs that respond to sympathetic nervous action of 5-HTP decarboxylase. system activity and neurohormones. All adrenergic receptors are metabotropic, which might surprise you given the Tryptophan need for speedy responses associated with the fight-or-flight functions of the sympathetic nervous system. Indoleamines, including serotonin and melatonin, are Tryptophan similar enough in chemical structure to the catecholamines hydroxylase

Figure 4.7 Noradrenergic Systems in the Brain

serotonin A major monoamine and indoleamine neurochemical believed to participate in the regulation of mood, sleep, aggression, social status, and appetite. melatonin An monomine synthesized from serotonin that participates in the maintenance of sleep and waking cycles. histamine An monoamine that plays important roles in the immune system and also serves as a neuromodulator involved in wakefulness.

5-Hydroxytryptophan (5-HTP) 5-HTP decarboxylase Serotonin

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Types of Neurochemicals

Figure 4.9 Serotonergic Pathways in the Brain Most serotonergic neurons are found in the raphe nuclei of the brainstem. Serotonin released by these neurons affects the spinal cord, cerebellum, limbic system, and cerebral cortex. These systems participate in the control of mood, sleep, social status, aggression, and appetite. Cerebral cortex

Thalamus

Amygdala Hippocampus Raphe nuclei

Cerebellum

111

and blood cells, but it also serves as a neuromodulator in the brain. All histamine released in the adult brain is produced in the tuberomammillary nucleus (TMN) of the hypothalamus. Like other neuromodulator systems, these TMN neurons project to nearly every other part of the brain. At least three and possibly four types of histamine receptors are found in both the CNS and PNS, and all are metabotropic (refer to Figure 4.10). As we will observe in Chapter 11, histamine activity is positively correlated with wakefulness (Kim et al., 2015), so antihistamines are the basis of most over-the-counter treatments for insomnia. Antihistamines are also used to reduce unpleasant symptoms of allergies. Newer versions that do not cross the blood–brain barrier manage to reduce peripheral allergy symptoms such as a runny nose without producing drowsiness. Although usually associated with arousal, histamine has other functions in the brain. The basal ganglia, and the striatum in particular, are rich in histamine receptors (Bolam & Ellender, 2016). Conditions involving the basal ganglia, including Parkinson disease and Tourette syndrome, might involve dysfunctions in the histamine system.

To spinal cord

Amino Acids Although as many as eight amino acids participate as neurochemicals, three Serotonergic pathways are especially significant: glutamate, gammaaminobutyric acid (GABA), and glycine. The idea that the amino acid aspartate also acts as a neuroto consume carbohydrates, leading to experimentation chemical remains controversial (Dalangin et al., 2020). with reuptake blockers to treat obesity. As we will discuss Glutamate (also known as glutamic acid) and glycine are in Chapter 11, serotonin activity varies systematically with among the 20 basic amino acids that are used to build other stages of wakefulness and sleep. Low levels of serotonin proteins. GABA is not. activity are associated with lower social rank, increased risk Glutamate is the most common excitatory neurotaking, and aggression (refer to Chapter 14). Although low chemical in the CNS, used by as many as 90 percent of the levels of serotonin activity have been linked traditionally synapses in the human brain (Schwartz, 2000). Glutamate to major depressive disorder, this association has been disis synthesized from α-ketoglutarate in the mitochondria. puted (Moncreiff et al., 2022). Once released, glutamate is taken up quickly by both neuMelatonin, which serves critical roles in the mainrons and astrocytes. The synaptic area must be cleared of tenance of our sleep and waking cycles, is synthesized excess glutamate because extended action of glutamate on from serotonin. Serotonin is converted into L-acetylseroneurons can be toxic. Only a tiny amount of the brain’s tonin through the action of serotonin N-acetyltransferase glutamate, perhaps about .01 percent, is found in the and acetyl-CoA. L-acetylserotonin is then converted into extracellular fluid, with the rest carefully packaged within melatonin through methylation of the hydroxyl group cells. Some people appear to be oversensitive to monosoby hydroxyindole O-methyltransferase and S-adenosyl dium glutamate (MSG), a combination of glutamate and methionine. Most melatonin is produced by the pineal sodium that occurs naturally in some foods and is used as gland, which lies outside the blood-brain barrier despite its location near the center of the brain. As we will discuss in Chapter 11, melatonin is secreted in the dark and breaks down rapidly in the presence of light, especially light in the short-wave or blue end of the visible spectrum (refer to Chapter 6). Histamine results from the action of histidine decarboxylase on the amino acid L-histidine (Schwartz et al., 1980). Most histamine is released by immune system cells

glutamate A major excitatory amino acid neurochemical. gamma-aminobutyric acid (GABA) A major inhibitory amino acid neurochemical. glycine An amino acid neurochemical that has inhibitory effects in the spinal cord and excitatory effects in conjunction with the NMDA glutamate receptor.

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Figure 4.10 Histamine Pathways in the Brain Histamine is released by cells located in the tuberomammillary nucleus of the hypothalamus. These cells project widely to the brainstem, limbic system, and cerebral cortex. The main effect of the neuromodulation provided by this system is to increase alertness. Cerebral cortex

To hippocampus and amygdala To striatum To midline thalamic areas

To posterior pituitary Tuberomamillary nucleus To ventral tegmentum and substantia nigra Medulla Cerebellum Spinal cord

a food additive. Reported adverse reactions include chest pain, headache, nausea, and rapid heartbeat. However, the blood–brain barrier (review Chapter 3) prevents dietary glutamate from entering the brain, and dietary glutamate does not have an effect on brain activity (Fernstrom, 2018). Glutamate receptors can be either ionotropic or metabotropic. Eight types of metabotropic glutamate receptors, known as mGluRs, have been identified. Three types of ionotropic glutamate receptors are named after the external substances that also activate them, in the same manner that ACh receptors were named nicotinic or muscarinic. The three ionotropic glutamate receptors are the N-methyl-D-aspartate (NMDA) receptor, the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor, and the kainate receptor. Both the AMPA receptor, which is the most common variety, and the kainate receptor operate by controlling a sodium channel. When these receptors bind molecules of glutamate, a sodium channel opens, and an EPSP is produced. The NMDA receptor, featured in Figure 4.11, has received a tremendous amount of attention due to its unusual method of action. NMDA receptors are apparently unique in that they are both voltage-dependent and chemical-dependent. In other words, they will not open unless glutamate is present and the postsynaptic membrane in their vicinity is depolarized at the same time. At the typical negative resting potentials of the postsynaptic

neuron, the ion channels of NMDA receptors are blocked by magnesium ions. However, because NMDA and AMPA receptors are usually found near one another on the same postsynaptic membrane, sodium moving through a nearby AMPA receptor will depolarize the membrane surrounding the NMDA receptor as well. When the membrane becomes sufficiently depolarized, the magnesium ions will be ejected from the NMDA receptor, allowing it to open in response to the binding of glutamate. NMDA receptors are also unusual in their ability to allow both positively charged sodium and calcium ions to enter the cell, which further depolarizes the cell. Normally, an ion channel admits a single type of ion, not two. Once inside a cell, calcium activates enzyme sequences that result in structural and biochemical changes. Because of calcium’s ability to trigger lasting changes in neurons, the NMDA receptor is believed to participate in functions such as long-term memory, which we will discuss in Chapter 12. The action of calcium upon entering the cell is also responsible for the toxicity of excess glutamate levels mentioned earlier. As more glutamate stimulates NMDA receptors, more calcium enters neurons. The resulting excess enzyme activity can literally digest and kill the affected neuron. This process might be responsible for much of the damage following strokes and in a number of brain diseases (Olney, 1994; refer to Chapter 15). GABA serves as the major inhibitory neurochemical of the CNS, involving as many as 40 percent of the synapses

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Figure 4.11 The NMDA Glutamate Receptor The NMDA receptor has two unusual qualities. First, it requires both the binding of glutamate and sufficient depolarization before it responds. At the resting potential, the ion channel is blocked by a molecule of magnesium (Mg2+). Depolarization ejects the Mg2+. If glutamate now binds with the receptor, the channel will open, and ions will be allowed to pass. Second, the receptor allows both sodium and calcium ions to enter the neuron. These features make the NMDA glutamate receptor a prime candidate for having a significant role in learning at the cellular level. Extracellular fluid

+

+

+

+

+

Glutamate Mg2+ +

Ca2+

+ +

Na+

+ +

+

+

Mg2+

+

+

Ca2+

Glutamate

+

+

Na+

+

AMPA receptor

(a) Glutamate Alone

Membrane near NMDA receptor is depolarized.

Na+

+

+

+

+

+ +

+

+ +

Ca2+

(b) Depolarization Alone

in the central nervous system. GABA is synthesized from glutamate through the action of the enzyme glutamic acid decarboxylase (GAD). There are three types of GABA receptors, referred to as GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ionotropic postsynaptic chloride channels, which allow negatively charged chloride ions to enter the cell. As presented in Figure 4.12, the GABAA receptor interacts with a number of psychoactive substances, which we’ll discuss in more detail later in the chapter. GABAB receptors are metabotropic potassium channels, which allow positively charged potassium ions to leave the cell. Hyperpolarization can occur whenever negative ions enter the cell or when positive ions leave the cell. Glycine acts directly as an inhibitory neurochemical by opening ionotropic chloride receptors. Glycine is synthesized when the enzyme serine transhydroxymethylase acts on serine in mitochondria. It is removed from the synaptic gap by reuptake. Glycine is found primarily in synapses formed by spinal cord interneurons and in smaller numbers elsewhere in the nervous system (refer to Figure 4.13). For example, about half of the amacrine cells of the retina release glycine (refer to Chapter 6; Wässle et al., 1998). Glycine receptors are blocked by the poison strychnine. Strychnine kills an organism by preventing the muscular inhibition normally provided by glycine, especially in the diaphragm. Although glycine is typically inhibitory, it plays an excitatory role in conjunction with glutamate at the NMDA receptor described earlier. Glycine’s interactions with NMDA receptors in the suprachiasmatic nucleus of the hypothalamus (SCN; refer to Chapter 11)

Na+ +

+

+ +

+

+

+

+

NMDA receptor Intracellular fluid

Mg2+

Ca2+

+

+

+

+

+

+

+ +

Na+

(c) Glutamate and Depolarization

contribute to the lower body temperatures typical of sleep. Because of this role in sleep, glycine has been proposed as a treatment for insomnia, although it is not currently approved for that purpose.

Figure 4.12 The GABAA Receptor Interacts With Several Drugs In addition to binding sites for GABA itself, the GABAA receptor also contains binding sites that interact with benzodiazepines, barbiturates, and ethanol (alcohol). These drugs depress nervous system activity by increasing the inhibition produced by GABA. Combining any of these drugs can produce a life-threatening level of neural inhibition. Benzodiazepine Alcohol

–

Barbiturate GABA

Extracellular fluid

Cl– ion – – –

– – –

Intracellular fluid

–

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Figure 4.13 Glycinergic Neurons Red fluorescence indicates strong concentrations of glycine in the amacrine cells of the mouse retina (refer to Chapter 6).

Figure 4.14 Caffeine and Adenosine Share Similar Structure Because of their similar structures, caffeine (left) and adenosine (right) compete at the binding sites of postsynaptic receptors for adenosine. Caffeine produces alertness by blocking the inhibitory effects of adenosine. O H3C O

N

N N

NH2

CH3

N

N HO O

N

N N

CH3 OH OH Caffeine

Adenosine Triphosphate (ATP) Adenosine triphosphate (ATP) and its by-products, particularly adenosine, act as neuromodulators-in the CNS and in connections between autonomic neurons and the vas deferens, bladder, heart, and gut. Adenosine results from the breakdown of ATP. As adenosine levels in the extracellular fluid rise, three types of metabotropic receptors are activated. Activation of one of these receptor types, A1, inhibits the release of glutamate, acetylcholine, norepinephrine, serotonin, and dopamine. Activation of another type of receptor, A2, facilitates the release of glutamate and acetylcholine while inhibiting the release of GABA. As a result, adenosine modulates a wide variety of functions, including the excitability of neurons and the coordination of neural networks (Garcia-Gil et al., 2021). The overall effect of high adenosine levels in the brain is inhibitory. We will note later in this chapter how caffeine acts at adenosine receptors to counteract adenosine’s inhibitory effects on neural activity (refer to Figure 4.14).

Neuropeptides There are at least 40 different peptides, or chains of amino acids, that act as neuromodulators and neurohormones. Neuropeptides, unlike the small molecules, are manufactured in the neural cell body and must be transported to the axon terminal, a process that could take as long as 1 day. Because of this, it is possible to “run out of ” neuropeptides during periods of active signaling. Neuropeptides often coexist in the same neuron with a small-molecule messenger and are co-released to modify its effect. A single neuron adenosine A neurochemical that is a by-product of adenosine triphosphate (ATP).

can contain and release several different neuropeptides. All receptors for neuropeptides are metabotropic (review Chapter 3). Deactivation of neuropeptides in the synapse occurs through diffusion or enzymatic degradation and is generally a slow process. Among the neuropeptides are substance P, which is involved in the perception of pain, and the endogenous morphines (endorphins), substances that act on the same receptors as opioids such as heroin. The distribution of receptors for endorphins in the brain is presented in Figure 4.15. Peptides involved with digestion, including insulin and cholecystokinin (CCK), have neuromodulating and neurohormone functions in addition to their better-known impacts on the processing of nutrients (refer to Chapter 9). Other peptides released from the pituitary gland, such as oxytocin and vasopressin, act as both neuromodulators and hormones.

Figure 4.15 Distribution of Opioid Receptors in the Human Brain This PET scan identifies areas of the brain rich in opioid receptors, which appear in red and yellow. These receptors respond both to naturally occurring and externally supplied opioids, including heroin and morphine.

Philippe Psaila/Science Source

Source: NIH.gov/Department of Neuroanatomy, Max-PlanckInstitute for Brain Research Frankfurt, Germany

Adenosine

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Types of Neurochemicals

Gasotransmitters The discovery of gasotransmitters has stretched the boundaries of our criteria for chemical messengers. Among the identified gasotransmitters are nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) (Wang, 2014). The mechanism for gasotransmission is unlike the processes we have discussed so far. Gaseous molecules dissolve easily in lipids, so they diffuse through membranes without needing vesicles or a release mechanism. They act on receptors located within cells rather than on receptors embedded in the membrane. It is even possible for gasotransmitters to travel through one cell and influence its neighbors. Gasotransmitters break down very quickly without needing the action of enzymes. In addition, gasotransmitters appear to transfer information from the postsynaptic neuron to the presynaptic neuron rather than the other way around. NO is a short-living free radical produced by the actions of the enzyme nitric oxide synthase (NOS), which is found in a small number of neurons (between 1 and 2 percent of those in the cerebral cortex), on the amino acid arginine. Prior to the 1990s, NO was best known as a precursor for acid rain. We now understand that NO is involved with neural communication, the maintenance of blood pressure, and penile erection (Furchgott & Vanhoutte, 1989; Snyder, 2000). The anti-impotence medication sildenafil citrate (Viagra) acts by boosting the activity of NO in the penis. In the central nervous system, NO is involved with pain perception, appetite, sleep, thermoregulation, neural development, and synaptic plasticity (Mir & Maurya, 2018).

Interim Summary 4.1

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2. ACh is found at the neuromuscular junction, in the autonomic nervous system, and within the CNS. Dopamine is involved with systems controlling movement, reinforcement, and planning. Norepinephrine pathways increase arousal and vigilance. Serotonin participates in the regulation of mood, appetite, social status, aggression, and sleep. Histamine activity is associated with wakefulness. Glutamate is the most common excitatory neurotransmitter in the CNS. GABA and glycine generally produce inhibition. ATP and its by-products act as neurochemicals. (LO2) 3. Small-molecule neurochemicals include acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, melatonin, histamine, glutamate, GABA, glycine, and adenosine. (LO3) 4. Neuropeptides include substance P and endorphins, among at least 40 others. (LO3) 5. Gasotransmitters diffuse through membranes and interact with internal receptors to transmit information. Gases can communicate from postsynaptic neurons to presynaptic neurons. (LO3)

Review Questions 4.1 1. How are neurotransmitters, neuromodulators, and neurohormones similar to and different from one another? 2. What are some of the distinctive features of receptors for ACh, dopamine, glutamate, and GABA?

Summary Points 4.1 1. Neurotransmitters affect adjacent cells across the synapse. Neuromodulators diffuse away from the synapse to target cells some distance away. Circulating neurohormones reach even more distant target cells. (LO1)

nitric oxide (NO) A gas that performs a type of signaling between neurons.

Summary Table 4.1: Characteristics of Selected Neurochemicals Neurotransmitter

Acetylcholine (ACh)

Locations ●

Neuromuscular junction

●

Movement

●

Preganglionic autonomic synapses

●

Autonomic function

●

Postganglionic parasympathetic synapses

●

Learning and memory

●

Attention

●

Wakefulness

●

Movement

●

Reinforcement

●

Planning

●

●

Dopamine

Functions

●

●

Basal forebrain projections to hippocampus and amygdala, the septum, the brainstem Substantia nigra and basal ganglia Ventral tegmentum projections to hippocampus, amygdala, and nucleus accumbens Ventral tegmentum projections to frontal lobe of the cortex

(continued)

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Summary Table 4.1: Characteristics of Selected Neurochemicals (Continued) Neurotransmitter

Locations ●

Norepinephrine

Serotonin

Histamine

Glutamate

Pons (especially locus coeruleus, which projects widely to spinal cord and brain)

●

Medulla

●

Hypothalamus

●

Postganglionic sympathetic synapses

●

Functions

Pons, (especially the raphe nuclei, which project widely to spinal cord and brain)

Sleep

●

Appetite

Cerebellum

Mood

●

●

Aggression

●

Social rank

●

Wakefulness

●

Movement

●

Excitation

●

Long-term memory

●

Inhibition

●

Mood

●

Seizure threshold

●

Inhibition

●

●

Glycine

Nitric oxide (NO)

●

●

●

Substance P

Mood

Medulla

The tuberomammillary nucleus (TMN) of the hypothalamus, projecting widely to the brain Widely distributed in the central nervous system

Widely distributed in the central nervous system

GABA

Endogenous opioids

Arousal and vigilance

●

●

●

Adenosine triphosphate (ATP) and by-products

●

Spinal interneurons, the retina, lesser role in the central nervous system

●

Excitation at the NMDA glutamate receptor

●

Sleep

●

Central nervous system

●

Pain modulation

●

Autonomic nervous system

●

Inhibition

●

In some axons containing catecholamines

●

Periaqueductal gray

●

Pain reduction

●

Pituitary gland

●

Feelings of well-being

●

Limbic system

●

Basal ganglia

●

Spinal cord

●

Ventral tegmentum

●

Spinal cord

●

Pain

●

Central and peripheral nervous systems

●

●

Smooth muscle

Relaxes smooth muscle cells in blood vessels

●

Erection

●

Possible retrograde signaling

Mechanisms of Neuropharmacology

neurochemicals, reuptake or enzyme activity following release, and interactions with either pre- or postsynaptic receptor sites.

Therapeutic and recreational drugs produce their psychoactive effects through presynaptic or postsynaptic actions. Drugs can affect the synthesis of neurochemicals, storage of neurochemicals within the axon terminal, release of

Agonists and Antagonists Drugs can boost or reduce the activity of a neurochemical. Drugs that enhance the activity of a neurochemical

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Mechanisms of Neuropharmacology

are known as agonists. Drugs that reduce the activity of a neurochemical are known as antagonists. Pharmacologists often limit the use of the terms agonist or antagonist to chemicals that act at receptor sites, but our broader use of the terms in behavioral neuroscience includes chemicals that influence activity in additional ways such as affecting the amount of neurochemical that is released. It is important to avoid equating agonists with postsynaptic or behavioral excitation and antagonists with postsynaptic or behavioral inhibition. The outcome of the action of an agonist or antagonist depends on the normal operation of a neurochemical at a specific receptor. If a neurochemical generally has an inhibitory effect on a postsynaptic neuron, the action of an agonist would increase the amount of this inhibitory effect. The action of an antagonist at this same receptor, interfering with the inhibitory neurochemical, would result in less inhibition. Consider the case of caffeine. Caffeine, as you are probably well aware, produces alertness. As we will discuss later in the chapter, caffeine is an antagonist for adenosine, which means it reduces adenosine’s effects. Because adenosine typically produces inhibitory effects, reduced inhibition due to caffeine equates to increased neural activity.

Drugs Influence the Production of Neurochemicals Manipulating the synthesis of a neurochemical will affect the amount available for release. Substances that promote increased production will act as agonists, while substances that interfere with production will act as antagonists. The simplest way to boost the rate of neurochemical synthesis is to provide larger quantities of the basic building blocks, or precursors. Serotonin levels can be raised temporarily by eating carbohydrates, which results in more tryptophan crossing the blood–brain barrier to be synthesized into serotonin (Wurtman et al., 2003). Drugs can also exert antagonistic effects by interfering with the synthesis pathways of neurochemicals. One example is the drug α-methyl-p-tyrosine (AMPT), which interferes with the activity of tyrosine hydroxylase (TH). As we observed earlier in the chapter, TH converts the substrate tyrosine into L-dopa. Consequently, AMPT reduces the production of dopamine, norepinephrine, and epinephrine.

Drug Effects on Neurochemical Storage Certain drugs have an antagonistic effect by interfering with the storage of neurochemicals in vesicles within the neuron. For example, the drug reserpine, used historically to reduce blood pressure, blocks the uptake of monoamines into synaptic vesicles. Molecules of monoamines

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left in the cytoplasm will be broken down by enzymes. As a result, smaller quantities of monoamines are available for release in response to the arrival of action potentials. Observations dating from the 1960s that some patients treated with reserpine experienced depression contributed to an influential monoamine hypothesis of depression (refer to Chapter 16). According to this hypothesis, depression was the result of lower activity of the monoamines, especially serotonin. Consistent with the previously discussed doubts about a relationship between serotonin and depression, evidence supporting the widely held belief that reserpine produces depression is poor (Baumeister et al., 2003; Zhu et al., 2019).

Drugs Affect Neurochemical Release Drugs often modify the release of neurochemicals in response to the arrival of an action potential. Some drugs affect release by interacting with presynaptic autoreceptors. Other drugs interact directly with the proteins responsible for exocytosis, which is the process responsible for the release of neurochemical molecules into the synapse (review Chapter 3). Exocytosis is promoted by agonists but blocked by antagonists. Methamphetamine serves as a dopamine agonist in an interesting manner. Initially, the methamphetamine molecules, which are quite similar in structure to dopamine, are taken up by the dopamine transporters. Once inside the axon terminal, the methamphetamine displaces dopamine in the vesicles. Some dopamine is deactivated by monoamine oxidase (MAO), but the higher concentration of dopamine in the intracellular fluid disturbs the actions of the transporters. Instead of moving dopamine from the synaptic gap back into the cell, the transporters reverse and start pumping dopamine into the gap, even in the absence of any action potentials. Because the transporters are malfunctioning, the released dopamine is trapped in the gap, where it can interact with postsynaptic receptors repeatedly. Other drugs act as antagonists by preventing the release of chemical messengers. As illustrated in Figure 4.16, powerful toxins produced by Clostridium botulinum bacteria, found in spoiled food, prevent the release of ACh at the neuromuscular junction and at synapses of the autonomic nervous system. The resulting disease, botulism, leads rapidly to paralysis and death.

agonist Substance that promotes the activity of a neurochemical. antagonist Substance that reduces the activity of a neurochemical. reserpine A substance derived from a plant that depletes supplies of monoamines by interfering with the uptake of monoamines into synaptic vesicles; used to treat high blood pressure and psychosis. methamphetamine A variation of amphetamine that is cheaply produced and widely abused in the United States.

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Figure 4.16 Drug Interactions at the Cholinergic Synapse Drugs can interact with many ongoing processes at a synapse. Agonists at the cholinergic synapse, which appear in green, include black widow spider venom, nicotine, dietary choline, and organophosphates. Spider venom enhances acetylcholine (ACh) release, and nicotine activates ACh receptors. Increased intake of dietary choline can increase production of ACh. Organophosphates break down the enzyme acetylcholinesterase (AChE), so they technically serve as ACh agonists. Although a reduction in AChE activity might initially boost ACh activity, it eventually has a toxic effect on ACh receptors. So ultimately, organophosphates depress ACh activity. Antagonists, which appear in red, include botulin toxin and curare. Botulinum toxin blocks the release of ACh, and curare blocks nicotinic ACh receptors. 1 Synthesis

Antagonist

Acetyl CoA + Choline Dietary choline increases production of ACh.

Black widow spider venom promotes ACh release.

ACh

2 Storage 3 Release

AChE breaks down ACh. 4 Action on receptor

Nicotine stimulates ACh receptors.

Botox® is the trade name for one of the seven botulinum toxins. Botox is used to paralyze muscles to prevent the formation of wrinkles and to treat a variety of medical conditions involving excess muscle tension. Because Botox reduces the release of neurochemicals associated with pain, it is also used as a treatment for migraine headaches (refer to Chapter 15). Concerns have been raised about the ability of Botox to move from the injection site back to the brain using retrograde transport in neurons (Antonucci et al., 2008; Galazka et al., 2015). Adverse reactions to Botox for both cosmetic and therapeutic uses, however, remain rare (Witmanowski & Błochowiak, 2020).

botulism A fatal condition produced by bacteria in spoiled food in which a toxin produced by the bacteria prevents the release of acetylcholine (ACh).

Organophosphates block the action of acetylcholinesterase. 5 Breakdown

Botulinum toxin blocks release of ACh. ACh receptors

Agonist

Curare blocks ACh receptors.

Drugs Interact With Receptors By far, the greatest number of drug interactions with our natural biochemistry occur at the receptor. In some cases, drugs are similar enough in chemical composition to mimic the action of natural neurochemicals at the receptor site. In other cases, drugs can block synaptic activity by occupying a binding site on a receptor without activating the receptor. Finally, many receptors have multiple types of binding sites. Drugs that occupy one or more of these sites can indirectly influence the activity of the receptor. Using the lock-and-key analogy of receptor site activity, both chemical messengers and agonists at the receptor site can act like keys that can open locks. Antagonists can act like a poorly made key that fits in the lock but fails to open it. As long as the ineffective key is in the lock, real keys can’t be used to open it either. As we mentioned in our earlier discussion of ACh, the nicotinic and muscarinic receptors received their names due to their ability to respond to both ACh and nicotine

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Mechanisms of Neuropharmacology

or to both ACh and muscarine, respectively. Consequently, both nicotine and muscarine are classified as cholinergic agonists. Other drugs, such as curare, act by blocking nicotinic receptors. Curare is derived from plant species found in the Amazon region of South America. People in this region have historically used curare to tip their darts for hunting and warfare. Beginning in the 1940s, curare was used to relax muscles during surgery, but it has since been replaced by more effective drugs. As presented in Figure 4.17, snake venom acts in much the same way as curare. Because curare and snake venom occupy the nicotinic receptors located at the neuromuscular junction without breaking down or being released, ACh is unable to stimulate muscle fibers. Inactivation of the muscles of the diaphragm, required for breathing, leads to paralysis and death. A number of important drugs exert their influence on the GABAA receptor, which is a complicated receptor with a number of different binding sites. The purpose for these multiple binding sites is not currently understood. Although only one binding site is activated by GABA itself, there are at least five other binding sites on the GABAA receptor. These additional sites can be activated by the benzodiazepines (tranquilizers including diazepam or Valium), alcohol, and barbiturates, which are used in anesthesia and in the control of seizures. Barbiturates can single-handedly activate the GABAA receptor without any GABA present at all (Bowery et al., 2004). Benzodiazepines and alcohol increase the receptor’s response to GABA but only when they occupy binding sites at the same time GABA is present. Because GABA has a hyperpolarizing, or inhibitory, effect on postsynaptic neurons,

Figure 4.17 Many Venoms Target Cholinergic Systems to Paralyze Prey

ANT Photo Library/Science Source

The inland taipan of Australia is considered to be the most venomous snake in the world. It is estimated that the venom released in one bite is sufficient to kill 100 people. The primary action of the venom is to block the release of acetylcholine, producing death by muscular paralysis in as little as 35–40 minutes.

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GABA agonists enhance inhibition. The combined action of alcohol, benzodiazepines, or barbiturates at the same GABAA receptors can produce a life-threatening level of neural inhibition.

Drugs Affect Reuptake and Enzymatic Degradation Second only to drugs acting at receptor sites in terms of number and importance are drugs that affect the deactivation of neurochemicals. Some of these drugs influence the reuptake of neurochemicals, and others act on enzymes that break down released neurochemicals. Drugs that interfere with either reuptake or enzymatic degradation of chemical messengers are usually powerful agonists. They promote the effects of the neurochemical by allowing more of the released substance to stay active in the synapse for a longer period of time. This, in turn, provides more opportunities for the neurochemical to interact with receptors. As demonstrated in Figure 4.18, drugs that inhibit the reuptake of dopamine include cocaine, amphetamine, and methylphenidate (Ritalin). Consequently, each of these drugs is a powerful dopamine agonist. Another important class of reuptake inhibitors includes those that act on serotonin. Selective serotonin reuptake inhibitors (SSRIs) block the transport of serotonin back into the presynaptic neuron. This group includes the antidepressant medication fluoxetine (Prozac), depicted in Figure 4.19. With slower reuptake, existing serotonin remains more active in the synapse for a longer period of time. The use of SSRIs as antidepressants has been justified historically by the monoamine hypothesis of depression. Given the challenges to that hypothesis discussed previously, further research is needed to establish a mode of action for SSRIs in the reduction of depression. Organophosphates such as sarin are pesticides that were originally developed as chemical warfare agents and are still unfortunately used as such. These chemicals interfere with the action of acetylcholinesterase (AChE). As presented earlier in Figure 4.16, AChE deactivates ACh. Drugs that interfere with AChE boost ACh activity, which can be helpful in conditions like the muscular disorder myasthenia gravis discussed in Chapter 8. In a person with normal ACh activity, however, too much ACh can produce autonomic disruptions, involuntary movements, and eventually, paralysis and death (Pope et al., 2005). curare A substance derived from Amazonian plants that causes paralysis by blocking the nicotinic acetylcholine (ACh) receptor. benzodiazepine A major tranquilizer that acts as a GABA agonist. barbiturate A drug that produces strong sedation by acting as a GABA agonist. reuptake inhibitor Substance that interferes with the transport of released neurotransmitter molecules back into the presynaptic terminal.

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Figure 4.18 Drug Interactions at the Dopaminergic Synapse L-dopa, prescribed in cases of Parkinson disease, serves as a dopaminergic agonist by promoting increased dopamine synthesis, and amphetamine increases the release of dopamine. Cocaine, amphetamine, and methylphenidate are dopamine reuptake inhibitors. Apomorphine activates dopaminergic receptors. Reserpine exerts an antagonistic effect by interfering with the uptake of monoamines into synaptic vesicles. Traditional medications used to treat schizophrenia, such as phenothiazines, block dopaminergic receptors. 1 Synthesis

Antagonist

Tyrosine

Agonist

L-dopa Additional L-dopa increases production of dopamine.

Dopamine

2 Storage

Reserpine interferes with storage of dopamine.

Cocaine, amphetamine, and methylphenidate (Ritalin) inhibit dopamine reuptake.

3 Release

5 Reuptake

Amphetamine increases release of dopamine. 4 Action on receptors

Dopamine receptors

Apomorphine stimulates dopamine receptors. Apomorphine may be helpful in treating Parkinson disease, but its use is not currently approved for that purpose.

Some medications used to treat schizophrenia block dopamine receptors.

Figure 4.19 Drug Interactions at the Serotonergic Synapse Agonists at the serotonergic synapse include tryptophans, MDMA (ecstasy), headache remedies, monoamine oxidase (MAO) inhibitors, and selective serotonin reuptake inhibitors (SSRIs), including Prozac. Antagonists for serotonin include reserpine and some medications used to treat schizophrenia. 1 Synthesis

Antagonist

Tryptophan Increased intake of foods containing tryptophan increases serotonin production.

5-HTP Serotonin 2 Storage

Reserpine interferes with storage of serotonin.

3 Release

MDMA (ecstasy) increases serotonin release.

Serotonin receptors are stimulated by a number of medications used to treat migraine headaches.

MAO

Agonist

MAO inhibitors (occasionally used to treat depression) interfere with the breakdown of monoamines (including serotonin) within the axon terminal. 6 Breakdown MDMA (ecstasy) and SSRIs (Prozac, etc.) inhibit the reuptake of serotonin. 5 Reuptake

4 Action on receptors Serotonin receptors

Some drugs used to treat schizophrenia block serotonin receptors.

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Basic Principles of Drug Effects

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nervous system, we need to review basic concepts related to drug effects.

Interim Summary 4.2 Summary Points 4.2 1. Agonists boost the activity of a chemical messenger, while antagonists interfere with the action of a neurochemical. (LO4) 2. Drugs affect behavior by interacting with a variety of processes occurring at the synapse, including synthesis, storage, release, reception, and deactivation. (LO5) Review Questions 4.2 1. For each of the major neurotransmitters, which drugs affect activity by influencing receptors? 2. Which drugs affect activity by influencing deactivation of a neurotransmitter?

Basic Principles of Drug Effects Before discussing specific types of psychoactive drugs and their interactions with natural chemical signaling in the

Administration of Drugs Drugs have different effects on the nervous system depending on their method of administration. Once in the blood supply, a drug’s effects are dependent on its concentration. Eating, inhaling, chewing, and injecting drugs deliver very different concentrations of the drug into the blood supply. Figure 4.20 demonstrates how nicotine concentrations in the blood over time are influenced by using smoking or chewing to administer the drug. Your body has several mechanisms designed to protect against toxins. The liver uses enzymes to deactivate substances in the blood. The blood–brain barrier, discussed in Chapter 3, prevents many toxins from entering the tissues of the central nervous system. The area postrema, located in the medulla, reacts to the presence of circulating toxins by initiating a vomiting reflex (Miller & Leslie, 1994). Ingested toxins posed the largest risk of poisoning for our ancestors, and vomiting clears the stomach to prevent area postrema A brainstem area in which the blood–brain barrier is more permeable that triggers vomiting in response to the detection of circulating toxins.

Figure 4.20 Concentration of a Drug in the Blood Supply Depends on the Method of Administration Drug effects are dependent on the concentration of the drug in the blood supply, and some methods of administration produce effective concentrations faster than others. In the case of nicotine, smoking a cigarette produces a much faster increase in blood nicotine concentration than chewing an equivalent dose of tobacco. However, chewing tobacco produces higher sustained concentrations of nicotine than smoking does.

20 Blood nicotine concentration (ng/ml)

Blood nicotine concentration (ng/ml)

20

15

10

5

0

0

30

60 90 Time (in minutes) Drug Peak administered response (a) Smoking Cigarettes

120

15

10

5

0

0 Drug administered

30

60 90 Time (in minutes) Peak response

120

(b) Chewing Tobacco

Source: Adapted from Bennett (1983).

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further damage. Obviously, this does little good in cases in which a toxin has been administered by other means, such as by directly injecting it into the bloodstream.

Drug effects experienced by individuals are influenced by a number of factors, including body weight, gender, and genetics. Larger bodies have more blood than smaller bodies and therefore require larger quantities of a drug to reach an equivalent concentration in the blood. Gender influences the effects of alcohol, which is diluted by the water in muscle tissue. Because men typically have more muscle than women of the same weight, the concentration of alcohol in a man’s blood will be lower than in a woman’s after consuming the same amount of alcohol. Genetic differences affect a liver enzyme, aldehyde dehydrogenase (ALDH), which participates in the metabolism of alcohol (Thomasson et al., 1991). With low levels of ALDH, alcohol by-products build up and produce unpleasant symptoms of flushing, rapid heartbeat, muscle weakness, and dizziness. The distribution of ALDH genetic variants varies across ethnicities (Edenberg, 2007). Asians are less likely to abuse alcohol and more likely to have genetic variants that are protective against alcohol abuse than people of other ethnicities (Li et al., 2011).

gain government approvals. The standard method for distinguishing between the effects of an active drug and placebo effects is the double-blind experiment. The first blind refers to the participant. If you agree to participate in such a study, you will not know whether you are receiving the active drug or an inactive substance (placebo). Unfortunately, the experience of known side effects or the failure to experience expected effects frequently unblinds the participants, so this is not a perfect system. The second blind refers to the researcher. To prevent biased observations, the researcher will not know which participants are receiving a placebo and which are receiving an active drug until after the experiment has concluded. Not all drugs lend themselves to this type of research. For example, efforts to determine the relative benefits of using smoked marijuana for medical purposes (as opposed to traditional pill-form pharmaceuticals containing cannabinoids) are handicapped by the obvious difficulty of finding a believable placebo (Koppel et al., 2014). It is virtually impossible to use a double-blind procedure effectively with stimulant drugs for the treatment of attention deficit hyperactivity disorder (ADHD) because the drug effects, such as increased heart rate, “unblind” the participants (Storebø et al., 2015). A solution in these cases is to use a nocebo, an inactive substance that produces the same number and severity of adverse reactions as the target substance. This practice, of course, raises significant ethical issues.

Placebo Effects

Tolerance and Withdrawal

Individual Differences in Responses to Drugs

Drug effects are often influenced by a user’s expectations, experiences, and motivations. These indirect outcomes are known as placebo effects. A placebo, from the Latin word for “I will please,” refers to the very real and measurable benefits of a treatment resulting from context effects. Placebo effects influence a wide variety of behaviors, including pain reduction, Parkinson disease, depression, and anxiety. Placebo effects can be substantial, and in some cases, more effective than medication or other treatments. Observations of brain activity correlated with a placebo effect show reductions in areas associated with pain and negative emotion coupled with increased activity in circuits connecting the frontal lobes and striatal circuits (Wager & Atlas, 2015). The latter changes probably support the processing of context (I’ve just consumed a pill) and learned responses (the last time I consumed a pill, I felt better). Pharmaceutical companies must show that their medications provide benefits above and beyond placebo effects to placebo effect Perceived benefit from inactive substances or procedures. double-blind experiment A research design in which neither the participant nor the experimenter knows whether the participant is receiving a drug or a placebo until after the research is concluded. nocebo An inactive substance that produces the same number and severity of adverse reactions as the target substance. tolerance The process in which more of a drug is needed to produce the same effect.

When a drug’s effects are lessened because of repeated administration, tolerance has developed. To obtain the desired effects, the person needs to administer greater and greater quantities of the drug. Tolerance effects can occur due to changes in enzymes, changes in receptor density, and learning. Not all effects of the same drug show equal levels of tolerance. For example, barbiturates produce both general feelings of sedation and depressed breathing. The sedative effect of barbiturates rapidly shows tolerance, but the depression of breathing does not. As people take more and more of the drug to achieve a sedative effect, they run an increasing risk of death due to breathing problems. Classical conditioning associated with drug use can also produce tolerance. The body’s efforts to compensate for drug administration become conditioned, or associated, with the stimuli involved with drug administration (refer to Chapter 12). This learned component of tolerance might contribute to some cases of drug overdose. Most individuals who die from heroin overdose do not take large amounts of the drug. Instead, they use the fatal dose in an unfamiliar context (Siegel, 2016). Animal research is supportive of this learning hypothesis of overdose. Siegel et al. (1982) gave rats injections of heroin every day until they began to show signs of tolerance to the drug. At that point, the rats received overdoses of the drug. Half the rats received overdoses in their home cages, and the other half received their overdoses in an unfamiliar environment. Nearly all the rats receiving the overdose in

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Basic Principles of Drug Effects

Figure 4.21 A Homeostatic Model of Tolerance and Withdrawal The body strives to maintain homeostasis or balance. Drug effects initiate compensatory efforts to counteract drug effects, leading to tolerance. When the drug effects are no longer present, compensatory adaptations show up as symptoms of withdrawal.

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consequences to the user (American Psychiatric Association [APA], 2022). Addiction overwhelms normal control of behavior, distorts typical systems of reward, and interferes with the recognition of problems.

Drug Normal brain function

Adaptation

Tolerance

Drug Adaptation

Source: Adapted from Littleton (1998).

the unfamiliar environment died, but only half of the rats receiving the drug in their familiar home cages died. The rats in the unfamiliar environment lacked the learned cues for triggering their bodies’ compensations for the drug. Without the ability to compensate, they were quickly overdosed. It is likely that similar factors influence the outcome of drug overdose for human beings. Withdrawal can occur when the use of psychoactive substances is reduced or discontinued. The severity of the withdrawal symptoms depends on the length and extent of use of a drug. In general, withdrawal effects are the opposite of the effects caused by the discontinued drug. A person in withdrawal from a sedative will become agitated, while a person in withdrawal from a stimulant will become lethargic. It is likely that most characteristics of a withdrawal syndrome reflect the same compensatory mechanisms that are responsible for tolerance (refer to Figure 4.21). Drug effects and compensatory mechanisms can cancel each other out, leading to fairly stable outcomes. When the drug is no longer present, the compensation alone becomes apparent. Symptoms of withdrawal might motivate a person to administer the drug again, but avoiding withdrawal symptoms is not the sole source of compulsive drug seeking and use.

Brain Correlates of Addiction When people are addicted to drugs, they stop making logical choices on the basis of long-term Drug Use outcomes (family, finances, avoiding jail) and persist in making impulsive choices on the basis of short-term outcomes (getting high). This reversal in normal, logWithdrawal ical decision-making results from changes in the relative strength of circuits involving reward, impulse control, and craving (Noël et al., 2013). Most addictive drugs have the ability to stimulate our natural neural systems of reward, which we experience as feelings of pleasure (refer to Chapter 9). These systems reward us for engaging in behaviors that are important either for our personal survival or for the survival of the species. When we eat due to hunger, drink due to thirst, or engage in sexual behavior, the same reward circuits of the brain are activated. These behaviors produce activity in the dopamine circuits in the brainstem and, quite notably, in the mesolimbic and mesocortical systems and in the nucleus accumbens. Addictive drugs produce a variety of behavioral effects, but most share the ability to stimulate more intense and longer-lasting dopamine release than we typically record in response to environmental events (Volkow et al., 2004). Drugs that do not influence either dopamine or the nucleus accumbens are often used habitually, but they do not seem to elicit the cravings and compulsive use associated with addiction. LSD seems to have little, if any, effect on dopamine circuits at recreational doses. People do not seem to be addicted to LSD, although they might choose to use it regularly because they enjoy the experience. Considerable research evidence shows that damage to the mesolimbic and mesocortical systems, including the nucleus accumbens, reduces an animal’s administration of addictive drugs. Animals can be addicted to drugs experimentally through regular injections. Once addicted, the

Addiction The traditional distinction made between physical and psychological dependence on a drug has probably outlived its usefulness. The defining feature of an addiction is the compulsive need to use the drug repeatedly despite negative

withdrawal The symptoms that occur when certain drugs are no longer administered or are administered in smaller quantities. addiction A compulsive craving for drug effects or other experiences despite negative consequences.

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animals will self-administer the drug by pressing a bar to activate an intravenous dose of the drug. Lesions of the nucleus accumbens reduce self-administration (Zito et al., 1985). In addition, selective damage to dopaminergic neurons will also reduce self-administration (Bozarth & Wise, 1986). Because damage to dopaminergic neurons and to the nucleus accumbens reduces drug dependency, you might be wondering why these techniques are not used to assist humans as well. We do not treat addiction in this manner because damaging these general reward circuits could abolish all feelings of reward permanently. It’s unlikely that anyone would choose this type of treatment for addiction. People with addictions cycle repetitively through three stages at rates that reflect the type of drug used and the severity of their addiction (Volkow et al., 2019). The first stage, intoxication, coincides with experiencing the drug effects and activity in the nucleus accumbens. The second stage, negative mood with or without withdrawal symptoms, is associated with activity in the amygdala. Finally, the person enters a craving stage, which involves activity in the prefrontal cortex and insula. Changes in the brain’s reward system resulting from drug use overwhelm the impulse control system managed by the frontal lobes (Noël et al., 2013). Activity in the insula correlates with ratings of craving for a drug of choice, and strokes that damage the insula completely eliminate the urge to administer an addictive drug (Verdejo-Garcia et al., 2012). When the person acts on these cravings and uses the drug again, the cycle repeats. Increased activity in the impulsive reward circuits of the brain coupled with less influence of the frontal executive circuits and increased craving sets the stage for a long-term maintenance of compulsive, addictive behavior. The use of addictive drugs can produce long-term, stable changes in gene expression in the brain (epigenetic change; refer to Chapter 5), leading to the maintenance of addictive behaviors and cravings that continue after months or years of abstinence (Stewart et al., 2021). Addiction Risk Genetics account for approximately 50 percent of the risk of addiction (Volkow & Boyle, 2018). The relevant genes influence individual responses to a particular drug or the ability to metabolize it, as we previously mentioned in the case of alcohol. Individual differences in genes producing a component of the nicotinic receptor predict which individuals are more likely to become addicted to nicotine. Adolescents are at particular risk of addiction, possibly due to the neuroplasticity of their brains relative to adults (refer to Chapter 5). The reward systems mature before prefrontal control circuits, which can lead to greater reward-seeking in adolescence. Immature prefrontal control can lead to impulsivity and risk-taking, and the further

development of the prefrontal cortex might be negatively impacted by addiction. Teens are also more vulnerable to social stress than adults, which might initiate additional epigenetic influences. Treatment of Addiction Once an addiction has been established, it is remarkably difficult to end it. Addiction is characterized by a strong risk of relapse, even after lengthy periods of abstinence. A variety of medications have been used to treat addiction, and many more are under development. Traditionally, methadone has been used to wean people away from heroin. Methadone prevents withdrawal symptoms, yet it does not produce the major psychological effects of heroin. Alcoholism is treated with disulfiram, or Antabuse, which interferes with the activity of the enzyme ALDH in metabolizing alcohol. This medication produces a number of unpleasant symptoms when alcohol is consumed. Further development can be based on the stages of the addiction cycle described above. The intoxication stage could be managed with medications that either restore normal responses to reward or block the rewarding effects of particular drugs. Medications could target the negative affect stage by reducing stress. Reduced prefrontal cortex activity leading to poor decision-making and cost-benefit analyses could also serve as a medication target. Because medications have not led to many successful recoveries, researchers are looking for alternate methods. Vaccinations that target nicotine, methamphetamine, cocaine, and heroin have been developed (refer to Figure 4.22). Vaccinations work by stimulating the immune system to bind molecules of the problem drug, preventing or delaying its movement across the blood– brain barrier into the brain (Shen et al., 2011). The use of noninvasive electrical or magnetic stimulation (review Chapter 1) could target the circuits affected by addiction, such as circuits in the prefrontal cortex. Peripheral nerve stimulation, developed to treat pain, might assist with managing withdrawal from opioids. Neurofeedback using EEG has improved executive functions in people with substance use disorders (Volkow & Boyle, 2018). Although our interests center on the biological actions of drugs, we should not lose sight of environmental factors that cause and maintain addiction. As the Vietnam War began to wind down, the American public health system braced for an anticipated epidemic of heroin addiction among the returning servicemen. Due to the obvious stress of war and the ready availability of heroin in Southeast Asia, many soldiers had used heroin habitually while overseas. However, their behavior on returning to the United States took health providers completely by surprise. Fewer than 10 percent of veterans relapsed, or returned to using heroin, in contrast to

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Figure 4.22 Vaccinations Against Drugs of Abuse Psychoactive drugs would not be psychoactive at all if they were unable to cross the blood–brain barrier to interact with the central nervous system (CNS). By developing antibodies that link with molecules of particular drugs of abuse, the drugs can be prevented from passing through the blood–brain barrier. Blood-brain barrier Antibody

Blood

National Institute on Drug Abuse

Antibody and drug molecule

Behavioral Neuroscience Goes to Work Addiction Counselors Changes in the legal management of people with substance use disorders that favor treatment over incarceration have led to an increasing need for trained addiction counselors. The U.S. Bureau of Labor and Statistics projects a growth of 31 percent in addiction counselor positions during the next decade, fueled by new insurance coverage for addiction and counseling services. Requirements for being an addiction counselor are set at the state level. Some states have requirements that are surprisingly low, given the licensing requirements for psychotherapists in general and the significant

the 70 percent of young civilians who relapse (Robins et al., 1975). Changes in the veterans’ environmental conditions had a tremendous impact on their motivation to use heroin.

Effects of Selected Psychoactive Drugs Psychoactive drugs are usually administered to obtain a particular psychological effect. By definition, these drugs

challenges inherent in recovering from an addiction. It is often possible to find employment as an addiction counselor without a bachelor’s degree. However, more states are requiring counselors to obtain more education, with a master’s degree becoming more common. Candidates are encouraged to obtain internships and other work experience in the counseling area. For students who have the compassion needed for the helping professions and who relish the challenge of working with clients who often resist treatment, this profession might be just perfect.

circumvent the protective systems of the blood–brain barrier to gain access to the CNS.

Stimulants Stimulant drugs share the capacity to increase alertness and mobility. As a result, these drugs have been widely

psychoactive drug A drug that produces changes in mental processes.

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embraced among cultures such as our own, in which productivity and hard work are valued. Caffeine As a graduate student, I participated in a research project on caffeine. The researchers calmly suggested to me that 20 cups of coffee a day (my reported intake) was “a bit much,” and they suggested I cut back to 8 or so. What is the caffeine A stimulant drug found in coffee, tea, cola, and chocolate that acts as an antagonist to adenosine.

nature of the attraction many of us have to caffeine? For most people, caffeine increases blood pressure and heart rate, improves concentration, and wards off sleepiness. The substance is found in tea, coffee, cola and energy drinks, chocolate, and a number of over-the-counter pain relievers (refer to Figure 4.23). Caffeine produces its behavioral effects by blocking adenosine receptors, reducing the normal inhibitory activity of adenosine. Caffeine’s interference with adenosine’s inhibition in the hippocampus and cerebral cortex probably accounts for the alertness associated with its use.

Figure 4.23 Caffeine Content of Common Products Brewed coffee— 8 oz.* Instant coffee— 8 oz.* Decaffeinated coffee— 8 oz.* Chocolate candy bar—1 oz.* No-Doz ® —1 tablet Anacin ® —1 tablet Black tea, brewed— 8 oz.* Green tea, brewed— 8 oz.* White tea, brewed— 8 oz.* Oolong tea, brewed— 8 oz.* Rooibos tea, brewed— 8 oz.* Tazo Chai Tea Latte, Starbucks— 16 oz.* Nestea iced tea— 12 oz.* Snapple iced tea— 16 oz.* Lipton Brisk iced tea— 12 oz.* Coke— 12 oz.* Pepsi— 12 oz.* Jolt Cola— 12 oz.* Mountain Dew— 12 oz.* Red Bull— 8.3 oz.* SoBe Essential Energy, berry or orange— 8 oz.* SoBe No Fear— 8 oz.* 20

40

60

80 100 120 140 Caffeine (in milligrams)

160

180

200

*Amount of caffeine depends on type of product, brewing method, and formulation. Source: Adapted from Byer & Shainberg (1995).

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Interference with normal adenosine activity in the basal cholinergic receptors in the ventral tegmental area, which, ganglia produces improvements in reaction time. By blockin turn, results in greater release of dopamine in the nucleus ing adenosine receptors, caffeine indirectly enhances the accumbens (Wills et al., 2022). This action on the nucleus activity of dopamine (Volkow et al., 2015), which, as you accumbens is the likely source of the addictive properties now know, might explain some of the attachment coffee of nicotine. Symptoms of withdrawal include the inability drinkers have to their favorite beverage. to concentrate and restlessness. Most people consume caffeine without experiencing Despite the known negative consequences of smoking, negative outcomes, but others are not so fortunate. Caffeine nicotine continues to be widely used. In the United States, can initiate cardiac arrhythmias. It crosses the placenta about 13 percent of people over the age of 18 smoke tobacco. easily, and the fetus and breastfed newborn are relatively Tobacco cigarettes are disproportionately used by racial unable to metabolize caffeine. Children exposed to “safe” and ethnic minorities and people with lower educational prenatal doses of caffeine demonstrated more externalizing attainment and income (Centers for Disease Control and behavior and brain structural differences when compared Prevention [CDC], 2022). Although combustible tobacco to children with no exposure (Zhang et al., 2021). Caffeine cigarette use is declining, the use of e-cigarettes, especially produces a withdrawal syndrome featuring headache and among youth, is climbing precipitously, from 1.5 percent in fatigue. Because caffeine reduces blood circulation to the 2011 to 20.8 percent in 2018 (Fadus et al., 2019). E-cigarette brain, withdrawal can produce severe headaches due to use by youth appears to produce a “gateway” effect, leading suddenly increased blood flow. to both cannabis use and the use of combustible cigarettes. On the more positive side, caffeine might prevent Nicotine dependence coincides with severe psychodementia and cognitive decline (Chen et al., 2020) and reduce logical disorders, including schizophrenia, bipolar disorrisk for Parkinson disease (Qi & Li, 2014; refer to Chapter 8). der, and major depressive disorder (refer to Figure 4.24). Risk for Parkinson disease decreased in a linear fashion with Sixty-five percent of patients with schizophrenia, 46 increasing doses of caffeine, although the relationship leveled percent with bipolar disorder, and 33 percent with out at the equivalent of about three cups of coffee per day major depressive disorder are dependent on nicotine (my 20 cups are not necessary, apparently). It is possible that personality or lifestyle factors associated with caffeine use are nicotine A stimulant drug that is the major active component responsible for this correlation, but evidence for caffeine’s abilfound in tobacco. ity to protect neurons from Parkinson-like damage has been reported in animals. A Parkinson-like syndrome can be artificially produced Figure 4.24 Adults with Psychological Disorders Use by injecting mice with a toxin known as MPTP, which reduces dopamine levels in More Tobacco Products the basal ganglia. If the MPTP injections People with psychological disorders are more likely to use tobacco products than are preceded by caffeine, little or no drop people with no diagnosed disorders. The reason for this remains unclear. People in dopamine occurs (Xu et al., 2010). with psychological disorders might use tobacco to offset their symptoms or the Nicotine After caffeine, the most commonly used stimulant in the United States is nicotine, usually delivered in the form of smoking or chewing tobacco. Nicotine increases heart rate and blood pressure, promotes the release of adrenaline into the circulation, reduces fatigue, and heightens cognitive performance. In the peripheral nervous system (PNS), nicotine produces muscular relaxation. Nicotine has its primary effect as an agonist at the nicotinic cholinergic receptor. These receptors exist not only at the neuromuscular junction but also at several locations in the brain. Nicotine’s action on the cholinergic system arising in the basal forebrain, described earlier, is probably responsible for increased alertness and cognitive performance. Nicotine stimulates

effects of other medications. Tobacco might play a causal role in the development of some psychological disorders. Finally, the same genetic vulnerabilities might underlie both psychological disorders and tobacco use. Current Use* of Any Tobacco Products Among Adults with Any Psychological Disorder Compared with Adults with No Psychological Disorder, 2016s 40.0% 35.0%

30.5%

30.0% 25.0%

Adults with any psychological disorder

34.6%

Adults with no psychological disorder

23.3%

20.0%

18.4%

15.0% 10.0%

6.2%

5.0% 0.0%

Any Tobacco Products

Cigarettes

4.5%

Cigars

3.4% 3.5%

Smokeless Tobacco

Source: https://www.cdc.gov/tobacco/disparities/mental-illness-substance-use/index.htm

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(Fornaro et al., 2022). Several explanations might account for these observations. People with severe psychological disorders could be seeking to relieve their symptoms through the use of nicotine, but recent experiments put this hypothesis in doubt (Hickling et al., 2018). The genes that make people vulnerable to serious psychological disorders might also confer vulnerability to nicotine dependence (Hu et al., 2018). Even more troubling are suggestions that nicotine use is a causal factor in the development of psychological disorders, especially depression (Wootton et al., 2020). Cocaine and Amphetamine The behavioral effects of cocaine and amphetamine are quite similar to one another because both drugs are powerful dopamine agonists. These drugs are among the most addictive drugs known. A single recreational dose of cocaine is sufficient to produce addiction in mice (Grueter et al., 2011). At lower doses, these drugs produce alertness, elevated mood, confidence, and a sense of well-being. At higher doses, these drugs can produce symptoms that are similar to schizophrenia (Hsieh et al., 2014; refer to Chapter 16). Users often experience hallucinations, cocaine A powerful, addictive dopamine agonist derived from the leaves of the coca plant of South America. amphetamine A highly addictive drug that acts as a potent dopamine agonist. ecstasy (MDMA) A close relative of amphetamine that produces its behavioral effects by stimulating the release of serotonin and oxytocin.

Figure 4.25 Methamphetamine Abuse Leads to Multiple Health Consequences

Michael Rubenstein/Redux

Not only does methamphetamine abuse frequently lead to hallucinations and delusions similar to those caused by schizophrenia, users also experience additional health issues, including a characteristic pattern of dental decay known as “meth mouth.” This condition results from the mouth dryness and the clenching and grinding of teeth caused by the drug.

particularly in the form of tactile sensations such as feeling bugs on the skin. They frequently experience paranoid delusions, thinking that others wish to harm them. In some cases, they show repetitive motor behaviors, particularly chewing movements or grinding of the teeth (refer to Figure 4.25). Cocaine was originally used by the indigenous people of Peru as a mild stimulant and appetite suppressant. Sigmund Freud recommended cocaine as an antidepressant in his 1885 book, Über Coca (On Coca). Freud became disenchanted with the drug after he became aware of its potential for addiction. Historically, many popular products contained some form of cocaine, as depicted in Figure 4.26. The original formulation of Coca-Cola included extracts of the coca leaf. When cocaine was designated as an illegal substance, the Coca-Cola company simply removed the cocaine but retained the remaining extracts of the coca leaf in its highly guarded secret formula. Amphetamine was originally developed as a treatment for asthma. Inhalers containing amphetamine were sold without prescription throughout the 1940s even though people were opening the inhalers and ingesting the contents. During World War II, the Korean War, and the Vietnam War, amphetamine was widely used by pilots and military personnel to ward off fatigue. In the 1960s, many Americans received prescriptions for amphetamine as a diet aid because it does suppress appetite. Methamphetamine has emerged as a major drug of abuse due to its cheap and easy manufacturing process. Despite the similarity in behavioral outcomes, the modes of action for cocaine and amphetamine are somewhat different. Both distort the action of dopamine transporters (review Chapter 3), but they do so differently. Amphetamine mimics dopamine, leading it to be captured and moved across the presynaptic membrane by dopamine transporters. Once inside the neuron, amphetamine enters synaptic vesicles, pushing the dopamine molecules out into the intracellular fluid of the axon terminal. The presence of large amounts of dopamine outside of vesicles makes the transporters begin to work in reverse, pushing dopamine out of the cell even in the absence of any action potentials. With the transporters working in reverse and unable to retrieve the released dopamine, the molecules of dopamine become trapped in the synaptic gap, stimulating receptors continuously. Cocaine’s action on the dopamine transporters is simpler. Cocaine simply blocks the transporters, keeping all previously released dopamine active in the synaptic gap. In both cases, the result is much higher activity than normal at dopaminergic synapses. Ecstasy (MDMA) MDMA (3,4-methylenedioxymethamphetamine, or ecstasy) is a synthetic relative of amphetamine. Structurally, MDMA is similar to both methamphetamine and the hallucinogen mescaline. MDMA increases heart rate, blood pressure, and body

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Figure 4.26 Cocaine Was an Ingredient in Many Widely Used Products

Historical/Getty Images

Bettmann/Contributor/Getty Images

Prior to World War I, many commercial products contained cocaine. Sigmund Freud originally believed that cocaine was an effective antidepressant. The ability of cocaine to produce rapid addiction eventually changed people’s minds about the safety of the drug.

temperature for a period of about three to six hours. In some cases, dehydration, exhaustion, hypothermia, hyponatremia (refer to Chapter 9), convulsions, and death occur (Rigg & Sharp, 2018). MDMA appears to produce increased sociability by stimulating the release of serotonin and the neurohormone oxytocin (Thompson et al., 2007; refer to Figure 4.27). MDMA influences serotonin, norepinephrine, and dopamine transporters in much the same way as we observed in the case of amphetamine. MDMA is taken up by transporters, causing them to reverse their action. Instead of removing monoamines from the synaptic gap, they are pumped into the gap, where they become trapped. In humans, MDMA has its strongest effects in serotonergic systems, but because it also increases dopamine activity, MDMA can produce dependency. Over time, MDMA reduces the function of serotonergic neurons, although researchers continue to debate whether these changes represent neural death or changes that can be reversed through abstinence (Gouzoulis-Mayfrank & Daumann, 2022). Despite concerns about its safety, researchers are exploring the use of MDMA for treating posttraumatic stress disorder, social anxiety in autism spectrum disorder, and anxiety associated with life-threatening illnesses (Mithoefer et al., 2016).

Opioids The term opioid is used to describe all substances that interact with endorphin receptors. The term opiate is restricted to substances derived from the sap of the opium poppy (Papaver somniferum), which include morphine and codeine. Heroin is synthesized from morphine. Opiates have legitimate medical purposes, including pain management, cough suppression, and the treatment of diarrhea. Before opiates became illegal in the United States around the time of World War I, many medicinal remedies, such as the opium-alcohol mix known as laudanum, were widely used by Americans in all walks of life. The United Nations estimates that about 62 million people worldwide use opioids today (World Health Organization [WHO], 2021; refer to Figure 4.28). At low doses, such as those typically used in medicine, opioids produce a sense of euphoria, pain relief, a lack of

opioid A substance that interacts with endorphin receptors. morphine A compound extracted from opium and used to treat pain. codeine An opium derivative used medicinally for cough suppression and pain relief. opiate An active substance derived from the opium poppy.

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Octopuses exposed to MDMA respond very similarly to humans (Edsinger & Dölen, 2018). After being immersed in a beaker containing a liquid form of MDMA, which they absorb through their gills, the normally not very social octopuses spent most of their time touching a cage containing another octopus with their tentacles and mouth parts. Like humans, the octopuses experienced MDMA effects on the serotonin transporter.

Opium is obtained from the opium poppy, Papaver somniferum. Afghanistan remains the world’s leading supplier of opium, where the crop makes up between 40 and 50 percent of the country’s gross domestic product.

anxiety, muscle relaxation, and sleep. The higher doses characteristic of abuse produce a tremendous euphoria or rush. The physical mechanism for this response is unclear. With even higher doses, opioids depress respiration, potentially leading to death. Pert et al. (1974) identified three metabotropic receptors, known as mu, delta, and kappa receptors, that bind with opioids. A fourth, opioid receptor like-1 (ORL 1), was discovered somewhat later. At about the same time, John Hughes, Hans Kosterlitz, and their colleagues (1975, 1977) identified neuropeptides produced within the body that activated receptors in the vas deferens of mice. The newly discovered neuropeptides were named endogenous morphines, shortened to endorphins. Two additional neuropeptides that interact with opioid receptors, enkephalins and dinorphin, were discovered shortly after. Endorphins interact preferentially with mu receptors, enkephalins with delta receptors, and dynorphin with kappa receptors. Most analgesic opioids, like morphine, show their strongest affinity for the mu receptor. Why would we have naturally occurring substances similar to opiates? These natural opioids probably help us escape emergency situations in spite of extreme pain. Opioids produce most of their effects by acting presynaptically to inhibit neurotransmitter release. They do so by inhibiting the entry of calcium into the presynaptic

AHMAD MASOOD/Reuters

Figure 4.28 Opium Is the Source of Several Psychoactive Substances

Khalil Ahmed/Shutterstock.com

Figure 4.27 MDMA Makes the Octopus More Social, Too

terminal (refer to Chapter 3), by enhancing the outward movement of potassium, which in turn shortens the duration of action potentials, and by interacting with normal enzyme cascades within neurons. Opioids are typically quite addictive, as one of the indirect consequences of their binding to opioid receptors is to increase dopamine activity. Opioids bind with mu receptors on cells that release GABA in the nucleus accumbens. This GABA typically inhibits the release of dopamine. Under the influence of the presynaptic inhibition produced by the opioids, however, these cells release less GABA, which in turn disinhibits the release of dopamine. Increased dopamine release in the nucleus accumbens, as we have observed with many other drugs, rapidly produces dependence. As presented in Figure 4.29, the United States is experiencing an unprecedented epidemic of opioid overdose deaths that began in the 1990s. The first of three waves in the epidemic resulted from the use of prescription opioids, including OxyContin. This was followed by a second wave consisting of heroin, probably due to a simultaneous restriction of prescription opioids and a reopening of opium poppy cultivation in Afghanistan. The third wave is resulting from synthetic opioids, primarily fentanyl. Fentanyl is 80–100 times more potent than morphine and is often added or substituted for heroin due to its reduced cost. Because the buyer on the street is unaware of what has been bought, overdoses are common.

Cannabis endorphin A naturally occurring neuropeptide that is very closely related to opiates. cannabis All products extracted from the Cannabis sativa or hemp plant.

Cannabis, from the Cannabis sativa or hemp plant, is another drug with a long human history. It was included in the pharmacy written by Chinese emperor Shen Neng nearly 5,000 years ago. Marco Polo’s writings documented

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Figure 4.29 Opioid Overdoses in the United States

Any Opioid

Other Synthetic Opioids (e.g., Tramadol or Fentanyl, prescribed or illicitly manufactured)

Wave 1: Rise in Prescription Opioid Overdose Deaths Started in 1999

Wave 2: Rise in Heroin Overdose Deaths Started in 2010

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Heroin Commonly Prescribed Opioids (Natural & semi-synthetic Opioids and Methadone)

2000

17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

1999

Deaths per 100,000 population

The current epidemic of opioid dependence and overdose shows three waves. The first resulted from the use of prescription pain medications, the second was due to heroin use, and the third is the result of synthetic opioids, such as fentanyl.

Wave 3: Rise in Synthetic Opioid Overdose Deaths Started in 2013

Source: https://www.cdc.gov/opioids/basics/epidemic.html

the rituals of the Hashashins, young men in the Middle East who used cannabis to prepare for war. The name of this group is the source of our English word, assassins. Cannabis first appeared in Europe when Napoleon’s soldiers brought it back to Paris from Egypt. Marijuana, which usually refers to the dried flowers, stems, leaves, or seeds of the Cannabis plant, came to the United States in the early 1900s. Marijuana experienced a huge increase in use during the 1960s and remains the most commonly used somewhat illegal substance in the United States today. As of 2022, marijuana remains illegal at the federal level, but recreational use is legal in 18 states and the District of Columbia. Medical use with a doctor’s recommendation is legal in 37 states. The behavioral effects of cannabis are often so subtle that many people report no changes at all in response to its use. Most individuals experience some excitation and mild euphoria, but others experience depression and social withdrawal. At higher doses, cannabis produces hallucinations, leading to its classification as a hallucinogen. Cannabis contains more than 50 psychoactive compounds, known as cannabinoids. Cannabinoids have been implicated in a wide variety of processes, including pain, appetite, learning, and movement. The most important of the cannabinoids in cannabis is tetrahydrocannabinol (THC). THC produces some of its behavioral effects by serving as an agonist at receptors for endogenous cannabinoids, substances produced within the body that are very similar to THC in chemical structure. Two types of cannabinoid

receptors have been identified, CB1 and CB2, that interact primarily with endogenous cannabinoids, anandamide and sn-2 arachidonylglycerol (2-AG), respectively (Devane et al., 1992; Stella et al., 1997). CB1 receptors are found in the basal ganglia, cerebellum, and cerebral cortex but are especially numerous in the hippocampus and prefrontal cortex. Anandamide’s main functions appear to be the removal of unwanted memories and slower movement, leading to relaxation. However, the effects of THC last much longer than the effects of anandamide. When THC binds to the CB1 receptors, changes in intracellular enzyme activity lead to less neurochemical release. This, in turn, produces an overall reduction in brain excitation. By inhibiting GABA release, however, THC actually disinhibits the release of dopamine in a process similar to the one we observed with opioids. Increased

marijuana The dried flowers, stems, leaves, or seeds of the Cannabis sativa plant; sometimes used interchangeably with cannabis. tetrahydrocannabinol (THC) The major psychoactive ingredient of cannabis. anandamide A naturally occurring chemical that interacts with CB1 cannabinoid receptors. sn-2 arachidonylglycerol (2-AG) A naturally occurring chemical that interacts with CB2 cannabinoid receptors.

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dopamine activity, of course, means that there is a risk of dependence associated with cannabis use. The presence of cannabinoid receptors in the hippocampus and prefrontal cortex might explain why THC appears to have negative effects on memory formation, attention, and working memory (refer to Chapter 12; Volkow et al., 2016). In addition to directly activating cannabinoid receptors in the hippocampus, THC might also adversely influence hippocampal activity and memory by inhibiting glutamate release (Colizzi et al., 2016). In a large longitudinal study, long-term users of cannabis lost an average of 5.5 IQ points between the ages of 18 and 45 and showed evidence of a reduction in hippocampal volume (Meier et al., 2022). Cannabis use and the development of psychosis are clearly related, but whether this relationship is causal is still under debate. Longitudinal studies show strong correlations between cannabis use in adolescence and the later development of psychosis (refer to Chapter 16; Volkow et al., 2016). As with all correlations, these data do not allow us to assume a causal relationship. As we observed in our discussion of nicotine use by people with severe psychological disorders, people might be self-medicating, or the same characteristics that lead to psychological disorders might also lead to cannabis use. However, researchers continue to argue for a causal role for early cannabis use in the development of later psychosis (Penzel et al., 2021). Because the adolescent brain is still developing, cannabis use at this point in time might have more impact than use by adults. Cannabis, compared to other drugs, might be uniquely related to psychosis. Patients with schizophrenia, even those who are cannabis-naïve, show abnormalities in their endogenous cannabinoid system (Ranganathan et al., 2016). Patients with schizophrenia who continue to use cannabis have worse outcomes than nonusers, as cannabis use might exacerbate structural changes in the brain due to schizophrenia.

Hallucinogens Hallucinogens are drugs that alter a person’s perceptions, thoughts, and feelings. The use of hallucinogens has a long history, primarily in the context of religious practice. Frequently used hallucinogens include LSD, psilocybin, mescaline, DMT, phencyclidine (PCP), and ketamine. LSD, psilocybin, mescaline, and DMT are “classic” hallucinogens, with the ability to disrupt serotonin signaling. PCP and ketamine are also known as dissociative hallucinogens because hallucinogens Drugs that alter a person’s perceptions, thoughts, and feelings; sometimes used interchangeably with psychedelic. lysergic acid diethylamide (LSD) A hallucinogenic drug that resembles serotonin. alcohol A substance that not only has its main effect as an agonist at the GABAA receptor but also stimulates dopaminergic pathways and antagonizes the NMDA glutamate receptor.

they can make people feel out of control or disconnected from their bodies or surroundings. Dissociative hallucinogens have their main effect on glutamate signaling. In 1938, the researcher Albert Hoffman reported some unusual sensations after absorbing the compound lysergic acid diethylamide (LSD) through his skin. LSD moved out of the laboratory and into the community after Timothy Leary and other investigators at Harvard University began experimenting with the drug. Hollywood embraced the new drug, and actor Cary Grant and others used LSD in psychotherapy (Regan, 2000). The glamour surrounding LSD didn’t last long. It became associated with the infamous killing rampages of Charles Manson and his followers. Timothy Leary was sent to jail, and LSD was classified as a Schedule I drug, having no known medicinal value. LSD produces tolerance but not withdrawal (Buchborn et al., 2015). It does not appear to cause addiction, although users might administer the drug habitually out of preference for the effects. LSD is chemically similar to serotonin and appears to act as an agonist at serotonergic autoreceptors in the prefrontal cortex, locus coeruleus, and the raphe nuclei (Litjens et al., 2014). LSD’s ability to produce hallucination is not well understood. However, animal research suggests that LSD interferes with the normal interaction between the hippocampus and the cortex. The result is hippocampal activity that is isolated from any external sensory input (Domenico et al., 2021). Perceptual distortions could easily result from these changes. A significant but uncommon negative consequence of LSD use is the experience of flashbacks in the form of intrusive and unwanted visual hallucinations, which can continue long after the person has stopped using the substance (Halpern & Pope, 2003). The experience of continued flashbacks is referred to as hallucinogen persisting perception disorder (HPPD). Because HPPD also occurs following use of a wide variety of hallucinogens having multiple modes of action, it is likely that the phenomenon does not have a single, simple cause (Martinotti et al., 2018). HPPD might result from damage to inhibitory cortical neurons that possess serotonergic receptors and release GABA. Loss of these cells might contribute to a reduction in the signal to noise ratio of the visual system, leading individuals to respond to signals that would normally be suppressed. At the same time, other researchers suggest that increased excitatory input to the primary visual cortex is sufficient to produce flashbacks (refer to Chapter 6). An imbalance between excitatory and inhibitory inputs to lower levels of the visual system might provide the best explanation for HPPD.

Alcohol Alcohol is one of the earliest drugs used by humans, dating back into our prehistory. Early humans possibly developed fermented drinks as a safety precaution against the ravages of contaminated water supplies.

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Neuroscience in Everyday Life Should Psychedelics Be Used in Therapy? The term psychedelic is often used interchangeably with hallucinogen but most often refers to LSD, psilocybin (from mushrooms), MDMA, DMT, and ketamine. Earlier, we classified MDMA as a stimulant rather than a hallucinogen, emphasizing the looseness of the psychedelic category. Prior to the 1970s, therapists experimented with these drugs to augment traditional therapies. When psychedelics were legally classified as Schedule 1 drugs, however, research regarding their use in therapy stalled (refer to Figure 4.30). In the late 1990s, the US government began to allow researchers to investigate the potential of psychedelics in therapy. The publication of a paper on the positive effects of a single dose of psilocybin prompted a burst of interest (Griffiths et al., 2006). Further research argued for the benefits of psilocybin in

helping smokers quit (Johnson et al., 2014), reassuring people with cancer (Griffiths et al., 2016), treating alcohol use disorder (Garcia-Romeu et al., 2019), treating depression (Davis et al., 2021), and treating posttraumatic stress disorder (PTSD; Davis et al., 2021). Barriers to further experimentation and use in therapy persist. Rescheduling some or all of these drugs to less restrictive legal categories would promote further investigation and eligibility for grant funds. Prior to widespread use, safety standards must be developed, and therapists would require training. The state of Oregon has taken a novel approach by training “facilitators” to administer psilocybin (Marks & Cohen, 2021). Further research is needed before we can determine whether psychedelics have a role to play in the treatment of psychological disorders.

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At lower doses, alcohol dilates blood vessels, providing a warm, flushed feeling. It reduces anxiety, promotes assertiveness, and reduces behavioral inhibitions, causing people’s behavior to be “silly” or “fun.” At higher doses, however, assertiveness becomes aggression, and disinhibition can lead to overtly risky behaviors. Motor coordination drops, leading to alcohol-induced carnage on streets and highways. At very high doses, coma and death can result from suppression of respiration or aspiration of vomit. Approximately 5.4 percent of Americans over the age of 12 meet the criteria for dependence, including tolerance, withdrawal, inability to stop drinking, and continued drinking in spite of significant problems (SAMHSA Center for Behavioral Health Statistics and Quality, 2020). Males are more likely to experience alcohol use disorder (AUD) than

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Figure 4.30 Interest in the Use of Psychedelics in Therapy Is Growing A search of the key terms “psychedelic therapy” shows strong growth after 2000. Barriers to further consideration of psychedelics in therapy include their legal status as Schedule 1 drugs and concerns about their safety.

females. AUD is moderately heritable, and GWAS methods have identified a number of genes related to the disorder (Kranzler et al., 2019). Alcohol initiates many changes to neurons, including epigenetic effects (Friedel et al., 2021). Membranes, ion channels, receptors, and enzymes are all affected. Alcohol binds directly to acetylcholine, serotonin, GABA, and NMDA glutamate receptors. Alcohol produces its main effects by acting as an agonist at the GABAA receptor, which normally produces neural inhibition. Alcohol’s antianxiety and sedative effects, which are not unlike those caused by the benzodiazepines, probably result from action at this site. Alcohol also stimulates dopaminergic pathways, which might explain the euphoric and addictive qualities of the drug. Alcohol’s antagonism at the NMDA glutamate

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especially at the GABAA receptor and the NMDA glutamate receptor. These changes can produce a dramatic and possibly life-threatLarge meta-analyses demonstrate that people who drink moderately ening withdrawal syndrome. The person will (about 20 grams of alcohol per day or about 1.4 servings) experience a experience sweating, nausea and vomiting, relatively lower risk of death than people who drink either no alcohol or sleeplessness, and anxiety. In some cases, halmore than 75 grams (about 5 servings) per day. The curve appears to be an artifact of the better health habits practiced by people who drink modlucinations and dangerous seizures occur. erately compared to abstainers and people who drink heavily. Alcohol has a number of detrimental effects on health. Chronic use of alcohol dam1.6 ages several areas of the brain, including the frontal lobes. Because alcoholics eat poorly, 1.4 alcoholism can lead indirectly to Korsakoff syndrome, in which the ability to form new memories is impaired. This condition is caused by 1.2 a lack of dietary thiamine (vitamin B1), which leads to damage to the hippocampus (refer to 1.0 Chapter 12). Alcohol can also have devastating effects on the developing fetus, which are 0.8 explained more fully in Chapter 5. Because the brain is still developing, adolescent binge drinking causes more damage than binge drinking in 0.6 0 25 50 75 100 125 150 adulthood, especially to the white matter of the Alcohol consumption (g/day) brain (McQueeny et al., 2009). The health benefits of alcohol are controSource: Adapted from Corrao et al. (2000). versial. As presented in Figure 4.31, a classic “j curve” shows that light to moderate alcohol consumption (about the same amount per day that raises the risk of breast cancer) is correlated with a reduced risk receptor might produce the characteristic memory probfor heart disease. However, further analysis shows that lems associated with alcohol. Opioid receptors in the amygpeople with light to moderate alcohol consumption also dala play essential roles in regulating alcohol intake (Bloodengage in more positive health-related behaviors, such as good et al., 2021). eating vegetables and maintaining a healthy weight, than Alcohol produces rapid tolerance. One source of tolerabstainers do. Statistically, the benefits of alcohol largely ance is an increase in the production of liver enzymes that disappear when lifestyle factors are controlled (Biddinger eliminate alcohol from the system. Another source of tolet al., 2022). erance is changes in receptor number and characteristics, Relative risk

Figure 4.31 Alcohol and Mortality

Thinking Ethically Drug Use Affects Future Generations Substance use disorders run in families and cannot be explained by an either/or approach to the question of heredity and environment. The usual techniques of analyzing twins and adopted children indicate a genetic influence on substance use disorders, but environmental influences are also well-supported by the data (Vassoler et al., 2014). Advances in our understanding of epigenetics, or changes in the way genes are expressed due to environmental factors, have led to possible explanations for these relationships. Somewhat more controversial is the idea of transgenerational heritability of epigenetic markers (refer to Chapter 5), although this is an active area of scientific investigation.

We are well aware that the use of many substances, even those that are quite benign in the adult, such as aspirin, can have catastrophic effects in the fetus. However, emerging evidence suggests that drug use by either parent long before conception can also impact offspring. At least in animal studies, alcohol, tobacco, cannabinoids, opiates, and cocaine used prior to conception by either parent influence fertility, anxiety, depression, and response to drugs in the offspring (Vassoler et al., 2014). Because the reproductive system is undergoing important changes during adolescence, cannabis use by youth between the ages of 15 and 17 years was associated with a six-time larger risk of preterm birth or (continued)

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Thinking Ethically Drug Use Affects Future Generations (Continued) low birth weight for the eventual children of these teens (Hines et al., 2021). It might seem frustrating to think that your own fertility, anxiety, depression, response to drugs, or risk of being born prematurely or with low birth weight might be the result of somebody else’s choices rather than your own. Realizing that choices made well in advance of becoming a parent, not just during a pregnancy, might impact your children in very real ways

is also somewhat uncomfortable. Even more disturbing is evidence that transgenerational transmission might not stop at one generation. Your choices might have the potential to influence many generations of your family in the future, just as you might be feeling the influence of choices made by ancestors who died before you were even born. Will further evidence along these lines change the way we think about our health habits?

profound pain relief and, in some forms, a remarkable sense of euphoria. (LO7)

Interim Summary 4.3 Summary Points 4.3 1. Drugs have very different effects depending on their mode of administration. Gender, size, and genetics influence individual differences in responses to drugs. (LO6)

4. The THC in cannabis is similar to endogenous cannabinoids and produces a mild euphoria and relaxation. Some users experience hallucinations. Hallucinogens, including LSD, produce altered perceptions, thoughts, and feelings. (LO7)

2. Placebo effects occur when inactive substances appear to produce behavioral and cognitive effects. Nocebo effects are adverse effects produced by an inactive substance. The continued use of some drugs can produce tolerance, withdrawal, and addiction. (LO6)

5. Alcohol interacts with the GABAA receptor, where it boosts the inhibition normally provided by GABA and antagonizes the NMDA glutamate receptor. (LO7)

3. Stimulant drugs increase alertness and mobility. This class includes caffeine, nicotine, cocaine, amphetamine, and ecstasy (MDMA). Opioids produce

1. What are the variables that influence individual responses to drugs?

Review Questions 4.3

2. Which drugs reverse the action of transporters?

Summary Table 4.3: Some Commonly Used Drugs and Their Effects Drug

Behavioral Effects

Mode of Action

Caffeine

Arousal; less need for sleep; reduces headache

Blocks adenosine receptor sites

Nicotine

Alertness; muscular relaxation

Stimulates nicotinic ACh receptors

Cocaine

Euphoria; excitement

Reuptake inhibitor for dopamine

Amphetamine

Alertness; appetite suppression; “rush”

Stimulates release of dopamine and norepinephrine; also a reuptake inhibitor for these neurochemicals

Ecstasy (MDMA)

Excitement; endurance; increased intimacy

Stimulates release of serotonin and oxytocin

Opioids

Pain reduction; euphoria; relaxation

Stimulate opioid receptors

Marijuana (cannabinoids)

Hallucination; vivid sensory experience; distortion of time and space; mild euphoria

Stimulates cannabinoid receptors

LSD

Hallucination

Unknown effects on serotonergic and noradrenergic systems

Alcohol

Reduced anxiety; mild euphoria; loss of motor coordination

Stimulates GABAA receptors; acts as an antagonist at the NMDA glutamate receptor; stimulates dopaminergic systems

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Chapter Review Thought Questions 1. Amino acids, due to their simplicity and ready availability, probably served as the original chemical messengers. What advantages might have led to the evolution of more complex types of chemical messengers? 2. With further advances in our understanding of the human genome, we may be able to identify individuals with higher vulnerability to addiction to particular drugs. What ethical issues would face a society that had this ability? What policies, if any, would you recommend? 3. Which commonly used recreational drug do you think is the safest? The most dangerous? State your reasons.

Key Terms acetylcholine (ACh) (p. 106) acetylcholinesterase (AChE) (p. 107) addiction (p. 123) adenosine (p. 114) agonist (p. 117) alcohol (p. 132) amphetamine (p. 128) antagonist (p. 117) barbiturate (p. 119) benzodiazepine (p. 119) caffeine (p. 126) cannabis (p. 130) catecholamine (p. 108) cocaine (p. 128) dopamine (p. 108) double-blind experiment (p. 122)

ecstasy (MDMA) (p. 128) endorphin (p. 130) epinephrine (p. 108) gamma-aminobutyric acid (GABA) (p. 111) gasotransmitter (p. 105) glutamate (p. 111) glycine (p. 111) hallucinogen (p. 132) histamine (p. 110) indoleamine (p. 108) lysergic acid diethylamide (LSD) (p. 132) melatonin (p. 110) mesolimbic pathway (p. 109) mesostriatal pathway or nigrostriatal pathway (p. 109) mesocortical pathway (p. 109) methamphetamine (p. 117) monoamine (p. 108) monoamine oxidase (MAO) (p. 108) neurohormone (p. 104) neuromodulator (p. 104) neuropeptide (p. 105) neurotransmitter (p. 104) nicotine (p. 127) nitric oxide (NO) (p. 115) nocebo (p. 122) norepinephrine (p. 108) opiate (p. 129) opioid (p. 129) placebo effect (p. 122) psychoactive drug (p. 125) reuptake inhibitor (p. 119) serotonin (p. 110) small molecule (p. 105) tetrahydrocannabinol (THC) (p. 131) tolerance (p. 122) withdrawal (p. 123)

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Chapter 5 Learning Objectives L01

Discuss the role of genes as the building blocks of human “nature,” distinguishing between genotypes, gene expression, and phenotypes.

L02

Review the main sources of genetic diversity.

L03

L04

Assess the importance of heritability and epigenetics to our understanding of the interactions between genetics and environment. Explain the processes of neurogenesis, migration, differentiation, apoptosis, synaptogenesis, and myelination.

L05

Analyze the importance of critical periods of development.

L06

Summarize the features and causes of developmental disorders affecting neural growth.

L07

Describe the changes in the nervous system that accompany healthy aging.

Genetics and the Development of the Human Brain Chapter Outline The Genetic Bases of Behavior

From Genome to Trait Sources of Genetic Variability Heritability Epigenetics

Interim Summary 5.1 Building a Brain

Prenatal Development Effects of Experience on Development

Disorders of Early Nervous System Development Interim Summary 5.2 The Brain Across the Life Span

Brain Changes From Adolescence to Adulthood The Healthy Adult Brain Adult Neurogenesis

Interim Summary 5.3 Chapter Review

Connecting to Research: Epigenetics, Gene Expression, and Stress Behavioral Neuroscience Goes to Work: Genetics Counseling Thinking Ethically: When Are Adolescents Responsible for Their Actions? Neuroscience in Everyday Life: The Epigenetic Effects of Diet on the Nervous System 137

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Chapter 5

Genetics and the Development of the Human Brain

The Genetic Bases of Behavior

Figure 5.1 Nature and Nurture Interact When pregnant mice are fed a diet containing bisphenol-A or BPA, commonly found in plastics and food cans, they are more likely to give birth to obese offspring with yellow fur. It is likely that BPA affects the expression of the Agouti gene to produce these results. This situation illustrates the interaction between our nature (genetics) and our nurture (what we experience, or in this case, eat).

There are about 19,000 protein-encoding genes in the human genome, although scientists are still debating the actual number (Salzberg, 2018). It is somewhat humbling to consider that yeast cells have about 6,000 genes, flies have about 13,000, and plants have 26,000. However, the number of actual genes is only part of the story. You have the same DNA in each of the 100 trillion cells in your body, with the exception of red blood cells and sperm and egg cells. How does any single cell know how to become a muscle fiber in your heart or a neuron or a skin cell? The answer is that genes can be turned on or off. Genes that are turned on are “expressed” or free to produce the proteins needed to build a particular type of cell. Each cell may contain the instructions for an entire human organism, but only about 10 to 20 percent of the genes in a particular type of cell are active. Gene expression in a neuron is going to be quite different than gene expression in a muscle cell. The rate of gene expression in the brain is one of the factors that distinguishes humans from other creatures. Human gene expression in the blood and in the liver is basically the same as in the chimpanzee, but human gene expression in the brain is much higher (Khaitovich et al., 2004). Genes turn on and off at precise points of time during development, but your ongoing interactions with the environment (what you eat, whether or not you smoke or drink, how much stress you experience) also influence the way your genes behave. This is why neuroscientists no longer argue about nature versus nurture. Instead, we view nature and nurture as intimately intertwining influences on the human body and mind (refer to Figure 5.1).

From Genome to Trait Each cell of the body contains two complete copies of the human genome, a set of instructions for constructing a human being. Your personal set of genetic instructions is your genotype, which interacts with environmental

genotype The genetic composition of an individual organism. phenotype The observable appearance of an individual organism. gene A functional hereditary unit made up of DNA that occupies a fixed location on a chromosome. gene expression The translation of the genotype into the phenotype of an organism. allele Alternative version of a particular gene.

© Randy L. Jirtle, Ph.D., Jirtle Laboratory at Duke University

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influences to produce your phenotype, or your observable characteristics. Your genotype might include one gene variant, or allele, for attached earlobes and one for free earlobes, while your phenotypical earlobes are free. Your genotype consists of 23 matched pairs of chromosomes. One chromosome of each pair was donated by your mother via her egg and the other by your father via his sperm. The chromosomes are made up of molecules of deoxyribonucleic acid (DNA). Smaller segments of chromosomal DNA form individual genes. Genes are constructed from combinations of four biochemicals known as bases or nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T). Each gene contains instructions for making a particular type of protein. Gene expression occurs when these genetic instructions are converted into a feature of a living cell. Figure 5.2 illustrates how sequences of bases in DNA are translated into proteins. A strand of DNA produces a copy of itself on a strand of ribonucleic acid (RNA). The bases along the DNA and RNA strands occur in groups of three, known as codons. Each codon provides instructions for the production of one of 20 amino acids, which are joined by ribosomes to form a chain. When complete, the chain folds into a shape based on its amino acid sequence and is now officially a protein. Different phenotypical traits result from the interactions between alternative versions of a particular gene, known as alleles. With two sets of chromosomes, an individual can have, at most, two versions of a gene. However,

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Figure 5.2 The Process of Gene Expression A strand of DNA transcribes itself into a complementary chain of RNA. Each set of three bases (a codon) instructs a ribosome to make a particular amino acid: in this example, alanine (Ala; GCC), methionine (Met; AUG), valine (Val; GUA), and lysine (Lys; AAA). The amino acids are linked together to form a protein. A

1 Transcription DNA partially unwinds and a strand of complementary RNA is made.

T

A

A A

G

C

A

G

C G G

T C T A A

C

A

G

T

RNA

G C

C G

C G

DNA

2 Translation RNA instructs ribosomes to produce amino acids.

T

G

C

C

A

A T

U

G

G

A T C C U A G G

U A

U

A

A

A

Codon

Codon

Codon

Codon

Ala

Met

Val

Lys

A

A

T

T A T

A

3 Completed protein

many more than two versions of a gene can exist within a population. Hundreds of alleles occur in the tumor suppression genes BRCA1 and BRCA2, but only a small percentage of these increase a woman’s risk of breast or ovarian cancer (refer to Figure 5.3). If a person has two identical alleles at a given site, the individual is considered to be homozygous for that gene. If a person has two different alleles, such as one for type A blood and one for type O, the individual will be considered heterozygous for that gene. A recessive allele will produce its phenotype only when it occurs in a homozygous pair. The allele for having no freckles is recessive, which means that the only way a person can have the no freckle phenotype is if a no freckle allele is inherited from each parent. A dominant allele produces a phenotypical trait regardless of whether its pair is homozygous or heterozygous.

Some genes show partial rather than complete dominance. In complete dominance, the phenotype of the heterozygote will be indistinguishable from the phenotype of one of the homozygotes. In partial dominance, the phenotype of the heterozygote will fall somewhere between

homozygous Having two identical alleles for a given gene. heterozygous Having two different alleles for a given gene. recessive allele A gene that will produce its characteristic phenotype only when it occurs in a homozygous pair. dominant allele A gene that produces its phenotype regardless of whether it occurs in a heterozygous or homozygous pair. partial dominance A situation in which the phenotype of the heterozygote will fall somewhere between the phenotypes of the two homozygote parents.

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Figure 5.3 Genes Can Have Many Alleles Some genes have a large number of alleles. Of the more than 500 alleles for BRCA1 (Breast Cancer 1), a small number are associated with an elevated risk of reproductive cancers. Actress Angelina Jolie, who possesses the highrisk alleles, chose to undergo a preventive mastectomy to reduce her chances of developing cancer.

Other genes feature codominance, which means that the phenotypes of both parents appear in an offspring. As presented in Figure 5.4, there are three different alleles for blood type (A, B, and O) that give rise to four blood types: type A (AA or AO), type B (BB or BO), type AB (AB), or type O (OO). The A and B alleles code for proteins found on the surface of red blood cells, while the O allele codes for no such proteins. A person receiving an A allele from one parent and a B from the other will have an AB genotype and blood cells featuring both proteins. Approximately 1 percent of mammals’ genes are imprinted, which means that only one allele of a pair is expressed. The identity of the expressed gene depends on which parent supplied the allele. In other words, only the father’s version is expressed in the case of some genes and only the mother’s in others. Expression of imprinted genes appears to be especially prevalent in the brain (Kopsida et al., 2011), and imprinted genes have been implicated in the development of autism spectrum disorder (ASD; Li et al., 2020; refer to Chapter 16).

Featureflash Photo Agency/Shutterstock.com

Sources of Genetic Variability

the phenotypes of the two homozygote parents. The serotonin transporter gene (SERT) has two alleles, long (L) and short (S). The SERT gene features partial dominance, so on behavioral measures such as a person’s emotional response to frequent bullying, people with the SL genotype fall midway between measures for people with the homozygous SS and LL genotypes (Sugden et al., 2010). If either the long or short version of SERT demonstrated complete dominance, individuals with the SL genotype would behave similarly to those with the homozygous dominant alleles. codominance A situation in which phenotypes of both parents appear in the offspring. imprinted gene Only one allele is expressed, either the father’s or the mother’s allele. meiosis Cell division that reduces the number of chromosomes in half in the reproductive cells.

Egg and sperm cells are formed through the process of meiosis. In meiosis, depicted in Figure 5.5, the parental chromosome pairs are divided in half, leaving only one chromosome from each pair in an egg or sperm cell. When the egg and sperm cells from the two parents combine, the resulting zygote once again contains the full complement of 23 pairs of chromosomes. Mathematically, the process of meiosis is analogous to shuffling a deck of cards. A meiotic division results in two egg or sperm cells, each containing one set of 23 chromosomes. As a result, a single human can produce eggs or sperm with 223 (8,388,608) combinations of their chromosomes. Add this to the diversity provided by the other parent, and you can understand why your brothers and sisters have some, but by no means all, features in common

Figure 5.4 Three Alleles Give Rise to Four Types of Blood The type A and type B alleles are dominant over type O, so a person with AO alleles will have type A blood and a person with BO alleles will have type B blood. Neither type A nor type B is dominant over the other, however, leading to the possibility of having type AB blood. AB blood type is an example of codominance, in which the phenotypes of both parents, A and B, can occur together. Genotype AA or AO BB or BO OO AB

Phenotype Type A Blood Type B Blood Type O Blood Type AB Blood

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The Genetic Bases of Behavior

Figure 5.5 Cell Division by Meiosis Sperm and egg cells are produced through meiosis. 1 Here is one of the 23 pairs of chromosomes found in body cells.

2 The chromosomes replicate themselves.

3 The cell now divides, with one pair of chromosomes in each daughter cell.

4 These cells divide a second time into sperm or egg cells, each containing only one chromosome rather than a pair.

with you. Genes that are physically located close to one another on the same chromosome are often passed along to offspring as a group in a process known as linkage. However, linked genes are not automatically inherited together. In the process of crossing over, depicted in Figure 5.6, chromosomes lining up prior to meiotic division physically cross one another and exchange equivalent sections of genetic material. This results in unique combinations of alleles not found in either parent. Mutations In the process of chromosome replication, errors, or mutations, happen. Human beings experience a very low rate of mutation, the equivalent of one base pair (a basic DNA building block such as cytosine linked to guanine) out of 30 million (Dolgin, 2009; Xue et al., 2009). This number is far lower than the rate of mutation found in chimpanzees and gorillas (Harris & Pritchard, 2017). The vast majority of mutations have little effect. There is some overlap in the genetic encoding of amino acids. If a segment of DNA that normally encodes a particular amino acid is somehow switched with another segment that produces the same amino acid, there will be no effect. Mutations might occur in segments of DNA linkage The characteristic of genes located adjacent to one another to be passed along as a group. crossing over A process occurring during meiosis in which chromosomes exchange equivalent segments of DNA. mutation A heritable alteration of genes.

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that do not appear to influence phenotypical traits, or a mutation might result in a recessive allele. Inheriting a dominant mutant allele or two copies of a recessive mutant allele will affect an organism’s phenotype. If the mutant allele conveys some advantage to the organism, it is likely to spread within the population. On the other hand, a mutant allele may have negative, even fatal, consequences for the organism. In the latter case, it will probably disappear from the population. The Special Case of the Sex Chromosomes In discussions of genetics, the word “sex” is used to refer to an organism’s underlying sex chromosome genotype. This is distinct from the use of the word “gender,” which encompasses psychosocial factors. Female sex is typically associated with an XX genotype, while male sex is typically associated

Figure 5.6 Crossing Over Contributes to Genetic Diversity The process of crossing over, in which two chromosomes exchange equivalent segments of genetic material, adds to diversity by shuffling the parental genes that are inherited together. 1 At the beginning of meiosis, paired chromosomes line up with each other.

2 Each chromosome replicates itself.

3 The chromosomes cross over.

4 The chromosomes exchange equivalent sections of genetic material.

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with an XY genotype, although we will discuss variations to these patterns in Chapter 10. Twenty-two pairs of human chromosomes are perfectly matched, but the remaining pair, the X and Y chromosomes, feature different sets of genes with only a small number of overlaps. Most of the approximately 70 active genes on the Y chromosome are involved with male fertility, although some support male viability in general (Bellott et al., 2014). The much larger X chromosome contains between 900 and 1,500 active genes (refer to Figure 5.7). Genes that do overlap between the sex chromosomes often perform differently based on whether they occur on the X or Y. The amelogenin gene appears on both the X and Y chromosomes and contributes to tooth enamel. It is often used by forensic experts to determine the sex of a genetic sample because its size is dependent on whether it is located on the X or Y chromosome (Akane, 1998). sex-linked characteristic Phenotypical characteristics that result from the expression of genes on the X chromosome that are not duplicated on the Y chromosome. X chromosome inactivation The process by which one X chromosome in each female cell is silenced to equalize the amount of proteins produced by males and females.

Sex-linked characteristics result from genes on the X chromosome that are not duplicated on the Y chromosome. For example, a recessive allele resulting in the blood clotting disorder hemophilia and alleles resulting in some forms of red-green color deficiency are located on the X chromosome. On chromosomes other than the X and Y, one would typically need two copies of a recessive allele or only one copy of a dominant allele to produce the trait in the organism. In the case of genes occurring on the X chromosome, however, a single recessive allele influences the phenotype when there is no corresponding gene on the Y chromosome. For this reason, organisms with an XY genotype experience many more sex-linked disorders than organisms with an XX genotype, who are likely to have a compensating dominant allele on their second X chromosome (refer to Figure 5.8). The lack of matching pairs for most genes on the sex chromosomes has led to a phenomenon known as X chromosome inactivation. Because many genes on the X chromosome are not duplicated on the Y chromosome, having two X chromosomes would result in double the amounts of some proteins compared to having one X and one Y chromosome. To compensate for this imbalance in organisms with an XX genotype, most of the genes

Figure 5.7 The X and Y Chromosomes Are Not a Matched Pair

Biophoto Associates/Science Source

Biophoto Associates/Science Source

The X chromosome (right) resembles most of the other 22 in appearance, but the Y (left) is quite unusual. Not only is it much smaller, with about 70 active genes compared with the X’s 900 to 1,500 or so, but it also has unusually high amounts of “junk” DNA that doesn’t seem to encode anything useful.

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The Genetic Bases of Behavior

Figure 5.9 X Chromosome Inactivation Inactivation of most of the genes on one X chromosome takes place randomly in the cells of females. Because the alleles for black and orange fur in cats exist at the same location on the X chromosome, a male cat will be either black or orange but not calico. The calico coloring of the female cat, like the author’s Coco, results from inactivation of the alleles for orange and black fur in different cells.

Courtesy of Laura Freberg

on one X chromosome in each cell are silenced. The actual identity of the silenced X chromosome genes (mother’s or father’s copy) varies from cell to cell, and a small percentage escape silencing altogether. An interesting example of this random X chromosome inactivation process is found in the coloring of calico cats (refer to Figure 5.9). Only female cats can be calicos because the alleles for orange or black fur are located at the same location on the X chromosome. A male cat could have only orange or only black fur, but not both, because he has only one X chromosome. A female cat with an orange allele on one X and a black allele on the other X will be a calico. In each cell, the fur-color alleles on one X chromosome will be silenced. In cells with a silenced orange allele, the fur will be black. In cells with a silenced black allele, the fur will be orange. As a result, the cat will have a random pattern of orange and black fur. On average, X inactivation should result in expressing 50 percent of X chromosome alleles from the father and 50 percent from the mother, but the exact ratio varies and forms an approximately normal curve for the population. Extreme skewing, in which 90 percent or more of expressed X chromosome alleles originate with one parent, has been associated with a number of diseases. This might account for sex differences in the rates of diagnosis of certain conditions, including autoimmune diseases (Brooks, 2016). Single Nucleotide Polymorphisms (SNPs) Genetics researchers are particularly interested in alleles whose

Figure 5.8 Probabilities of Hemophilia Hemophilia is a sex-linked condition in which blood fails to clot. If a mother carries the hemophilia allele on one of her X chromosomes (XH) and the father has a typical X chromosome, each daughter will have a 50 percent chance of being typical and a 50 percent chance of being a carrier of the hemophilia allele. The couple’s sons have a 50 percent chance of having hemophilia. Without a healthy X to counteract the X carrying the hemophilia allele, sons will have the condition if they inherit the hemophilia allele from their mothers.

XHX Mother

XHX

XX

XHY

XY

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genetic code differs in only one location. These variations are known as single nucleotide polymorphisms, or SNPs (pronounced “snips”). A SNP occurs when a sequence of nucleotides making up one allele differs from the sequence of another at just one point, such as AAGGTTA to ATGGTTA. For example, the apoliproprotein E (APOE) gene on chromosome 19 produces a protein that combines with fats to form lipoproteins. Lipoproteins package cholesterol and other fats and carry them through the bloodstream. There are three alleles for the APOE gene, known as ε2, ε3, and ε4. Each APOE allele has 299 codons, or sets of three nucleotides. As demonstrated in Figure 5.10, the 112th codon on this string encodes cystine in the ε2 and ε3 alleles but arginine in the ε4 alleles. The 158th codon encodes arginine in ε3 and ε4 but cystine in ε2. These are tiny differences when compared to the volume of DNA in our bodies, yet they have great significance in the development of conditions such as Alzheimer disease, a degenerative and ultimately fatal illness marked initially by memory loss, which is discussed in Chapter 15. Alzheimer disease is more likely to

XY Father single nucleotide polymorphism (SNP) Variation between alleles involving a single base.

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Figure 5.10 SNPs and Disease Single nucleotide polymorphisms (SNPs) occur when one allele differs from others by only a single nucleotide. Tiny variations in the APOE gene have dramatic consequences for a person’s susceptibility to Alzheimer disease. The APOE gene is located on chromosome 19.

The three alleles of the APOE gene differ at only two of the total 299 codons.

may or may not include one or more genes and can result from insertions, deletions, or duplications of segments of DNA. CNV regions encompass about 12 percent of the human genome (Redon et al., 2006). CNVs can arise spontaneously (“de novo”) or be inherited from a parent. Huntington disease, discussed in Chapter 8, is a heritable condition caused by excess repeats of DNA segments in the huntingtin gene. Copy number variations have been implicated in a number of psychological disorders, including autism spectrum disorder, schizophrenia, intellectual disability, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, obsessive compulsive disorder (OCD), and depression (Rees & Kirov, 2021).

Heritability

Codon 112

Codon 158

Allele

Amino acid encoded by codon 112

Allele

Amino acid encoded by codon 158

2

Cys

2

Cys

3

Cys

3

Arg

4

Arg

4

Arg

A person with two copies of the APOE  4 allele has a 91 percent chance of developing Alzheimer disease; average age at onset is 68 years.

occur in individuals with two ε4 alleles than in individuals with one or two of the ε2 or ε3 alleles (Huang et al., 2011). Copy-Number Variations (CNVs) Copy-number variations (CNVs), depicted in Figure 5.11, occur when the number of copies of a segment of DNA differs from individual to individual (Joober & Boksa, 2009). CNVs copy-number variation (CNV) Variation resulting from insertions, duplications, or deletions of sections of DNA.

As noted in Chapter 1, heritability describes how much variation in a trait occurs in a population due to genetic differences. This is a concept that is frequently misunderstood. Heritability always refers to populations, not to individuals. If genes play no part in producing phenotypical differences between individuals, heritability is zero. For example, genes are responsible for building hearts, but there is no variation in the population in terms of the presence of a heart—we all have one. Therefore, heritability for having a heart is zero. In contrast, heritability for Huntington disease is 100 percent. If you inherit a defective allele from one parent (the defective allele is unfortunately dominant), you will develop the condition. Heritability of most human traits typically falls between these extremes, in the range of 30 to 60 percent. If we say that the heritability of ASD traits (refer to Chapter 16) is about 57 percent (Hoekstra et al., 2007), this does not mean that 57 percent of a single individual’s ASD traits are due to genetics and 43 percent are due to the individual’s environment. Instead, these findings mean that 57 percent of the variation we find in ASD traits in a population can be accounted for by genetic differences. Heritability cannot be assessed without taking the environment into account, which is another source of confusion. If the environment is constant (everybody is treated exactly the same way), the heritability of a trait will be exaggerated. For example, childhood growth is influenced by milk consumption (Guo et al., 2020). If you limited your study of height to a population of children either from communities with consistently high milk consumption, such as Sweden, or to those with consistently low milk consumption, such as China, heritability will look too high. With environmental variables like milk consumption held at a fairly constant level, a sizable percentage of the differences in height you observe is likely to result from heredity. In samples of children from communities with a range of milk consumption, such as the United States, the environments vary more widely; thus, heritability of height in these samples would be lower. Researchers assessing heritability of human traits attempt to do so within a “typical” range of environments,

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Figure 5.11 Copy Number Variations (CNVs) CNVs occur when the number of copies of a segment of DNA differs from individual to individual. The copies might or might not include complete genes. CNVs have been implicated in a number of conditions, including Huntington disease. Number of repeats

Maternal Chromosome

3

Individual 1 Paternal Chromosome

3 Repeated segment

Maternal Chromosome

5

Individual 2 Paternal Chromosome

1

Maternal Chromosome Individual 3

3

Paternal Chromosome

5

Source: https://www.genome.gov/genetics-glossary/Copy-Number-Variation

as in the previously cited work on ASD traits (Hoekstra et al., 2007). Studies comparing identical, or monozygotic, and fraternal, or dizygotic, twins raised together or raised apart by adoptive parents have been used to assess the relative contributions of heredity and environment. Monozygotic (MZ) twins share the same genes, and dizygotic (DZ) twins share the same number of genes (about 50 percent) as ordinary siblings. All twins, however, share a similar environment, both before and after birth, while ordinary siblings who are born at different times experience greater variations in their environments. The Minnesota Study of Twins Reared Apart (MISTRA; Bouchard et al., 1990) was a classic, long-term study of twins. According to the researchers, the pairs of identical twins in the study were quite similar, regardless of whether they were raised together. Some traits were highly correlated between identical twins, such as the number of ridges in a fingerprint. Other traits showed relatively low correlations, such as nonreligious social attitudes (e.g., political beliefs). The critical finding was that identical twins raised either apart or together were similar, whether the correlation for a particular trait was high or low. Twin studies, however, are not without methodological flaws and weak assumptions. MZ twins are treated more similarly than DZ twins are (Joseph, 2022), which weakens the assumption that all twins share an environment similarly. Due to screening, adoptive parents rarely represent as much diversity as the biological parents whose children they adopt. If all adoptive families provide a consistent environment, this could inflate the apparent heritability of characteristics examined in adopted children.

Epigenetics Epi is Greek for “over” or “above,” so epigenetics refers to the development of potentially heritable traits due to changes in gene expression that do not involve changes in the underlying DNA. In other words, a phenotype can change without a corresponding change in genotype. Expression of a gene can be turned on or off in response to internal factors (hormones and other chemical signals) or external factors (diet or toxins). Epigenetic change is greatest in the fetus and diminishes with age. Some epigenetic changes are reversible, while others might last a lifetime. In particular, the epigenetic effects of early trauma or maltreatment predict physical and mental health throughout the lifespan (Parade et al., 2021). Processes that produce changes in gene expression include histone modification, DNA methylation, and gene silencing by non-coding RNA (refer to Figure 5.12). The DNA in each of your cells is tightly wound around protein structures known as histones. If the DNA were unwound, it would be nearly 4 feet in length (Grant, 2001). Histones have a core and a tail, both of which can epigenetics The reversible development of traits by factors that determine how genes perform. histone modification Changes in the structure of histones that make it more or less likely that a segment of DNA will be transcribed. DNA methylation Addition of a methyl group to a DNA molecule turns off the gene. gene silencing by non-coding RNA Regulation of gene expression by segments of RNA that are not translated into protein.

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Figure 5.12 DNA Methylation and Histone Modification DNA methylation and histone modification are two major sources of epigenetic change. (a) When a methyl group is added to the DNA molecule, it essentially makes the DNA inaccessible, rendering the gene inactive. (b) When epigenetic tags interact with the histone structure as presented in the two boxes, nearby DNA may be more or less likely to be transcribed.

Methyl group Epigenetic factor

Chromosome

DNA

(a) DNA methylation Histone e tail ta a ail Hi Histo tone modification dification ti (b) Histone Histone His Hi istto one e tail t il

Gene G e

DN A ac ibl gene active ti DNA accessible, Histone Hi H iston ne

DNA DN NA inac inacc ina inaccessible, acce ac esssi e sible ib e e,, ge gene gene ina inactive active a activ vve

be modified in ways that affect how a segment of DNA is transcribed. Some modifications make it more likely that a sequence of DNA will be transcribed, while other modifications essentially silence a section of DNA. DNA methylation occurs when a methyl group is added to the DNA molecule. Genes that are methylated can no longer be read, like pages of a book that have been stapled together. This process performs essential roles in cell differentiation and embryonic development, described in more detail later in this chapter. Abnormal DNA methylation is believed to contribute to a number of diseases. For example, the methylation of tumor suppression genes promotes the spread of cancer. Gene silencing can also occur due to the normal actions of non-coding ribonucleic acid (RNA) either before or after transcription. As was presented earlier in Figure 5.2, transcription refers to the copying of information from a segment of DNA onto a segment of messenger RNA interference (RNAi) Inhibition of gene expression by noncoding RNA molecules that disable messenger RNA.

RNA. Messenger RNA carries the transcribed instructions to ribosomes (refer to Chapter 3), where the instructions are used to produce specific proteins. Not all molecules of RNA carry out this “coding” task, however. Non-coding RNAs are molecules of RNA that are not translated into a protein. In the process of transcriptional gene silencing (TGS), non-coding RNAs have the ability to initiate epigenetic changes, usually in the form of DNA methylation, prior to transcription (Weinberg & Morris, 2016). Other small, non-coding RNA molecules participate in a post-transcription process known as RNA interference, or RNAi (refer to Figure 5.13). These molecules keep cells from making unwanted proteins, including those introduced by viruses, by disabling messenger RNA (mRNA). Because the job of mRNA is to carry instructions to ribosomes, disabling the messenger will prevent the ribosomes from producing the protein. Unlike changes made due to RNAi, epigenetic modifications due to TGS can be passed on to daughter cells during cell division. A further understanding of gene silencing could lead to effective treatments for many diseases, including Huntington disease (refer to Chapter 8).

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The Genetic Bases of Behavior

Figure 5.13 The Search for Very Purple Petunias While trying to develop a super-purple petunia, plant scientists inserted additional copies of a gene encoding for a protein known to contribute to pigmentation of the flower’s petals. Much to their surprise, the over-expressed gene did not produce dark purple flowers at all, but rather flowers ranging from pure to partially white. The added gene activated RNA interference (RNAi), a process that usually silences unwanted genes such as those from viruses, resulting in the silencing of the pigmentation gene.

Source: (From left to right): Jan Kooter; Natalie Doetsch; Rich Jorgensen

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Several interesting examples of epigenetic change have been demonstrated. As we observed in Figure 5.1, a gene called Agouti produces yellow fur and obesity in mice when it is turned on, but brown fur and normal weight when it is turned off (Dolinoy et al., 2007). Mother mice fed a diet containing bisphenol-A, or BPA (a common chemical found in food and beverage containers) produced more obese pups with yellow fur, suggesting that BPA exposure could turn on the Agouti gene. As will be discussed in more detail in a later section, infant rats that are licked by their mothers (the rat equivalent of a hug) were calmer in the face of later stress than rats that were not licked frequently (Champagne et al., 2003). By licking her pups, the mother rat changes the expression of genes related to the function of stress hormones. Scientists are intrigued by the possibility that some epigenetic changes might be passed to later generations. Transgenerational epigenetic inheritance has been demonstrated in plants and worms (Fitz-James & Cavalli, 2022; Heard & Martienssen, 2014). For this to be possible in mammals, however, typical reprogramming, or the removal of epigenetic tags, must be bypassed. Reprogramming is

Connecting to Research Epigenetics, Gene Expression, and Stress One of the more dramatic demonstrations of the effects of epigenetics on later behavior was the work by Francis et al. (1999) on maternal nurture and stress responses in offspring. Rat mothers differ in the amount of time they spend licking and grooming their pups, the rat version of a hug from mom. Do these differences in maternal nurture impact the later behavior of their offspring? The Question: What are the epigenetic effects of differing levels of maternal nurture on responses to stress by offspring?

Methods To explore the effects of differences in nurture on the later behavior of offspring, Francis et al. (1999) cross-fostered some of the pups to different types of mothers. In other words, they were able to compare the behavior of pups raised by their own biological mothers or by a similar type of mother with the behavior of pups raised by a mother whose nurturant style differed from their own biological mother.

Results Tolerance for stress can be easily assessed in rodents by open-field tests. Stressed rodents will not stay out in the open as long as a less-stressed rodent. All pups

raised by an attentive mother (high licking and grooming) explored the open space longer than pups raised by an inattentive mother (low licking and grooming) no matter what type of biological mother they had. Increased time spent in the open field is related to the expression of glucocorticoid receptors in the hippocampus. Glucocorticoids, such as cortisol (refer to Chapters 11 and 14), are released in response to stress and help mobilize the body for emergency responses. Higher glucocorticoid receptor gene expression is correlated with resilience to stress later in life. As presented in Figure 5.14, pups born to attentive mothers show greater expression of glucocorticoid receptors in the hippocampus (more resilience to stress) than pups born to low attentive mothers. However, Francis et al. (1999) were able to elicit more attentiveness from the normally less attentive mothers by handling their pups. When the handled pups are returned to the mother, she licks and grooms them more. Handling had no effect on the gene expression of pups with attentive mothers, but it had a significant effect on the pups of low attentive mothers. The levels of glucocorticoid receptor gene expression in the hippocampus of handled pups of normally low attentive mothers could not be distinguished from that of the pups of attentive mothers. (continued)

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Connecting to Research Epigenetics, Gene Expression, and Stress (Continued) Maternal origin

Figure 5.14 Nurture Affects Gene Expression The pups of nurturant (high) mothers showed elevated levels of glucocorticoid receptors (GR; shown in red) in the hippocampus regardless of whether they were handled (H) or not handled (NH). However, pups of non-nurturant (low) mothers showed nearly normal levels of gene expression when handled, but reduced levels when not handled.

GR mRNA

Eric Isselee/Shutterstock.com

High-NH

High-H

Low-NH

Low-H Source: Adapted from Francis et al. (1999).

Conclusions Maternal licking and grooming of pups stimulated epigenetic processes, which in turn resulted in greater gene expression related to glucocorticoid receptors and greater tolerance to stress. In relatively safe circumstances, resistance to stress is probably adaptive, as

especially robust during the production of germ cells (precursors to sperm and egg cells) and in the development of the zygote (discussed further in the next section). Support for human transgenerational epigenetic transmission is controversial at best. In a large-scale

chronic stress is linked to a host of negative outcomes (refer to Chapter 14). However, in an unsafe environment (and that’s probably the norm for rodents), the less attentive mothers might be doing their pups a favor by making them more sensitive to stress. After all, the “open field” is where a rodent is most likely to meet my cat.

Swedish study, early paternal smoking was associated with higher body weight in sons. The paternal grandfathers’ diet in mid-childhood predicted grandsons’ mortality, while the paternal grandmothers’ food supply predicted the mortality of granddaughters (Pembrey

Behavioral Neuroscience Goes to Work Genetics Counseling Genetics testing giant 23andMe provides subscribers with information relevant to a variety of pathological conditions, including a person’s APOE ε4 status. You are not told if you have one or two copies, just whether you have an allele associated with Alzheimer disease. What is the average person expected to do with that information? Run out and purchase a long-term care insurance policy? Ignore it and live your life? Although healthcare providers do their best to clarify such situations, there are times when we need the assistance of a professional who combines knowledge of the science of genetics with counseling expertise. Genetics counselors, most of whom have master’s degrees and are affiliated with medical practices, assist people making

diverse types of decisions based on genetic information. Genetics counselors usually specialize in pregnancy planning for those with a family history of disease, advising those whose fetus appears to have a genetic disorder, assisting parents with caring for a child with a genetic disorder, or counseling people with genetic risk factors for conditions such as cancer or dementia. Our rapidly increasing knowledge of genetics is stimulating a growing need for genetics counselors. If you like both the science and the idea of being in one of the helping professions, you might consider investigating one of the graduate genetics counseling programs accredited by the American Board of Genetics Counselors (American Board of Genetics Counseling [ABGC], 2022).

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The Genetic Bases of Behavior

et al., 2005). It is clear that nutrition and exposure to toxins in the fetus and child can influence later development, but transgenerational epigenetic change is not the only explanation for such effects. It is possible that instead of passing along specific epigenetic tags, exposure to factors that produce epigenetic changes in the parents might produce a more global epigenetic instability in the offspring (Blake & Watson, 2016). Interpreting possible transgenerational effects is further complicated by the challenging task of controlling confounding variables, such as nutrition after birth. Further research using emerging technologies should help us understand these processes more fully.

Interim Summary 5.1 Summary Points 5.1 1. The human genome contains two copies of 23 chromosomes made up of DNA. DNA sequences,

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or genes, provide instructions for producing proteins. Alternative versions of a gene, or alleles, can be dominant or recessive. (LO1) 2. Genetic diversity is assured by meiosis, linkage, crossing over, and mutations. (LO2) 3. Heritability provides an estimate of the amount of variability in a trait across a population determined by genetics. Epigenetics refers to reversible changes in gene expression. (LO3) Review Questions 5.1 1. What are the implications of differences between the sex chromosomes and the other 22 pairs of chromosomes? 2. How do heredity and environmental factors interact to produce the phenotype of an individual?

Summary Table 5.1: Important Concepts in Genetics Concept

Definition

Significance

Genome

The complete set of chromosomes for a species

Identifies the characteristics that define a species. Example: The entire human genome.

Genotype

An individual’s set of chromosomes

Identifies the genetic basis for individual characteristics. Example: Having one allele for Type A blood and a second allele for Type O blood.

Phenotype

The observable characteristics of an individual

Identifies the end result of the interactions between genes and environment. Example: Having hazel eyes or being 6 feet tall.

Chromosome

Bodies found within the nuclei of cells that are made up of DNA

Twenty-three pairs of chromosomes make up the entire human genome. Example: The X and Y sex chromosomes.

Gene

A functional hereditary unit occupying a fixed location on a chromosome

Genes are responsible for the production of particular proteins. Example: Genes for blood type or for the production of dopamine receptors.

Allele

Alternative versions of a particular gene

Trait variations between individuals in a species. Example: The A, B, and O alleles for blood type.

Meiosis

Cell division that reduces the number of chromosomes to half in reproductive cells

Meiosis creates a vast number of possible genetic combinations. Example: A single human can produce eggs or sperm with 223 (more than 8 million) combinations of his or her chromosomes.

Mutation

A change in a gene or chromosome that can be passed to offspring

Results of mutations can be advantageous, neutral, or disadvantageous. Example: A mutation causes the disease cystic fibrosis, which causes premature death.

SNPs (“snips”)

Variations that occur in a gene when a single base is changed from one allele to the next

SNPs can be a major source of variation between individuals of a species. Example: APOE alleles ε2, ε3, and ε4 that affect a person’s chances of developing Alzheimer disease.

Copy-Number Variations (CNVs)

The number of copies of a segment of DNA differs from individual to individual

CNVs can make the difference between a healthy genotype and an unhealthy one. Example: Abnormal huntingtin genes, having more than 36 CAG codons producing the amino acid glutamine, produce Huntington disease. People with fewer repeats remain healthy.

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Building a Brain Beginning with the merger of a mother’s egg and a father’s sperm and the complex interactions of the genes they contain, we grow adult human bodies containing approximately 100 trillion cells. About 86 billion of those cells will be found in the brain, with another 1 billion ending up in the spinal cord. Although the process of development does not always proceed smoothly, we still enjoy a remarkable record of accuracy, considering the enormous complexity of the organism we are building.

Prenatal Development The initial cell formed by the merger of egg and sperm is known as a zygote. From gestational week two to eight, the developing individual is known as an embryo. From gestational week eight until birth, the individual is a fetus. At the end of gestational week one, about the time it arrives at the uterus, the human zygote has already formed three differentiated bands of cells known as germ layers. The outer layer is the ectoderm, which will develop into the nervous system, skin, and hair. The middle layer is the mesoderm, which forms connective tissue, muscles, blood vessels, bone, and the urogenital systems. The final layer is the endoderm, which will develop into many of the internal organs, including the stomach and intestines. zygote The cell formed by two merged reproductive cells. embryo In humans, the developing individual between the second and eighth week after conception. fetus The developing organism between the embryonic stage and birth. ectoderm The germ layer that develops into the nervous system, skin, and hair. mesoderm The germ layer that develops into connective tissue, muscle, blood vessels, bone, and the urogenital systems. endoderm The germ layer that develops into internal organs, including the stomach and intestines. neural plate A layer formed by differentiating neural cells within the ectoderm of the embryo. neural tube A structure formed by the embryonic neural plate that will develop into the brain and spinal cord. prosencephalon One of three early divisions of the neural tube that will develop into the forebrain. mesencephalon One of three early divisions of the neural tube that will develop into the midbrain. rhombencephalon One of the early three divisions of the neural tube that will develop into the hindbrain. diencephalon A division of the prosencephalon that will contain the thalamus, hypothalamus, and retina of the eye. telencephalon A division of the prosencephalon that develops into the bulk of the cerebral hemispheres. myelencephalon A division of the rhombencephalon that develops into the medulla. metencephalon A division of the rhombencephalon that develops into the pons and cerebellum. neurogenesis The birth of new neurons and glia.

From the second week through the ninth month of gestation, the human nervous system transforms from a thin layer of relatively undifferentiated cells into a complex system that can process sensory input and organize movements (Monk et al., 2001). Gestational weeks three and four are especially important for human nervous system development. During gestational week three, cells in the ectoderm located along the dorsal midline of the embryo begin to differentiate into a new layer known as the neural plate. Remaining cells in the ectoderm will form the skin. As the ectodermal cells begin to differentiate, a groove or depression forms along the midline of the neural plate. Further cell divisions produce two ridges of tissue on either side of the groove that eventually join to form the neural tube. This process is complete by gestational day 28. The interior of the neural tube will be retained in the adult brain as the system of ventricles and the central canal of the spinal cord (as discussed in Chapter 2). The surrounding neural tissue will form the brain and spinal cord. Adjacent to the neural tube are neural crest cells, which give rise to the peripheral nervous system. Before the neural tube has even finished closing, it develops three bulges, the prosencephalon (future forebrain), the mesencephalon (future midbrain), and the rhombencephalon (future hindbrain). As displayed in Figure 5.15, the neural tube bends twice, once at the junction of the rhombencephalon and what will be the spinal cord (this bend straightens out later) and again in the area of the mesencephalon. In the following week, the prosencephalon further differentiates into the diencephalon (thalamus, hypothalamus, and retina of the eye) and the telencephalon (remainder of the cerebral hemispheres). Around the same time, the rhombencephalon divides into the myelencephalon (medulla) and the metencephalon (pons and cerebellum). The mesencephalon does not undergo any further divisions. The development of the nervous system proceeds in a series of six distinct stages: 1. neurogenesis, or the continued birth of neurons and glia; 2. migration of cells to their eventual locations in the nervous system; 3. differentiation of neurons into distinctive types; 4. formation of connections between neurons; 5. death of particular neurons; and 6. rearrangement of neural connections. Neurogenesis Neurogenesis refers to the birth of new neurons and glia. Bipolar neuroepithelial cells arising from the ectoderm span the neural tube from the lining of the ventricle (the ventricular zone) to the developing pia mater (Martínez-Cerdeño & Noctor, 2018). These progenitor (reproducing) cells divide by mitosis, producing two identical “daughter” cells. Both daughter cells remain in the ventricular zone and continue to divide. After the closure of the neural tube in gestational week four, the neuroepithelial cells begin to transition into

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Building a Brain

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Figure 5.15 The Neural Tube Divides (a) Before neural tube closure is complete at the end of gestational week four, three bulges are apparent: the prosencephalon (forebrain), the mesencephalon (midbrain), and the rhombencephalon (hindbrain). (b) In the following week, the prosencephalon divides once more to form the telencephalon and diencephalon, while the rhombencephalon divides to form the myelencephalon and metencephalon. The mesencephalon does not make an additional division.

Telencephalon Rhombencephalon

Prosencephalon Metencephalon Diencephalon

Myelencephalon

Spinal cord

Mesencephalon

Diencephalon (a) Telencephalon Prosencephalon

Rhombencephalon

Metencephalon Myelencephalon (b)

radial glia, which have the ability to develop into neurons or glia. The radial glia, which maintain the bipolar structure of the neuroepithelial cells, continue to divide symmetrically. After gestational week seven, some radial glia in the ventricular zone begin to produce a daughter cell that remains in the zone and a daughter cell that is destined to migrate outward to the adjacent subventricular zone. In the subventricular zone, the now migrated daughter cell divides symmetrically to produce a pair of daughter neurons or glial cells. As presented in Figure 5.16, radial glia producing two additional, identical daughter cells divide along a cleavage line that lies perpendicular to the surface of the ventricular zone. In contrast, radial glia that produce a migrating daughter cell divide along a cleavage line that is parallel to the ventricular zone surface. The parallel cleavage line means that the daughter cell to the outside will not be attached to the ventricular zone once the division is complete. This cell will be free to migrate. The identical daughter cells are symmetrical, meaning they contain similar content after division. In contrast, a division producing a migrating cell results in asymmetry, as the contents of the two daughter cells are not equal following division. In humans, a period of rapid neural cell proliferation takes place between the second and fifth gestational months. Up to 250,000 new neurons per minute might be born at the peak of this rapid cell proliferation process.

These neurons are still somewhat immature, consisting of a cell body and a process that will become an axon later in development. Proliferation slows somewhat after the fifth gestational month, but with the exception of small amounts of later adult neurogenesis, the vast majority of neurons have been formed by the time an infant is a few months old. Many conditions, including certain genetic disorders, maternal alcohol use, and excess vitamin A, can produce microcephaly, or an unusually small brain, by interfering with neurogenesis and neural proliferation. Viral infections, including cytomegalovirus, toxoplasmosis, and Zika (discussed further in Chapter 15), can lead to microcephaly by destroying progenitor cells. Cell Migration Migration of newborn neurons covers significant distances and typically does not occur in a random manner. Disorganized migration has been implicated in a number of disorders, including epilepsy, dyslexia, autism spectrum disorder, and schizophrenia (Miyazaki et al., 2016). radial glia Special glial cells that radiate from the ventricular layer to the outer edge of the cerebral cortex, which continue to produce new daughter cells and serve as a pathway for migrating neurons. migration The movement of cells to their mature location.

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Figure 5.16 Neurogenesis Up until about gestational week seven, daughter cells in the ventricular zone divide along lines that are perpendicular to the zone, producing additional progenitor cells. Subsequently, some daughter cells divide along lines that are parallel to the ventricular zone, forming cells that will migrate away from the zone. Human embryo at 7 weeks Forebrain

Midbrain

Hindbrain

Spinal cord Ventricle

Daughter cell will become a progenitor cell.

Ventricle

Migration proceeds in two main directions, as presented in Figure 5.17. First, neurons can migrate radially toward the pia mater. These neurons tend to release glutamate and thus are excitatory in effect (Hwang et al., 2019). Secondly, neurons can migrate in a tangential manner (Rahimi-Balaei et al., 2018). These neurons are likely to release GABA with inhibitory results. Some neurons switch their mode of migration repeatedly, referred to as a “random walk.” Migrating neurons feature a leading process or branch and a trailing process. The leading process of the cell points in the direction of movement and interacts with its environment, including the radial glia and attractant chemicals. As the leading process reaches forward, the cell body and the nucleus within it are pulled along. Eventually, the cell loses its trailing process. Migrating cells form the cerebral cortex in an insideout fashion. Cells arising from the same groups of progenitor cells in the ventricular zone form organized columns in the cortex. We will discuss examples of these types of cortical columns in Chapter 6. Cells destined for the outer cortical layers must travel through the inner layers. In other words, a cell migrating to Layer IV of the cortex must bypass Layers VI and V en route to its final

Daughter cell will migrate.

Dividing cells

Figure 5.17 Radial Glia Guide the Migration of New Cells About two-thirds of the new cells formed in the ventricular layer migrate along radial glia, which are distributed like spokes in a wheel. These cells are likely to differentiate into excitatory neurons. The remaining third migrate horizontally without apparent need for radial glia. These cells are likely to differentiate into inhibitory neurons. Pia mater

Radial migration

Migrating excitatory neuron Raidal glia cell

Ventricular surface

Migrating inhibitory neuron

Tangential migration

Source: Hwang, H. M., Ku, R. Y., & Hashimoto-Torii, K. (2019). Prenatal Environment That Affects Neuronal Migration. Frontiers in Cell and Developmental Biology, 7. doi:10.3389/fcell.2019.00138

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Building a Brain

destination (refer to Chapter 2). The journey of early migrating cells lasts just a few hours. In contrast, cells migrating to the outermost layers of the cerebral cortex face a journey of up to two weeks. Due to the timing of this migration pattern, cells forming a layer in the cortex are approximately the same age. Prior to the 22nd week of gestation, the volume of radial migration pathways is much larger on the left hemisphere than on the right and in the posterior parts of the brain compared to the anterior parts (Miyazaki et al., 2016). The tangential pathways do not show these localized differences. As migration concludes, the radial glia begin to retract their processes. Some retain the ability to divide, which has important implications for adult neurogenesis, discussed later in the chapter. Differentiation Pluripotent precursor cells, characteristic of the zygote and embryo, can develop into any type of body cell. Neurogenesis produces multipotent precursor cells, or cells that have the ability to develop into a subset of cell types, including neurons and glia. Differentiation, or the development of more specialized cell types from precursor cells, results from the action of extracellular signaling factors on gene expression. These extracellular factors take many forms, but neurogenin-2 (NGN2) seems to play a particularly important role in differentiating cells into specific types of neurons, such as dopaminergic neurons or motor neurons (Hulme et al., 2022). NGN2 allows researchers to develop functional neurons in the laboratory for use in the study of neurodevelopment, diseases, drug screening, and neural replacement therapies. Earlier, we saw how some cells in the ectoderm differentiated to form the neural plate while others differentiated into skin cells. The neural tube experiences two additional types of differentiation. The first process differentiates the dorsal and ventral halves of the neural tube. The second process differentiates the neural tube along its rostral-caudal axis. In response to various extracellular factors, neurons in the ventral half of the neural tube develop into motor neurons, and neurons in the dorsal half of develop into sensory neurons. Recall from our discussion of neuroanatomy in Chapter 2 that the ventral roots of the spinal cord carry motor information to muscles and glands, and the dorsal roots carry sensory information back toward the central nervous system (CNS). This ventral-motor/dorsal-sensory organization extends up through the hindbrain and midbrain. For example, we find the superior and inferior colliculi, which participate in the senses of vision and hearing, respectively, on the dorsal surface of the midbrain, while the substantia nigra, which plays a significant role in movement, is located in the ventral half of the midbrain. This organization does not, however, describe the location of sensory and motor areas of the forebrain.

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The second differentiation process occurs along the rostral-caudal axis of the neural tube, resulting in the division of the nervous system into the spinal cord, hindbrain, midbrain, and forebrain. In a fashion similar to the ventral-dorsal differentiation, extracellular factors stimulate gene expression along the length of the tube (Brambach et al., 2021). Growth of Axons and Dendrites Once the neurons are in place, they must form working connections with each other. This step begins around the tenth week of gestation with the development of processes or branches known as neurites. These processes will mature to become axons and dendrites. Figure 5.18 demonstrates how neurites end in growth cones, or swellings. The growth cones have both sensory and motor abilities that help the neurite find the right pathway. Growth cones have three basic structural parts: 1. a main body containing mitochondria, microtubules, and other organelles; 2. filopodia, or long, spiky extensions differentiation The development of precursor cells into more specific types of cells. neurite An immature projection from a neuron. growth cone The swelling at the tip of a growing axon or dendrite that helps the branch reach its synaptic target. filopodia Long, fingerlike extensions from a growth cone.

Figure 5.18 Growth Cones Guide Neurites to Their Targets Growth cones interact with the extracellular environment, guiding the growth of a neurite to the target cell. Filopodia are the fingerlike extensions from the growth cone and lamellipodia appear as webbing or veils between the filopodia. Microtubules provide structure as the neurite extends.

Source: https://www.mechanobio.info/cytoskeleton-dynamics/what -is-axon-guidance-and-the-growth-cone/. Image provided courtesy of the Mechanobiology Institute, National University of Singapore”

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from the core; and 3. lamellipodia, fan-shaped extensions from the core located between the filopodia. The filopodia and lamellipodia are capable of movement, expanding and contracting as they sample the surrounding environment. They also have the ability to stick to structural elements of the extracellular environment, pulling the growing neurites along behind them. Microtubules from the main body of the cone move forward as the cone extends, forming a new segment of the neurite. As demonstrated in Figure 5.19, filopodia can signal the growth cone to move forward, move backward, or turn in a particular direction. The filopodia respond to both attracting and inhibiting chemicals released by guidepost cells along the way. Guidepost cells are glia that release chemicals that either attract or repel an approaching lamellipodia Flat, sheetlike extensions from the core of a growth cone.

growth cone (Colón-Ramos & Shen, 2008). A dramatic example of this process can be observed in the growth of visual axons near the optic chiasm. In humans, the half of the visual axons closest to the nose cross the midline at the optic chiasm and continue contralaterally, while the half from the outer portion of each retina remain on the same side of the midline, proceeding ipsilaterally. When dye was applied to the retina and the course of the dyed axons to the optic chiasm was charted, the growing axons appeared to respond to a group of guidepost cells located at the midline of the optic chiasm (Godement et al., 1994). The contralateral axons made contact and passed these guidepost cells, but the ipsilateral axons appeared to be repelled by these cells. Neurites that are growing in the same direction often stick together in a process known as fasciculation. Molecules on the surfaces of the neurites, known as cell adhesion molecules (CAMs), cause the neurites to stick together as they proceed in the same direction. As the

Figure 5.19 Growth Cones Respond to a Variety of Cues To reach their eventual targets, growth cones respond to the extracellular environment by (a) sticking to the surfaces of other cells, (b) sticking to other neurites traveling in the same direction, (c) growing toward chemical attractants, and (d) being repulsed by chemicals.

Growth cone

Target cell

Target cell Neurite adheres to the surface of certain cells.

Neurite adheres to nearby axons.

Neurite (a)

(b) Guidepost cells release chemicals, which repulse the growth cone.

Target cell Guidepost cells release chemicals, which attract the growth cone.

(c)

New synapses form on target cell.

(d)

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Building a Brain

Figure 5.20 Abnormalities in Synaptogenesis Underlie Many Neurocognitive Disorders Compared to healthy controls, individuals with schizophrenia show fewer dendritic spines and presynaptic terminals. In individuals with autism spectrum disorder (ASD), dendritic spine density is increased, and immature synapses are common.

Schizophrenia

ASD

Control

synaptic specificity The process by which a neurite identifies appropriate postsynaptic target cells from the many cells in the vicinity. apoptosis Programmed cell death.

Figure 5.21 Steps in the Formation of a Synapse Complex chemical communication occurs as a growth cone approaches its target postsynaptic cell. (a) The incoming growth cone approaches a dendrite. (b) Synaptic vesicles are produced and transported to the connection site. (c) The synaptic vesicles are docked in place and the active zone, from which they will be released, is established. On the postsynaptic side, a dendritic spine is formed, and postsynaptic receptors are inserted in the membrane. A Axon Synaptic vesicles Active zone

Dendrite

Microtubules Actin Postsynaptic density

B

Postsynaptic proteins Postsynaptic receptors

C

Synaptic development

Formation of Synapses The adult human brain features more than 100 trillion (1014) synapses (ColónRamos & Shen, 2008). Any errors in the formation of these synapses during development can have profound effects on the ability of the nervous system to function. For example, errors in synapse formation are implicated in intellectual disability, schizophrenia, and ASD (Wang et al., 2018; refer to Figure 5.20). To complete the process of wiring the nervous system, the incoming neurite first identifies appropriate postsynaptic targets out of the many cells in the vicinity, a process known as synaptic specificity. Complex chemical interactions between incoming neurites and potential postsynaptic partners allow the cells to recognize one another and determine whether a relationship is warranted (Sanes & Zipursky, 2020). Once an appropriate partner has been identified, the synaptic structure must be assembled (refer to Figure 5.21). Special cell adhesion molecules (CAMs) bridge the gap between the two neurons. Materials needed at the synapse must be synthesized in the cell body and transported to the appropriate locations in axons and dendrites. On the presynaptic side of the synapse, these materials include precursors for synaptic vesicles and

structural components of the active release zone, or the site of exocytosis (described in Chapter 3). On the postsynaptic side of the synapse, receptor proteins are required. Once the precursor materials arrive at the right location, their further movement must be stopped, and they must be locked in place. In the CNS, astrocytes play important roles in synapse formation (Chung et al., 2015). Astrocytes release chemicals that increase the number of synapses formed by a neuron. Cells in culture lacking astrocytes grow neurites but make few functional synapses. Cell Death Following migration, as many as 40 to 75 percent of cells die in a process known as apoptosis, which is a

Source: Habela et al. (2016).

growth cones approach their target, they begin to form either dendrites or axon collaterals (review Chapter 3). Now that the branches are in the correct general area, experience will interact with intrinsic factors to fine-tune the new connections.

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D

Source: Dickens, E. M., & Salinas, P. (2013). Wnts in action: From synapse formation to synaptic maintenance. Frontiers in Cellular Neuroscience, 7. doi:10.3389/fncel.2013.00162

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Percent Max

type of programmed cell death. The term apoptosis comes higher in children with ASD than in healthy controls (Qin from the Greek word for “falling leaves.” Apoptosis can be et al., 2016). Higher than normal levels of neurotrophins distinguished from necrosis, or the death of a cell due to indicate too little apoptosis. injury or pathology. Compared to necrosis, apoptosis is a highly controlled process in which the cell membrane is Synapse Elimination Not only do we appear to lose not compromised. In necrosis, the cell membrane genlarge numbers of neurons during the course of developerally bursts, spilling cell contents into the surrounding ment, we also seem to lose large numbers of synapses as tissue and producing inflammation. well. Just as the brain initially overproduces neurons, folApoptosis is a general biological phenomenon, lowed by a refinement in their numbers through apoptoresponsible for a wide range of processes from the loss of a sis, we experience a burst of synaptic growth followed by tadpole’s tail as it turns into a frog to the separation of the a period of synapse elimination, also known as synaptic endometrium from the uterus at the start of a menstrual pruning. In synapse elimination, the number of functional period. Apoptosis during neurodevelopment was investisynapses is reduced. gated by Hamburger (1975), who observed that nearly half Synapses are added at an accelerated pace from the of the spinal motor neurons produced by chick embryos fifth gestational month through the first year of infancy. died before the birds hatched. Cohen et al. (1954) were The increased number of synapses is one of the factors able to isolate a substance they called nerve growth factor contributing to the rapid growth of brain size during (NGF) that seemed to regulate this process. Advancing infancy. Beginning around the age of one year, synapses neurites absorb NGF released by target cells. Target cells begin to experience elimination. Between this time and produce limited quantities of NGF, for which advancing adulthood, approximately one-half of all synapses will be neurites compete. Neurons that fail to receive adequate culled (Südhof, 2018). As presented in Figure 5.22, the amounts of NGF experience apoptosis, while neurons that absorb NGF are spared. NGF is now known as one member of a class of chemicals called neurotrophins. Neurotrophins influence the survival of a neuron neurotrophin Substance released by target cells that contributes to by interrupting cellular suicide programs that culminate the survival of presynaptic neurons. in apoptosis. All cells appear to contain cell death genes. synaptic elimination The process in which functional synapses are maintained and nonfunctional synapses degenerate; also When activated by cell death genes, enzymes known as known as synaptic pruning. caspases break up DNA and proteins, which quickly leads to cell death. When neurotrophic factors bind to receptors on a neuron, caspase Figure 5.22 Synaptic Rearrangement Over the Life Span activity is inhibited, and the In the human visual cortex (solid blue line), the number of synapses peaks at the age of four cell survives. Failure to obtain to eight months and decreases until the age of four years. The number of synapses in the sufficient stimulation from visual cortex remains relatively stable in adulthood. The number of synapses in the prefrontal neurotrophins will result cortex (dotted orange line) peaks around the age of one year, drops until about age 20, and in the expression of the cell then remains stable over the remainder of the life span. death genes and the activa100 tion of caspases, and the cell Visual cortex will die. Prefrontal cortex 90 Apoptosis serves cru80 cial functions as the nervous 70 system develops. You can think about the developing 60 nervous system as similar to 50 a beautiful marble statue. The 40 sculptor begins with a big slab of marble (the mass of 30 cells produced in neurogene20 sis) and patiently chips away to reveal the beautiful shape 10 within (the adult brain). Too 0 many surviving cells (too 0 2 4 6 8 10 1 2 4 6 8 10 20 30 40 50 60 70 80 much marble) might result in Months Years problems. Peripheral blood Source: Adapted from Huttenlocher (1994). levels of neurotrophins were

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Building a Brain

time course of synapse elimination differs between areas of the brain. Synapse elimination is not just part of brain development. It is a lifetime process required by the need to update circuits. In the hippocampus, nearly 100 percent of dendritic spines are replaced every two weeks (Attardo et al., 2015). We have noted previously that competition for neurotrophins determines which neurons survive and which die. It is likely that a similar competition determines which synapses are retained. The nervous system clearly operates according to a “use it or lose it” philosophy. Changeux and Danchin (1976) first suggested that only those synapses that participate in functional neural networks are maintained. A functional neural network is one in which the activity of presynaptic neurons reliably influences the activity of postsynaptic neurons. Astrocytes appear to play significant roles in the regulation of synapse elimination in the CNS. They can act directly as phagocytes, engulfing and absorbing unwanted synapses. They also act indirectly by releasing chemicals that increase the production of signaling factors used to “tag” synapses for elimination. Tagged synapses are digested by microglia (refer to Chapter 3). It is possible that distortions of this process take place in neurodegenerative diseases, such as Alzheimer disease, which is characterized by excessive synapse elimination (refer to Chapter 15).

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the time of birth, but the process is by no means complete at such an early age (refer to Figure 5.23). Myelination in the PNS is typically mature around the age of two years. The last area to be myelinated is the prefrontal cortex, which is responsible for some of our most sophisticated cognitive functions. Myelination of the prefrontal cortex continues well into the third decade of life (Williamson & Lyons, 2018). As discussed later in this chapter, the immaturity of the prefrontal cortex in adolescents relative to adults might explain some of their risky and impulsive decision-making.

Effects of Experience on Development Ongoing adjustments to our neural wiring occur as a result of the strengthening or weakening of existing synapses due to experience. Without this flexibility, or plasticity, it is unlikely that we would be able to learn and store new memories. In general, synapses are strengthened when the pre- and postsynaptic neurons are simultaneously active and weakened when their activity is not synchronized. The importance of correlated activity in strengthening synapses was first suggested in the 1940s by Donald Hebb (refer to Chapter 12). As a result, synapses strengthened by simultaneous activity are often referred to as Hebb synapses. Synapses are not only strengthened by activity, but they might also be removed due to lack of activity. As we observed earlier, synapses that are not part of functional circuits are tagged for elimination. In Chapter 12, we will learn how maintaining functional synapses requires ongoing work on the part of neurons. Plasticity is not constant over the lifespan. Early in development, the brain demonstrates a high degree of plasticity. With maturity, circuits become more stable and

Myelination Myelination of the developing nervous system proceeds in an orderly manner starting in the PNS and progressing to the spinal cord, hindbrain, midbrain, and forebrain. Sensory pathways are myelinated first, followed by motor then association pathways. Within the forebrain, myelination proceeds simultaneously from inferior to superior and from posterior to anterior. Deeper structures, such as the basal ganglia, are myelinated before plasticity Ability to adjust neural wiring. more surface structures, such as the cerebral cortex. Myelin in the CNS has early roots in gestational week eight, when some radial glia begin to form oligoFigure 5.23 Human Myelination Continues Into dendrocyte precursor cells (OPCs). Adulthood These cells are produced throughout Although myelination is extensive early in life, the process of myelination is not life but at greater rates prior to the complete in humans until the mid-20s. These diffusion tensor images (DTI) indicate age of 50 years, at which time progreater organization of white matter pathways resulting from myelination. The color duction slows (Fletcher et al., 2021). scale indicates the degree of organization in the fiber pathways. OPCs give rise to pre-myelinating oligodendrocytes. Only about 20 percent of these go on to form myelin, while the rest die (Williamson & Lyons, 2018). Myelination in the PNS begins between gestational weeks 12 and 18. In the CNS, myelination begins around gestational month four. Like many animals, human beings expeSource: Tau & Peterson (2010). rience a burst of myelination around Copyright 2024 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

Chapter 5

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less subject to change. This stability is positive in the sense that it leads to the retention and automation of important functions, but it has the downside of limiting the potential to change in response to new data. You can indeed teach an old dog new tricks, but not always as readily as you can teach a puppy. Critical Periods Exposure to certain types of input can have greater effects at one point in time compared to either previous or subsequent periods. If appropriate input is not provided at just the right time, the resulting deficits can be difficult to remedy. We refer to a window of increased plasticity as a critical period. Among the functions that demonstrate critical periods are sensory systems, language learning, and music learning. Critical periods for development have endpoints. Lorenz (1952) found that imprinting in baby geese, or their willingness to follow a parent, would occur during the first two days of life but not at later ages. Owners of new puppies are encouraged to expose their pups to a variety of people and situations before the age of 16 weeks (refer to Figure 5.24). Very few people who learn a second language after puberty will be able to pass as native speakers. Several processes might account for critical periods. Both the opening and closing of a critical period are dependent on the maturity of circuits supporting GABA inhibition (Cisneros-Franco et al., 2020). At the outset of a critical period, GABA inhibition is weak, resulting in an excess of excitation that promotes rapid learning. As the window begins to close, “plasticity brakes,” which include the maturation of inhibitory GABA systems, lead to the stability of circuits characteristic of adulthood. Growth spurts in myelin have been observed in parts of the human brain involved with language and spatial relations between the ages of 6 and 13 (Thompson et al., 2000). The conclusion of this growth period coincides with reduced abilities to speak additional languages without a foreign accent. Not all aspects of language share the same critical periods. Genie, the famous child discovered at age 13 who could not speak due to lack of exposure to language, was able to acquire vocabulary at an accelerated pace compared to typically developing children (Fromkin et al., 1974). However, her acquisition of the basic rules of grammar remained poor. Finally, epigenetic mechanisms might regulate critical periods. The development of ocular dominance, discussed in more detail below, is known to have a critical critical period A period of time during development in which experience is influential and after which experience has little to no effect. imprinting The process in which baby animals learn to follow their mother that usually coincides with the baby’s mobility.

Figure 5.24 Critical Periods Plasticity is not equal across the lifespan. Critical periods occur when experience has a greater effect at some points in development than at others. Dogs, like this service dog in training, should be exposed to a wide variety of environments and stimuli prior to the age of 16 weeks for optimum adjustment.

© Pete Markham/Wikimedia Commons

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period. Experience following the end of the critical period does not change the way the visual cortex responds to input from each eye. Histone modification appears to be regulated differently before and after the time of critical period closure, and the application of enzymes that actively modify histones “re-opens” the ocular dominance cells to change (Tognini et al., 2016). Similarly, enhancing the activity of certain neurotrophins appears to return the brain into a more plastic state following the end of a critical period (Miskolczi et al., 2019). This raises the possibility of new treatment options for problems arising in critical periods. Experience and the Visual System Figure 5.25 presents the effects of grafting a third eye onto a frog embryo on the eventual organization of the frog’s visual centers in the brain. Normally, the frog’s right eye connects with the left optic tectum, its equivalent of the human superior colliculus, and the left eye connects with the right optic tectum. The frog’s normal brain development is not prepared to manage input from a third eye. However, the experience of processing information from a third eye produces a rearrangement of the optic tectum. Competition between axons originating from an original eye and the grafted eye for the same area of optic tectum results in a pattern of alternating connections from one eye and then the other. This same type of interaction between experience and structural development shapes the human visual system.

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Building a Brain

Figure 5.25 Input Influences the Development of the Optic Tectum If a third eye is grafted onto a frog embryo, axons from the third eye compete with one of the original eyes for synapses in the frog’s optic tectum. As a result of the competition, the axons from each competing eye connect with alternating bands of tectum. Right optic tectum

Left optic tectum

Optic nerves

Retina Grafted third eye Source: From Constantine-Paton & Law (1978).

As we will discuss in Chapter 6, input from the retinas of the two eyes remains separate in both the lateral geniculate nucleus (LGN) of the thalamus and in the primary visual cortex of the occipital lobe. Early in development, the cells of the LGN and the primary visual cortex receive input from both eyes. The first axons to arrive at the LGN originate from the eye on the opposite (contralateral) side of the head. Shortly thereafter, axons from the eye on the same (ipsilateral) side of the head arrive at the LGN. During this initial period of development, input from the two eyes is not segregated in the layers of the LGN, as will be the case in the mature animal. Segregation, in which LGN cells become selectively activated by input from one eye or the other, appears to proceed according to the process suggested by Hebb. As demonstrated in Figure 5.26, input from the two eyes competes for the control of a given LGN cell. The input that is more highly correlated with activity in the LGN cell will be retained, while the input from the other eye, which is not as well correlated with activity in the LGN cell, will be weakened. When we say the input from one eye is “correlated” with the output of the LGN cell, this means that the synapse is active at the same time as many others influencing the same LGN cell. Eventually, a given LGN cell will be activated only by input originating in a single eye. A similar process takes place as the LGN axons arrive in the primary visual cortex, located in the occipital lobe.

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Initially, LGN axons processing information from the two eyes are not segregated in the visual cortex. Later on, however, the cortex becomes organized in highly defined ocular dominance columns, or areas of cells that respond to only one eye or the other. Once again, simultaneous activity appears to be the critical factor responsible for segregation. In a series of elegant experiments, Hubel and Wiesel (1965) demonstrated how experience with the sensory environment could influence the segregation of inputs into ocular dominance columns in cats. By suturing one eye of newborn kittens closed and recording from cells in the visual cortex, Hubel and Wiesel (1965) were able to chronicle the effects of experience on the organization of ocular dominance columns in the cortex (refer to Chapter 6). Figure 5.27 presents recordings from a normal cat, demonstrating that most cells in the visual cortex responded to light falling in either eye. However, Hubel and Wiesel found other cells that responded to only one eye or the other. In the kitten subjected to monocular deprivation, the right eye was sutured closed for the first three months of life. Then, the right eye was opened, and the left eye was sutured closed for the next three months. Subsequent recordings showed that the reversal of open eyes had a minor impact on the organization of the kitten’s visual cortex. Most cells continued to respond only to light falling in the left eye, which had been open during the first three months of life. Unlike the results from the typically developing cat, none of the cells in the monocularly deprived cat responded to light falling in both eyes. Hubel and Wiesel argued that these data support the existence of a critical period during which the visual cortex can be modified by experience. Although the concept of suturing the eyes of baby animals closed is disturbing, many children have benefited from the resulting knowledge that corrective surgery for vision must take place as early as possible. Experience, Social Behavior, and Cognition Certain experiences might be necessary to refine the development of brain areas related to complex social behaviors as well as the sensory systems. Konrad Lorenz (1952) described the phenomenon of imprinting in several species of birds. If a newly hatched chick saw Lorenz right away instead of the mother bird, it persisted in treating Lorenz as its mother. J. P. Scott (1962) bottle-fed an orphaned lamb for 10 days before returning it to its flock. The lamb persisted in following people and continued to graze independently from the flock three years later. The development of these types of complex social behavior is often constrained by critical periods. Unfortunate conditions maintained in Romanian orphanages in the 1970s provided further insight into the effects of social stimulation on human development. Children in these orphanages, like those in Figure 5.28, had few opportunities to interact with other people or

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Figure 5.26 Input From Both Eyes Competes for the Control of Target Cells in the LGN

Optic chiasm

Lateral geniculate nucleus (LGN) of the thalamus

Retinas

Optic nerves Axon from left eye

Axons from right eye

Target cell in LGN Action potential

Neurotransmitters Postsynaptic receptors 1 The axon from the left eye releases neurotransmitters, but not enough to create an action potential in the target LGN cell.

Neurotrophins 2 The two axons from the right eye release sufficient neurotransmitters to activate the target cell. The target cell releases neurotrophins, which are taken up by the axons.

the environment. Elenor Ames (1997) followed the progress of Romanian orphans adopted by Canadian parents. Children adopted before six months of age appear to have recovered from their earlier deprivation. Children adopted later in life improved but did not make as good a recovery as the children adopted earlier. Compared to non-deprived children, the deprived children had higher rates of attention deficit hyperactivity disorder (ADHD) symptoms, lower total brain volume, and lower IQ, despite the nurture provided by their adoptive families (Mackes et al., 2020). These findings suggest that some aspects of human cognitive development are also subject to critical periods.

3 The nonfunctional axon from the left eye retracts; additional axon terminals from the right eye take its place.

The Benefits of an Enriched Environment We mentioned earlier that brain development is similar to the production of a beautiful marble sculpture. In many ways, experience plays the role of the sculptor in shaping the adult brain. The conditions in the 1970s Romanian orphanages provided a tragic example of the need for a stimulating environment for cognitive development. Because of the obvious ethical concerns, most research on the effects of early enrichment has been conducted with animals (refer to Figure 5.29). Rats exposed to other rats, new toys, and other novel practices experienced different brain development and demonstrated better learning abilities than rats raised in conventional laboratory cages (Krech et al., 1960).

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Building a Brain

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Figure 5.27 Early Experience Affects the Organization of Ocular Dominance Columns In a classic series of experiments by Hubel and Wiesel, manipulation of input during the critical period of visual development changed the organization of the primary visual cortex in cats. Cells labeled 1 or 2 respond primarily to input from the contralateral eye, while cells labeled 6 or 7 respond primarily to input from the ipsilateral eye. Cells labeled 3, 4, or 5 respond equally to either eye. Normal experience (a) results in a fairly equal distribution of cells responding to each eye. Suturing one eye closed for the first three months of life (b) reduces the number of cortical cells responding to the closed eye or to both eyes. 60

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4 5 6 7 Equal Contralateral Ipsilateral Ocular dominance (a) Normal Adult Cat

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Ocular dominance (b) Kitten With Monocular Deprivation

Source: Adapted from Hubel & Wiesel (1965).

The observed advantages of the enriched environment result from two factors: higher connectivity in neural networks due to more synapses and enhanced flexibility due to more responsive dendritic spines (Jung & Herms, 2014). Enriched environments are not only beneficial to learning and memory. These environments seem to provide longterm protection against anxiety and exaggerated responses to stress (Ball et al., 2019). A number of psychological disorders, such as major depressive disorder and schizophrenia, are more frequent in individuals in lower socioeconomic circumstances, where the environment could be characterized as impoverished as opposed to enriched (refer to Chapter 16). In addition, these disorders appear to be influenced by stress levels. The protection from stress effects enjoyed by more affluent people exposed to enriched environments during development might help explain why they are less likely to experience these disorders. However, the factors that constitute an “enriched” environment for humans are wildly diverse and in need of clarification. For example, one study proposed that living in proximity to forests seemed beneficial to amygdala integrity (Kühn et al., 2017).

Disorders of Early Nervous System Development Given the complexity of cell production, migration, differentiation, and connection, it seems to be a major miracle that most of us end up with a reasonably functional brain. Severe developmental errors usually result in miscarriage, also known as spontaneous abortion. A small percentage of children will be born with a variety of abnormal conditions due to errors in early neural development. Neural Tube Disorders As we observed earlier, an important part of development is the closing of the neural tube, which takes place between gestational days 21 and 28 in humans. Neural tube disorders include anencephaly, spina bifida, and encephalocele. Anencephaly, in which significant portions of the brain and skull fail to develop, occurs when the rostral anencephaly Defect in the rostral closure of the neural tube resulting in incomplete development of brain and skull.

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lower back. Approximately 1 out of 1,427 babies born in the United States are born with spina bifida (CDC, 2020b). The condition can Romanian orphans adopted before the age of six months recovered from their earlier range from mild to life threatensocial deprivation, but those adopted at later ages did not make as good a recovery. As ing, and attempts to provide more depicted in (a), total brain volume in the children with social deprivation was lower than effective interventions are under in control children. In (b), the length of deprivation was negatively correlated with total active investigation. Surgical corbrain volume. Source: Mackes et al. (2020). rection of the protruding neural tissue is a common approach, and has about the same benefits whether performed prenatally or postnatally (Inversetti et al., 2019). Encephalocele involves a protrusion of brain and membrane material outside the skull, usually as a sac that forms at the back of the head. This condition affects approximately 1 out of 10,500 babies in the United States (CDC, 2020c). Surgery is used to return the protruding tissue back inside the skull. Although the exact causes p < 0.001 p < 0.001 1,300 d = –1.13 r = –0.41 of neural tube defects remain unknown, genetic factors may 1,200 play a role. Neural tube disorders tend to run in families. Rates 1,100 differ across race and ethnicity, with higher rates among His1,000 panics followed by non-Hispanic whites and African-Americans 900 (CDC, 2020a, 2020b, 2020c). Deficiencies of dietary folic acid are linked to neural tube dis800 Non-deprived Deprived 20 30 40 10 orders. Folic acid occurs naturally Deprivation duration in dark green leafy vegetables, egg (a) (b) [months] yolks, fruits, and juices. It is also Source: Mackes, N. K., Golm, D., Sarkar, S., Kumsta, R., Rutter, M., Fairchild, G., . . . Schlotz, added to fortified breakfast cereals W. (2020). Early childhood deprivation is associated with alterations in adult brain structure and other packaged products. The despite subsequent environmental enrichment. Proceedings of the National Academy of Sciences fortification of commercial food of the United States of America, 117(1), 641–649. doi:10.1073/pnas.1911264116 products with folic acid was followed by reduced rates of neural neural tube does not develop properly. The majority of tube disorders. However, the average American diet still fetuses with anencephaly either die in utero or do not surdoes not contain sufficient levels of folic acid to effectively vive for more than a few hours after birth. Approximately prevent neural tube disorders. Because neural tube closure 1 out of 4,600 babies in the United States are born with occurs so early in development, any possibility of becoming anencephaly (Centers for Disease Control and Prevention pregnant should be accompanied by the consumption of 400 [CDC], 2020a). mcg of folic acid per day as a vitamin supplement in addiIn spina bifida, the caudal portion of the neural tube tion to the maintenance of a healthy diet (CDC, 2020d). The fails to close normally, leading to the protrusion of a part of exact mechanism linking folic acid to neural tube disorders the spinal cord and some spinal nerves through a hole on the is unclear, but folic acid is well known as an epigenetic factor influencing methylation (Imbard et al., 2013). Total brain volume [cm3]

Cynthia Johnson/Getty Images

Figure 5.28 Social Deprivation Affects Intellectual Development in Humans

spina bifida Defect in caudal neural tube closure that results in mobility problems. encephalocele A neural tube defect in which brain and membrane material protrudes from the skull.

Genetic Disorders A wide variety of genetic errors can occur in early development, and it is beyond the scope of our current discussion to provide more than a sample.

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Building a Brain

Figure 5.29 Enriched Environments Produce Long-Lasting Effects on Cognitive Development Rodents provided with opportunities to explore novel toys develop heavier brains and demonstrate better learning abilities than rodents raised in standard laboratory cages. The increased brain weight is partly due to more extensive branching of dendrites and more developed dendritic spines.

Source: Adapted from Zhao et al. (2018)

attainment of second-grade academic skills and requires living and working in a supervised setting. Physical features of Down syndrome include a small skull, large tongue, almond-shaped eyes, a flat nasal bridge, and abnormalities of the hands and fingers. The number one cause of death among people with Down syndrome is Alzheimer disease (Fortea et al., 2021). The 21st chromosome contains the APP gene, which encodes amyloid precursor protein. Some APP variants are highly correlated with early onset Alzheimer disease, discussed further in Chapter 15. An improved understanding of the role played by an extra APP gene and the development of Alzheimer disease would be beneficial to patients with and without Down syndrome. A relatively common heritable condition is fragile X syndrome, which affects about 1 in 4,000 males and 1

Figure 5.30 Maternal Age Is a Risk Factor for Down Syndrome Down syndrome usually results from errors in maternal meiosis, which increase with age. Rates of Down syndrome in offspring begin to rise when a mother reaches her mid-30s. Prevalence of Down Syndrome by Mother’s Age Prevalence (per 10,000 live births)

Down syndrome, also known as trisomy 21, is characterized by having an extra copy of all or a segment of chromosome 21. The major cause of trisomy 21 is abnormal division, or disjunction, of the mother’s 21st chromosome during the final meiosis that results in a mature ovum or egg. Disjunction is related to maternal age rather than the inheritance of a faulty gene, so the risk of producing a child with Down syndrome is not higher in families that already have a member with this condition (refer to Figure 5.30). The relationship between the extra 21st chromosome and the physical and mental characteristics of Down syndrome is currently unknown. Individuals with Down syndrome usually function in the moderate range of intellectual disability. This level of intellect allows

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in Chapter 3, these unipolar cells feature a single process leaving the cell body that subsequently divides into two branches. One branch extends to the periphery, ending in a mechanoreceptor. The other branch travels centrally by joining the dorsal roots of the spinal cord.

Thumb

Lip

Big toe

Sole Forearm Back of foot of torso

Calf

As noted in Figure 7.17, the sensory fibers of the peripheral nervous system are classified into four categories based on diameter and speed. The largest fibers, called Aα (alpha-alpha), carry information from the muscles and will be discussed in Chapter 8. The smaller three sets of

Figure 7.17 The Four Classes of Sensory Axons Differ in Size and Speed The largest, fastest afferent axons (Aa) serve the muscles and will be discussed in Chapter 8. The second-largest and fastest axons (Ab) serve the mechanoreceptors. Fast, sharp pain and skin temperature are carried by the myelinated Ad fibers, while the small, unmyelinated C fibers carry dull, aching pain and skin temperature. Class of Axon

Diameter of Axon

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Aa (Alpha-alpha) fibers

13–20 mm

80–120 m/sec

Feedback from muscle fibers

Axon Myelin

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35–75 m/sec

Mechanoreceptors of skin: Meissner corpuscles Merkel cells Pacinian corpuscles Ruffini endings

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1–5 mm

5–30 m/sec

Pain, temperature receptors of skin: Free nerve endings

C fibers

0.2–1.5 mm

0.5–2 m/sec

Pain, temperature receptors of skin: Free nerve endings

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fibers serve the mechanoreceptors. The second-largest set, the Aβ (alpha-beta) class, carries information from the Meissner corpuscles, Merkel cells, Pacinian corpuscles, and Ruffini endings toward the central nervous system (CNS). The smallest two groups, the myelinated Aδ (alpha-delta) fibers and the unmyelinated C fibers, carry information from the free nerve endings regarding pain and skin temperature. The area of the skin surface served by the dorsal roots of one spinal nerve is known as a dermatome. As presented in Figure 7.18, dermatomes are easily identified in the disease known as shingles, which is caused by the same virus responsible for chickenpox (varicella zoster virus or VZV).

Medical Images/BOB TAPPER

In some people, the virus awakens decades after the original infection and produces skin eruptions. In addition, the virus increases the excitability of the sensory neurons, producing a burning, painful sensation along the dermatome. The reactivated virus appears to confine its mischief to a single dorsal root, leading to symptoms in one-half of an individual dermatome. Fortunately, an effective vaccine for VZV is now available. The pathways leading from the mechanoreceptors to the brain are presented in Figure 7.19. When the axons from the mechanoreceptors enter the spinal cord, they follow a route called the dorsal column–medial lemniscal pathway. As suggested by the pathway’s name, axons join the white matter of the ipsilateral dorsal column and make their first synapse in the dorsal column nuclei of the dermatome The area of skin surface served by the dorsal root of a medulla. The lack of synapses until this point greatly conspinal nerve. tributes to the speed of this system. dorsal column–medial lemniscal pathway The pathway taken by Axons from the dorsal column nuclei form a large touch information from the mechanoreceptors to the brain. band of white matter known as the medial lemniscus, which crosses the midline of the medulla. From this point forward, sensory information is processed contralaterally. In other words, the left side Figure 7.18 Dermatomes Are Areas of Skin of the brain processes touch, pain, and skin Served by the Dorsal Roots of One Spinal Nerve temperature information from the right side of the body. The medial lemniscus continues The existence of dermatomes can be demonstrated by observing the to travel rostrally through the medulla, pons, effects of shingles, a virus that affects a single dorsal root. This condition involves the reactivation of the chickenpox virus later in life and the producand midbrain before synapsing on the vention of skin eruptions that follow one-half of a dermatome band. tral posterior (VP) nucleus of the thalamus, portrayed in Figure 7.20. Axons from the VP nucleus travel to the primary somatosensory cortex of the parietal lobe. Touch information from the head reaches Spinal cord the VP nucleus by alternate routes involving a number of cranial nerves. Sensation from mechanoreceptors in the skin of the face, Cervical mouth, tongue, and the dura mater of the brain travels along branches of the trigeminal Thoracic nerve (cranial nerve V; refer to Chapter 2). Additional input from other parts of the head is carried by the facial nerve (VII), the glosLumbar sopharyngeal nerve (IX), and the vagus nerve (X). Axons forming these cranial nerves synapse on their respective ipsilateral nuclei in the brainstem, which serve the same purSacral pose as the dorsal column nuclei. From these cranial nerve nuclei, axons cross the midline and travel to the VP nucleus, which, in turn, passes the information to the primary somatosensory cortex in the parietal lobe. You may be wondering what the dorsal column nuclei, cranial nerve nuclei, and the VP nucleus might be doing to the incoming Shingles on left side of sensory information. These synapses provide T12 dermatome opportunities for the cortex to influence the input it receives through descending pathways. In addition, activity in one neuron in

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The Body Senses

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Figure 7.19 Touch Pathways The mechanoreceptors send information to the thalamus via the dorsal column–medial lemniscal pathway. From the thalamus, information flows to the primary somatosensory cortex in the parietal lobe. Primary somatosensory cortex (parietal lobe) Forebrain Somatosensory cortex Ventral posterior (VP) nucleus of the thalamus

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Medial lemniscus Medulla Dorsal column nuclei Spinal cord Dorsal column Mechanoreceptor

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Medial lemniscus

2 Dorsal column

Dorsal column nuclei

these areas inhibits its neighbor, leading to a sharpening or enhancement of its signal. Somatosensory Cortex The primary somatosensory cortex, also known as S1, is found in the postcentral gyrus of the parietal lobe, just caudal to the central sulcus that divides the parietal and frontal lobes. The secondary somatosensory cortex (S2) is located within the lateral sulcus. Using single-cell recording, we can demonstrate that the areas of the cortex serving the head and neck are located at the lower, ventral part of the postcentral gyrus, while areas serving the legs and feet extend over the top of the gyrus onto the medial surface of the parietal lobe. A map of the body’s representation in the cortex is known as

3

3 VP nucleus of the thalamus

Primary somatosensory cortex

a homunculus, or “little man.” An example of a homunculus can be found in Figure 7.21. Areas of the body receive cortical representation according to their need for precise sensory feedback. In humans, the hands and face are represented in a much larger portion of the cortex than their size would suggest. Rats devote a great deal of space to whiskers, and lips seem to have a high priority in squirrels and rabbits. Plasticity of Touch The somatosensory cortex is capable of plasticity, which means it can rearrange itself in response to changes in the amount of input it receives. Both reductions and increases in input can initiate plasticity. In adult monkeys that have had a finger surgically removed, the areas of the somatosensory cortex

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Figure 7.20 Somatosensory Areas of the Thalamus Somatosensory information is processed by the ventral posterior (VP) and intralaminar nuclei of the thalamus.

Thalamus

Medial dorsal nucleus

Intralaminar nuclei

Medial geniculate nucleus Lateral geniculate nucleus

previously responsive to the missing finger now respond to stimulation of adjacent fingers (Kaas et al., 1981). When monkeys were trained to use specific fingers to discriminate between tactile surfaces to earn a food reward, the area of the somatosensory cortex receiving input from the trained fingertips actually expanded (Wang et al., 1995). Clinical studies in humans are consistent with these experiments in monkeys. Amputation of a limb can cause phantom pain, in which pain is perceived as arising in the missing body part, or referred sensations, in which touching a body part such as the cheek is perceived as touch of the missing limb (Ramachandran, 2005). In one example of referred sensation, brain imaging confirmed that the part of somatosensory cortex previously responsive to a now amputated arm subsequently responded to touching the face (Ramachandran & Rogers-Ramachandran, 2000). Other types of referred sensation occur as well. One patient was embarrassed to report that he experienced a sensation of orgasm in his missing foot. phantom pain Pain that is perceived as arising from a missing body part. referred sensations The perception of touch of a body part as arising from a missing body part.

Ventral posterior nucleus

Figure 7.21 The Sensory Homunculus Just as body parts are not equally sensitive, they do not get the same amount of representation in the somatosensory cortex. Relative representation may be mapped as a homunculus. For over 70 years, textbooks have featured versions of the original homunculus published by Penfield and Boldrey (1937), which depicts a male. Only recently have scientists attempted to map the female somatosensory cortex in a similar manner. One attempt, shown here, outlines the female “hermunculus” against the dotted lines of the original male image by Penfield and Boldrey. Breast Aurbach et al., 2009

Nipple Rothemund et al., 2005; Komisaruk et al., 2011

Index finger Rothemund et al., 2005

External genitals Yang & Kromm, 2004; Genital region Erikson, 1945

Clitoris Allison et al., 1996 Clitoris, vagina, cervix Komisaruk et al., 2011; Labia, buttock, breast Penfield & Rasmussen, 1950 Clitoris Michels et al., 2010

Source: Di Noto, P. M., Newman, L., Wall, S., & Einstein, G. (2012). The Hermunculus: What Is Known about the Representation of the Female Body in the Brain? Cerebral Cortex, 23(5), 1005–1013. doi:10.1093/cercor/bhs005

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Connecting to Research Phantom Limbs, Mirrors, and Longer Noses Some patients experienced movement as well as sensation in their missing limbs. In some instances, this results in pain. One patient experienced the sensation of a tightly clenched hand that could not be relaxed. The phantom nails dug into the palm of the phantom hand, resulting in excruciating sensations of pain. Use of a mirror box to superimpose the reflection of the real hand on the felt location of the phantom left hand allowed the patient to gain relief by “unclenching” the phantom hand (refer to Figure 7.22). The phantom nose demonstration produced dramatic effects. After only a few seconds, the blindfolded person began to sense that their nose had been stretched or dislocated.

We assume that the mapping of touch in the brain is a simple matter, but research shows us a different story. Ramachandran and Rogers-Ramachandran (2000) explored the impact of amputation on the brain’s processing of touch. Ramachandran and Hirstein (1997) demonstrated a tactile illusion in people who had not experienced amputation. The Question: How does the brain process unusual

tactile input?

Methods Eighteen individuals with arm amputations verbalized their sensations when various parts of their bodies were touched. A “phantom nose” demonstration was conducted with people who had not experienced amputation. Two people sit side-by-side with one person blindfolded. The experimenter uses the blindfolded participant’s left index finger to tap the other person’s nose in a random, unpredictable manner and their right index finger to perform the same movements on their own nose.

Conclusions Observations of the individuals with amputation support a remapping hypothesis. Loss of a limb initiates plasticity in the somatosensory cortex, leading to a repurposing of the cells formerly responding to the now missing limb. The results of the phantom nose demonstration reflect an assumption that the matched tapping of nose and finger cannot be occurring by chance, resulting in the brain’s use of the “simpler” explanation that the nose is displaced. Sensory systems might have evolved to extract statistical regularities from the natural world. This strategy usually works, but illusions can demonstrate how tenuous the relationship between “reality” and our beliefs about reality can really be.

Results

Doro Guzenda/Shutterstock.com

Among the group of individuals with arm amputations, eight perfectly referred sensation from the face to the now-missing limb. In other words, touching specific parts of the face produced simultaneous feelings of the face and the missing arm. The sensations were also modality specific, such as feeling hot or cold or massage.

The increased representation due to training that was observed in monkeys has another parallel in the cortical organization of some musicians. Highly trained string musicians, especially those who studied music from a young age, have a larger than normal area of somatosensory cortex representing touch in the fingers (Münte et al.,

Figure 7.22 Mirror Boxes and Phantom Pain Phantom pain from a missing limb can be alleviated using mirrors. The patients place their unaffected limb in the side with the mirror and their affected limb on the other side out of sight. The reflection gives the illusion of once again having two limbs, which relieves many symptoms of phantom pain.

2002). A similar reorganization of somatosensory cortex occurs when individuals with visual impairments learn to read Braille (Pascual-Leone & Torres, 1993). Somatosensory Disorders Damage to the primary somatosensory cortex produces deficits in both sensation

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Figure 7.23 Drawings by a Patient With Neglect Syndrome Damage to the secondary somatosensory cortex, particularly on the right hemisphere, results in neglect syndrome. Patients with this syndrome have difficulty perceiving a part of the body or a part of the visual field. Because patients attempting to copy the model cannot perceive the entire visual field, they draw only part of each object. Patients seem to be blissfully unaware they have this problem until others point it out to them.

Source: From Springer, S. P., Deutsch, G., Left Brain, Right Brain. New York: W. H. Freeman, 1989, p. 193. Reprinted by permission.

and movement of body parts served by the damaged area. Damage to the secondary somatosensory cortex, particularly on the right side of the brain, results in an odd phenomenon known as neglect syndrome. Patients with this syndrome have difficulty perceiving either a part of the body or a part of the visual field. Drawings by a patient with neglect syndrome are presented in Figure 7.23. Oliver Sacks (1985) described a patient with neglect syndrome who believed that the hospital staff was playing a horrible joke on him by putting an amputated leg, which was actually his own very firmly attached leg, into his bed. While trying to remove the leg from his bed, the man frequently fell on the floor.

opioids, are relatively ineffective for managing this type of pain, although efforts to manage chronic pain have contributed to opioid epidemics. Chronic pain is more than an extension of acute pain and probably involves some reorganization of neural circuits. In particular, chronic pain reduces neurogenesis in the hippocampus, suggesting that memory plays an important role in this experience (Barroso et al., 2021). No other sensory modality is as dramatically affected by culture, emotion, context, and experience as our sense of pain. The connection between culture and the experience of pain is vividly demonstrated by the hook-swinging ritual practiced in India (Melzack & Wall, 1983). This ritual, designed to promote the health of children and crops, involves hanging a male volunteer from steel hooks embedded into the skin and muscles of his back. Instead of suffering excruciating pain, the volunteers appear to be in a state of exaltation. Highly individual, subjective responses to painful stimuli result from numerous variables, including genetics, gender, age, and experience. Women demonstrate greater sensitivity to pain, while aging is associated with greater sensitivity to some, but not all, types of pain (Fillingim, 2017). A person’s number of endogenous opioid receptors (refer to Chapter 4) also influences pain sensitivity. If you’re wondering how pain responses are evaluated experimentally, this is usually done with a cold pressor test, depicted in Figure 7.24.

Figure 7.24 The Cold Pressor Test for Pain Pain perception and tolerance is often measured experimentally using the cold pressor test. Participants immerse one hand in a container of ice water as long as they can tolerate the pain, up to three minutes. Your author demonstrates the method in this photo, but she did not last long.

Pain

neglect syndrome A condition resulting from damage to the secondary somatosensory cortex that produces difficulty perceiving a body part or part of the visual field. pain An unpleasant sensory and emotional experience associated with tissue damage.

Courtesy of Laura Freberg

Pain is defined as an unpleasant sensory and emotional experience associated with tissue damage. Pain occurring subsequent to an injury is often referred to as acute pain. In contrast, chronic pain refers to pain lasting three or more months (Barroso et al., 2021). As many as 20 percent of adults in the United States experience chronic pain. Typical medications, such. as aspirin and

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A Purpose for Pain Pain is not a perfect warning system for tissue damage. In many potentially fatal conditions, such as some types of cancer, pain does not surface until the condition is quite advanced. In other cases, the pain people experience far exceeds any threat to their safety. Given the anguish experienced by people in pain, you might think it would be miraculous to be rid of this sensory modality altogether. Research on those born without effective pain reception, like Gabby Gringas (depicted in Figure 7.13) suggests otherwise. Patients who perceive no pain frequently die prematurely due to injuries and degeneration of the joints and spine. We need pain to remind us to stop when we are injured, to assess a situation before proceeding, and to allow the body time to heal. Receptors for Pain Free nerve endings that respond to pain are called nociceptors. Nociceptors respond to a variety of stimuli associated with tissue damage. Some nociceptors respond most vigorously to mechanical injury such as the damage caused by a sharp object. The pressure of the mechanical stimulus on the nociceptor membrane opens mechanically gated ion channels, leading to the generation of action potentials. Other nociceptors respond to extreme temperature. Another group of nociceptors appears to respond to both mechanical stimulation and temperature. A variety of chemicals can also activate nociceptors. Chemicals released when a cell is damaged, such as potassium ions, enzymes, histamine, and adenosine triphosphate (ATP), stimulate nociceptor activity. The soreness we experience after exercising vigorously is produced by a buildup of lactic acid. Lactic acid produces an increase in hydrogen ions in the extracellular fluid. These ions activate nociceptors, which in turn send unpleasant messages of soreness to the brain. An interesting class of nociceptors responds to chemicals known as vanilloids, a group that includes capsaicin (Caterina et al., 1997). Capsaicin is best known as the ingredient found in hot peppers, and it is responsible for the heat sensations we experience while eating spicy foods. Pain Pathways to the Brain Information from the nociceptors is carried toward the CNS by two types of nerve fiber (refer back to Figure 7.17). The faster, myelinated Aδ (alpha-delta) fibers are responsible for that quick, sharp “ouch.” The slower, unmyelinated C fibers are responsible for dull, aching types of pain sensation. Both types of ascending pain fibers use glutamate as their primary neurotransmitter. Figure 7.25 depicts pain fibers from the skin entering the spinal cord via the dorsal root. Visceral pain fibers follow a similar, but separate route. Once inside the cord, the pain fibers synapse in the substantia gelatinosa, a group of cells in the outer gray matter of the dorsal horn. These cells also receive descending input from the brain. In addition to releasing glutamate, pain fibers are capable of releasing the neuropeptide Substance P in the dorsal

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horn of the spinal cord. Substance P enhances the rapid communication of pain information by sensitizing cells in the substantia gelatinosa to glutamate. Melzack and Wall (1965) proposed an influential gate theory of pain, characterized by a feedback loop in the dorsal horn that determines which signals ultimately reach the brain (refer to Figure 7.26). Excitatory signals from gate cells open the gate, allowing the message to continue. Chronic stress can make the opening of the gate more likely, and many people are more acutely aware of pain when stressed. Inhibitory signals from gate cells can close the gate, stopping the pain message from proceeding to the brain. High levels of arousal during emergencies can close the gate, making people unaware of how badly they have actually been injured. Fibers originating in the substantia gelatinosa immediately cross the midline of the spinal cord to join the spinothalamic pathway that runs the length of the ventral surface of the spinal cord. These fibers travel up through the brainstem and finally synapse within the thalamus. Pain information from the head and neck is transmitted to the thalamus in a similar manner. This information travels first along the trigeminal nerve, which synapses in the spinal trigeminal nucleus of the brainstem. Fibers from the spinal trigeminal nucleus form the trigeminal lemniscus, which terminates in the thalamus. The spinothalamic and trigeminal lemniscus fibers synapse in one of two locations in the thalamus. Some fibers synapse in the VP nucleus, which also receives information from touch receptors. However, input regarding pain remains separate in the VP nucleus from input regarding touch. Other fibers connect with the intralaminar nuclei of the thalamus, presented in Figures 7.20 and 7.25. Both areas of the thalamus then form connections with the anterior cingulate cortex (ACC) and, to a lesser degree, the somatosensory cortex of the parietal lobe. The ACC participates in our anticipation and emotional responses to pain. If participants are told to expect a mild amount of pain from placing their hands in hot water, the ACC is less active than when they are told to expect more pain (Rainville et al., 1997). People who chose an immediate but large electric shock over a delayed but smaller shock, nociceptor A free nerve ending that responds to painful stimuli. substantia gelatinosa A group of cells in the outer gray matter of the dorsal horn that receives input from pain fibers. Substance P A neurochemical associated with the sense of pain. gate theory of pain An explanation of the effects of context on the perception of pain. spinothalamic pathway A pathway carrying pain information from the substantia gelatinosa to the thalamus. trigeminal lemniscus A pathway for pain information from the head and neck that connects the spinal trigeminal nucleus and the thalamus. intralaminar nuclei Nuclei within the thalamus that receive pain information.

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Figure 7.25 Ascending Pain Pathways Upon entering the dorsal root, pain fibers form synapses within an area known as the substantia gelatinosa. The messages then travel centrally along spinothalamic pathways. Primary somatosensory cortex Forebrain Somatosensory cortex Intralaminar nuclei of the thalamus

3

Ventral posterior (VP) nucleus of the thalamus

Anterior cingulate cortex

Brainstem

2

Spinothalamic pathway Spinal cord Substantia gelatinosa Dorsal root

1 Pain fiber Ventral root

Spinothalamic pathway

Nociceptors Dorsal root axons 1 Nociceptors

Spinothalamic pathway

3 3

Anterior cingulate cortex (emotional experience of pain) Thalamus Somatosensory cortex (sensation of pain)

demonstrating that they “dreaded” the upcoming shock, experienced increased activity in the ACC (Berns et al., 2006). Remembering pain and anticipating further pain, perhaps when facing a second similar surgery for the same condition, activates the prefrontal cortex. Activity in the prefrontal cortex is correlated with cognition and executive control related to pain. Managing Pain Although pain certainly has its purpose, we are also motivated to help those in pain. In some cases, the pain signal can be modified by additional sensory input. Most of us spontaneously respond to bumping our elbow by rubbing it vigorously. Rubbing your elbow might actually lessen the ability of pain receptors to

communicate with the brain. According to the gate theory discussed previously, activity in touch fibers inhibits the activity of nociceptors in the substantia gelatinosa. This effectively reduces the amount of pain information reaching the brain. In other cases, descending control from the brain has a dramatic influence on our perception of pain. This descending system provides a mechanism for the influence of cognitions, emotions, and memory on the pain experience. As noted in Chapter 2, many higher-level brain structures form connections with the periaqueductal gray (PAG) of the midbrain, which also receives ascending pain signals (refer to Figure 7.27). The convergence of descending control and ascending pain information in the PAG

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Figure 7.26 The Gate Theory of Pain According to the gate theory of pain, incoming pain messages can be influenced by factors such as chronic stress (opening the gate wider and producing a greater sensation of pain) or rubbing an injured body part (closing the gate and reducing the sensation of pain).

EVENT OR INJURY

Gate in spinal cord

Factors that close the gate (e.g., rubbing elbow, high levels of arousal) Juriah Mosin/Shutterstock.com

Factors that open the gate (e.g., chronic stress)

Pain experienced depending on how far the gate is open or closed.

provides an opportunity for the modification of incoming pain messages by higher-level cognitive processes. Electrical stimulation of the PAG generally produces a significant reduction in pain. In addition, the PAG contains large numbers of opioid receptors, which interact with opioids such as morphine. The pain relief achieved through the use of opioids probably occurs in large part due to the drugs’ actions in the PAG. Downstream in the substantia gelatinosa, activity in the descending pain system can enhance the release of additional endogenous opioids. Being disabled by pain during an emergency is not in the best interests of survival, so it should come as no surprise that extreme stress often reduces the perception of pain. Stress impacts the pain system at several levels. As discussed previously, the high arousal that occurs in stressful situations might act to close pain gates in the substantia gelatinosa. In addition, stress might produce analgesia, or pain relief, by promoting the release of endorphins in the brain. Chronic stress has the opposite effect. Under the influence of chronic stress, pain gates open more than under normal circumstances, making people even more aware of existing problems. Using profanity lessens the subjective intensity of pain, at least for people who use profanity sparingly (Stephens & Umland, 2011). This is likely due to profanity’s ability to distract a person and the initiation of arousal. As mentioned previously, high levels of arousal reduce the perceived intensity of ascending pain signals. As in the case of the hook-swinging ritual, attitudes toward pain and experience with pain also play significant roles in our perceptions of the experience (refer to

Figure 7.28). Athletes and nonathletes share similar pain thresholds, or levels of stimulation identified as painful. However, these groups are quite different in their tolerance of pain (Sternberg et al., 1998). In particular, athletes in contact sports such as boxing, rugby, and football appear to tolerate higher levels of pain before identifying a stimulus as painful. A sense of control can reduce the sensation of pain. Providing a feeling of being in control is an essential component in prepared childbirth training. Patients who are allowed to self-administer opioids for pain actually require less medication and report more pain relief than patients who receive injections from hospital staff (McNicol et al., 2015).

Interim Summary 7.2 Summary Points 7.2 1. The vestibular system provides information about the position and movement of the head. (LO4) 2. Major mechanoreceptors located within the skin include Meissner corpuscles, Pacinian corpuscles, Merkel cells, Ruffini endings, and free nerve endings. (LO4) 3. Touch information travels along the dorsal column– medial lemniscal pathway to the dorsal column nuclei of the medulla, then to the contralateral ventral posterior nucleus of the thalamus and to the primary somatosensory cortex of the parietal lobe. (LO4)

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Figure 7.27 Descending Messages Influence Pain Perception Many higher-level structures of the brain form connections with the periaqueductal gray (PAG) of the midbrain, a major locus for endogenous opioid activity. The PAG, in turn, forms connections with the raphe nuclei in the medulla and neurons in the spinal cord that can modulate incoming pain information.

Forebrain Frontal cortex

1

Thalamus Hypothalamus Amygdala

Midbrain Periaqueductal gray 2 Medulla Raphe nuclei 3

Spinal cord Dorsal horn

4

1 Forebrain • Frontal cortex • Thalamus • Hypothalamus • Amygdala

2

3

Periaqueductal gray

Figure 7.28 Individuals Experience Different Pain Intensities Health care providers often need to assess a person’s subjective experience of pain, which can be very different from person to person. With adult patients, simply asking individuals to rate their pain on a scale of one to ten is often sufficient. With children, the Faces Pain Scale can be useful.

4 Raphe nuclei

Dorsal horn

4. Pain is sensed by free nerve endings called nociceptors. Ascending pain fibers synapse in the substantia gelatinosa, the thalamus, and the anterior cingulate and somatosensory cortices. Descending information regarding pain is transmitted to the periaqueductal gray (PAG). (LO4) Review Questions 7.2

0

2

4

6

8

10

Source: Hicks et al. (2001). The Faces Pain Scale–Revised: toward a common metric in pediatric pain measurement. Pain, 93(2), 173–183

1. How is the primary somatosensory cortex organized? How does experience change the organization of the primary somatosensory cortex? 2. What factors modify an individual’s perception of a painful stimulus?

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The Chemical Senses

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Summary Table 7.2: Somatosensory Pathways Sensory Modality

Vestibular system

Receptor Types

Hair cells within the saccule, utricle, and semicircular canals

Axon Types

Route to Somatosensory Cortex ●

Fibers join the auditory nerve (cranial nerve VIII).

●

Axons synapse in cerebellum and vestibular nuclei.

●

Various ●

● ●

●

Touch

Mechanoreceptors

Ab fibers

●

Pain

Olfaction Historically, human olfaction has been viewed as relatively poor compared to other creatures. This is not entirely fair. Human olfactory bulbs contain about the same number of neurons as many other mammals (McGann, 2017). At the same time, we are not anywhere close to your dog in terms of the number of olfactory receptors and surface area of

Axons join the dorsal column and synapse in the dorsal column nuclei of the medulla. Axons from the dorsal column nuclei form the medial lemniscus and synapse in the VP nucleus of the thalamus. Cranial neurons V, VII, IX, and X carry touch information from the head to brainstem nuclei, which form connections with the VP nucleus of the thalamus. The VP nucleus projects to the primary somatosensory cortex in the parietal lobe. Fibers enter spinal cord via dorsal root. Fibers synapse in substantia gelatinosa.

●

Philosopher Immanuel Kant (1798/2006) considered olfaction, or the sense of smell, to be the “most dispensable” sense. Nonetheless, our chemical senses, olfaction and gustation, provide essential warnings of danger, such as smelling smoke from a fire or tasting spoiled food. Contrary to Kant’s view, people who have lost their sense of smell due to a head injury often experience profound depression (Doty et al., 1997). Reduced olfactory sensitivity in older adults is strongly associated with the later development of dementia (Adams et al., 2018) and reliably predicts the probability of death within the next 5 years (Choi et al., 2021).

Fibers enter spinal cord via dorsal root.

●

Ad fibers and C fibers

The Chemical Senses

Information travels from the VP nucleus to the primary somatosensory cortex and motor cortex.

●

●

Nociceptors (free nerve endings)

Vestibular nuclei axons project to the spinal cord motor neurons and to the VP nucleus of the thalamus.

Pain information travels via the spinothalamic pathway and trigeminal lemniscus to the VP nucleus and intralaminar nuclei of the thalamus. Information is transmitted to the anterior cingulate cortex, primary somatosensory cortex, and prefrontal cortex.

the epithelium on which the receptors sit. We also have relatively limited space for processing olfactory information in the brain due to other priorities, both sensory and cognitive. Olfaction begins when air containing olfactory stimuli is taken in through the nostrils and circulated within the nasal cavities connected to the nostrils. The congestion you experience during a bad cold limits this circulation, reducing your ability to smell. Molecules suspended in the air serve as olfactory stimuli and tend to be small and water-repellant. We cannot sense every type of molecule suspended in the air. Natural gas, for example, has no detectable odor, so power companies add an odorant so we can sense potentially dangerous gas leaks in our homes. Individuals vary in their sensitivity to smell. As we age, our sensitivity to smell decreases (Rawson, 2006). Females are slightly more sensitive to smell than males (Sorokowski et al., 2019). Smokers are less sensitive to smell than nonsmokers, an effect that lasts at least 15 years after a smoker olfaction The sense of smell.

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quits (Siegel et al., 2019). Women using oral contraceptives are less sensitive than naturally cycling women to odors, particularly those associated with social and sexual behaviors, such as musk (Renfro & Hoffmann, 2013). Our ability to perceive a particular odor is also affected by how long we are exposed to the odor. Smell adapts rapidly, a fact to keep in mind when applying your favorite scent. olfactory epithelium The nasal cavity area containing olfactory receptors.

Olfactory Receptors The neural receptors for olfaction are contained in a thin sheet of cells within the nasal cavity known as the olfactory epithelium, depicted in Figure 7.29. Unlike most other types of neurons, olfactory receptor cells regularly die and are replaced in a cycle lasting approximately four to six weeks. In addition to the receptor cells, the olfactory epithelium also contains gliatype support cells that produce mucus. Stem cells in the epithelium give rise to new receptors when needed. Infection of the olfactory support cells, not the neural receptor cells, by the SARS-CoV2 virus causes the characteristic,

Figure 7.29 Olfactory Information Travels From the Epithelium to the Brain Thalamus Hypothalamus

Medial dorsal nucleus of the thalamus Olfactory cortex

Orbitofrontal cortex

Hippocampus Olfactory bulb

Amygdala

To limbic system

Inhaled air

Olfactory bulb Olfactory neuron Glomerulus (enlarged for clarity) Olfactory receptor cell

Olfactory nerve (to brain) Axons of olfactory receptor cells Bone

Basal cell Supporting cell

Olfactory epithelium

Cilia of olfactory receptors Mucus Odorant molecules

Air flow

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The Chemical Senses

temporary loss of olfaction associated with Covid-19 (Brann et al., 2020). The approximately 10,000 olfactory receptor cells in each nostril are bipolar, having two branches extending from the cell body. One branch reaches out to the surface of the epithelium. Cilia extend from the end of this branch into the mucus that covers the epithelium. Molecules dissolved in the mucus bind and interact with these cilia. The binding of an odorant molecule to a receptor site on a cilium begins a process that results in an influx of sodium and calcium into the receptor neuron. If the resulting depolarization is large enough, it will produce action potentials sent along the branch of the receptor neuron that projects toward the olfactory bulb. These fibers collectively form the olfactory nerve (cranial nerve I). Olfactory receptors must catalog the over one trillion different smells that we are able to discriminate (Bushdid et al., 2014). Buck and Axel (1991) suggested that mammals can have approximately 1,000 types of receptor cells to accomplish this task, although human beings have about 400 (Trimmer et al., 2019). How do such a small number of receptor types encode information about a wide array of odorants? We still don’t know. A shape-pattern theory suggests that odorant molecules interact with receptors like keys fitting into locks. A modification of this approach suggests that odorants can activate specific combinations of receptors. Overall patterns of receptor activity, as opposed to the response of a single type, could distinguish among many separate odorants. Other researchers believe that the olfactory system responds to the vibration of odorant molecules rather than to their shapes (Brookes et al., 2007; Turin, 2002). Olfactory Pathways One of the dramatic features of the olfactory system is the speed with which information is processed. Just two synapses separate the olfactory receptors from the olfactory cortex. In vision, two synapses don’t even get you out of the retina. The axons from the olfactory receptor cells make their way to one of two olfactory bulbs via the olfactory nerve (cranial nerve I). The olfactory bulbs, along with the hippocampus, are a destination for cells produced in adult neurogenesis (refer to Chapter 5). Cells originating in the ventricular zone of the lateral ventricles migrate forward to the olfactory bulbs, regularly providing a fresh supply of cells for this structure. As the olfactory nerve proceeds toward the olfactory bulbs, it is quite vulnerable to damage, particularly from traffic accidents. As the head is jerked back and forth due to impact, the olfactory fibers leaving the nose can be sheared by the nearby edges of the skull bones (think of the nasal “triangle” of the skeleton). People typically respond to the resulting loss of their sense of smell by developing symptoms of depression and often resort to flavoring their food with pepper sauce to give it some noticeable flavor. In our upcoming discussion of taste, we will find that the

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flavor of a food results from a combination of taste and olfaction, with olfaction playing a leading role. Receptor axons synapse within olfactory bulb structures known as glomeruli. In each glomerulus, approximately 25,000 olfactory receptor axons form synapses on about 100 olfactory neurons. Each glomerulus receives information from only one type of receptor cell. In this manner, precise information about the odorant stimulus is transmitted to the olfactory bulbs. It is likely that the bulbs also participate in some initial sorting of odorant categories, but further work is necessary before an odorant can actually be identified. The processing of components making up complex odors remains separate in the olfactory bulb, suggesting that the integration of these components and the recognition of odors (the perfume of a rose, for example) occurs at even higher levels of processing in the brain. Olfaction is unique among the major senses in that information travels to the cerebral cortex without synapsing in the thalamus first. Axons from the olfactory bulbs form the olfactory tracts. Axons from the olfactory tracts synapse in the olfactory cortex. The olfactory cortex is located at the base of the frontal lobe extending onto the medial surface of the temporal lobe. Unlike the structured organization found in the olfactory bulb, the connections made by the olfactory tracts seem almost haphazard. We do not find that adjacent cells process similar information, perhaps rose and gardenia, as we found in the primary visual, auditory, and somatosensory cortices. How the cortex sorts out this input remains largely unknown. The medial dorsal nucleus of the thalamus, which in turn projects to the insula and the orbitofrontal cortex, finally learns about olfactory input through connections from the olfactory cortex. The orbitofrontal cortex participates in the identification of the pleasant or unpleasant qualities of olfactory stimuli. The olfactory cortex also forms connections with many subcortical structures, including the amygdala and hypothalamus. Olfactory input is intimately associated with the functions of these structures, including the processing of fear and appetite. Disordered Olfaction Olfaction is disturbed in a number of psychological disorders. People with schizophrenia experience deficits in olfaction, possibly due to general problems with frontal lobe functioning (refer to Chapter 16). Recall that most of the olfactory cortex is olfactory bulb Structure receiving input from the olfactory nerves. glomeruli Structures within the olfactory bulb where olfactory receptor axons form synapses with olfactory neurons. olfactory tract A fiber pathway connecting the olfactory bulbs to the olfactory cortex. olfactory cortex Cortex in the frontal and temporal lobes that responds to the sense of smell. medial dorsal nucleus The area of the thalamus that processes olfactory information.

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located within the frontal lobe. Patients’ immediate family members also demonstrate deficits in olfaction relative to healthy controls, suggesting a genetic basis for differences in olfactory function (Compton et al., 2006). Individuals with major depressive disorder, anorexia nervosa, and alcohol use disorder experience specific patterns of olfactory deficits, illustrating the complex relationships between olfaction and emotion (Lombion-Pouthier et al., 2006). Olfaction typically becomes less sensitive with age, but more serious dysfunction in olfaction predicts the development of REM sleep behavior disorder (refer to Chapter 11), Parkinson disease, and Lewy body disease by up to seven years prior to the emergence of other symptoms (Driver-Dunckley et al., 2014). Different patterns of olfactory deficits characterize Alzheimer disease, which might be useful in diagnosing this condition at an early stage.

Gustation The most likely original purpose of our sense of gustation, or taste, was to protect us from eating poisonous or spoiled food. Many bitter-tasting substances are actually poisonous. We are attracted to tastes that boost our chances of survival, such as those associated with sugars and fats. When we eat, we perceive not only the taste of the food but also qualities such as temperature, texture, and consistency (Gibson, 1966). In addition, gustation interacts with olfaction to give us the flavor of a food. You have probably noticed that food just doesn’t taste very good when your sense of smell is decreased by a bad cold. If you close your eyes and hold your nose, you are unable to distinguish between a slice of apple and a slice of raw potato. Gustation begins with the dissolving of molecules in the saliva of the mouth. Saliva is similar in chemical composition to saltwater. Substances that do not dissolve in saliva cannot be tasted, although you can still obtain information about the size, texture, and temperature of objects in the mouth. Five major categories of taste have been identified: sweet, sour, salty, bitter, and umami. Umami tastes are associated with proteins, especially glutamate. In addition, some taste receptors respond to free fatty acids, enabling us to detect the fats in food (Besnard et al., 2016). Still other receptors might alert us to the presence of complex carbohydrates independently of those processing sweetness (Low et al., 2017). Gustation features wide individual differences in sensitivity. Linda Bartoshuk (2000) identified people whom she has named “supertasters,” because they could detect normally subthreshold levels of bitter substances like gustation The sense of taste. umami A taste category associated with the presence of proteins. papilla A bump on the tongue that contain taste buds. taste bud A structure that contains taste receptors.

propylthiouracil (PROP). Not only do these individuals experience taste with greater intensity, giving them what Bartoshuk refers to as a “neon” sense of taste compared to the “pastels” experienced by others, but they also appear to be more sensitive to oral pain and to the texture of foods. If you’re wondering whether you are a supertaster and you don’t have any PROP handy, here are a few clues. People who dislike bitter foods (dark chocolate, black coffee, broccoli) and citrus are more likely to be supertasters. It was believed initially that supertasters have a higher density of papillae, but this does not appear to be the case (Garneau et al., 2014). The reasons for supertaster sensitivities must lie elsewhere. Gustatory Receptors Receptors for taste are found not only on the tongue but also in other parts of the mouth and even in the gut. For our present purposes, we’ll confine our discussion to the receptors of the tongue, displayed in Figure 7.30. Each bump on the surface of the tongue, known as a papilla, contains somewhere between one and 100 taste buds, which are too small to be seen with the naked eye. Some papillae, such as those in the very center of the tongue, contain no taste buds at all. In total, the average person has about 6,000 taste buds, although significant variation can occur from one person to the next. The tongue also contains pain receptors that are sensitive to capsaicin, the main “hot” ingredient in peppers. Mice lacking capsaicin receptors happily consumed water containing capsaicin at levels that were rejected by normal mice (Caterina et al., 1997). Most taste buds contain somewhere between 50 and 150 taste receptor cells. Each taste receptor has a number of thin fibers known as microvilli that extend into the saliva and interact with chemicals processed as tastes. Each taste bud contains a combination of four different types of cells. A first type is structurally similar to an astrocyte and is believed to process sodium (salt). Cells of the second type respond to one of three of the main tastes: sweet, bitter, or umami. A third type processes sour tastes. The fourth type consists of precursor cells that will replace the others as part of a constant renewal process. Taste buds have an average life of 10 days. For many years, researchers believed that receptors for different taste qualities were located in different parts of the tongue. You are probably aware of little maps of the tongue distinguishing between areas where each taste was supposedly sensed. This earlier view is incorrect. Receptors for all taste qualities are found within each taste bud in all areas of the tongue (Huang et al., 2006). While thresholds for certain types of taste might vary by location on the tongue, the differences are so small as to be irrelevant. Gustatory Pathways Pathways linking the taste receptors to the brain are presented in Figure 7.31. Taste receptors make contact with fibers that form parts of cranial nerves VII, IX, and X. These nerves, in turn, form

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The Chemical Senses

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Figure 7.30 The Taste Receptors Tongue

Taste bud Supporting cells

Papillae

Cross-section of a papilla

Taste receptor cells

Microvilli

Ed Reschke/Getty Images

Papilla

Axons of cranial nerves X, IX, and VII

Taste buds

Figure 7.31 Gustatory Pathways to the Brain Primary gustatory cortex

2

Thalamus Forebrain Gustatory cortex

X 1

Cranial nerves VII, IX, X

Medulla Gustatory nucleus

Tongue Cranial nerves VII, IX, X Taste receptors

1

2 Gustatory nucleus

VPM nucleus of the thalamus

Ventral posterior medial (VPM) nucleus of the thalamus

2 Gustatory cortex

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Frank Schwichtenberg//Wikimedia Commons

Cranial nerve VII IX

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synapses with the gustatory nucleus, which is a part of the solitary nucleus of the medulla. Axons from the gustatory nucleus synapse in the ventral posterior medial (VPM) nucleus of the thalamus. Finally, axons from the VPM nucleus synapse in the gustatory cortex at the junction of the frontal and parietal lobes, extending into the anterior insula (de Araujo & Simon, 2009). The

gustatory nucleus A location within the solitary nucleus that receives gustatory input from cranial nerves VII, IX, and X. ventral posterior medial (VPM) nucleus of the thalamus The nucleus of the thalamus that receives information regarding taste. gustatory cortex Area at the junction of the frontal lobe, parietal lobe, and insula that processes gustatory information. synaesthesia Experience in one sensory pathway elicits an automatic activation in another sensory pathway.

recognition of a type of taste is probably determined at this level. Other fibers make their way to the orbitofrontal cortex. As in the case of olfaction, this input probably encodes the pleasantness, or emotional qualities, of taste. The orbitofrontal cortex is also the likely location for a convergence between olfaction and taste leading to the perception of flavor. Taste information is sent to the hypothalamus and amygdala to support reward and appetite processing related to taste.

Synaesthesia In synaesthesia, a stimulus in one sensory modality immediately elicits an involuntary perception in another modality, such as hearing smells or seeing tastes (Brang & Ramachandran, 2011). The relationship between the

Behavioral Neuroscience Goes to Work What Is a Perfumer? scents, known as an “organ.” After further training, the perfumer will be tasked with creating new fragrances. Because of the complexity involved in the training, perfumers usually specialize in fine fragrances (perfumes), personal care fragrances, and household fragrances. Do perfumers have a naturally superior sense of smell? According to brain imaging studies of student and expert perfumers, the answer to this question is probably “no” (Plailly et al., 2012). Instead, the extensive training and experience of the expert perfumers appears to enhance their ability to generate olfactory mental images. Changes in the primary olfactory cortex, orbitofrontal cortex, and hippocampus are associated with improved memory for odors.

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A quick tour of your home will reveal a large number of products containing scent, from your shampoo to your laundry detergent. Who designs these scents, and what is their method? A perfumer, often called “a nose,” is responsible for creating fragrances to be used not just in perfume but in many other household products as well. For many years, perfumers learned their craft as apprentices, but professional training schools have emerged in the past few decades. Entrance to these schools usually requires a background in chemistry. Training to become a perfumer begins with the memorization of hundreds of both natural and synthetic materials, followed by learning how to combine “notes.” Figure 7.32 presents a “nose” at work in front of her array of

Figure 7.32 A Perfumer at Work A perfumer, or “nose,” works at her organ. Perfumers must develop the ability to remember large numbers of scents.

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Synaesthesia

combined modalities is one-way. A person for whom a particular musical note elicits a color will not hear the note when seeing the color first. Synaesthesia develops spontaneously in about four percent of the population but can also occur as a result of epilepsy, brain damage, or the use of hallucinogens. Developmental synaesthesia usually appears for the first time in childhood and remains stable within individuals. In other words, a person seeing the letter “A” as red will do so consistently over time. However, the specific associations take many forms across the population that experiences synaesthesia. Synaesthesia has a strong genetic component and is associated with higher levels of artistic and creative behavior (refer to Figure 7.33; Ward et al., 2008). Grapheme-color synaesthesia, the combining of letters or numerals and color, has been the most thoroughly studied variety. Evidence from brain imaging supports more of a bottom-up than top-down basis for this experience (Brang & Ramachandran, 2011). In other words, grayscale letters stimulate activity in parts of the visual cortex known to process color in the brains of people who associate letters with particular colors. A top-down approach would predict more activity in higher order

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association areas of the brain, but this is not supported by the data. People with synaesthesia also have increased connectivity and white matter volume in relevant areas of their brains, possibly due to lower levels of synaptic pruning early in development (refer to Chapter 5). Synaesthesia might also result from imbalances between excitatory and inhibitory circuits, which might explain why it appears in cases of epilepsy, brain damage, or the use of hallucinogens. A dramatic case of synaesthesia was described by the Russian neuroscientist Alexander Luria (1968). Luria’s patient, Shereshevskii, not only experienced synaesthesia but also possessed a remarkable memory due to the distinctiveness of his sensory experiences. Shereshevskii described a tone as “a brown strip against a dark background that had red, tongue-like edges. The sense of taste he experienced in response to this tone was like that of sweet and sour borscht, a sensation that gripped his entire tongue” (Luria, 1968, p. 23). Despite Shereshevskii’s experience of enhanced memory, the memory of most people with synaesthesia is better than controls but not by extraordinary amounts (Ward et al., 2019). The difference between people with and without synaesthesia was more pronounced in long-term memory than in working memory (refer to Chapter 12).

Interim Summary 7.3

Figure 7.33 Musicians Report Experiencing Synaesthesia

Summary Points 7.3

Among the many professional musicians who report synaesthesia between sound and color is Pharrell Williams. People with synaesthesia often exhibit better than normal creativity.

1. Olfactory receptors lining the olfactory epithelium of the nasal cavity respond to airborne molecules by sending messages via the olfactory nerve to the olfactory bulb. The olfactory bulb axons project to the olfactory cortex, which forms widely distributed connections with the cerebral cortex and the limbic system. (LO5)

Frank Schwichtenberg//Wikimedia Commons

2. Interactions between taste receptors and dissolved chemicals activate parts of cranial nerves VII, IX, and X, which synapse with the gustatory nucleus of the medulla. Gustatory nucleus axons synapse in the ventral posterior medial nucleus of the thalamus, which in turn projects to the gustatory cortex and to the orbitofrontal cortex. (LO5) 3. Some individuals have cross-modal sensory experiences, known as synaesthesia. For example, they might see a particular grayscale letter as having a consistent color. (LO6) Review Questions 7.3 1. What are the major features of olfactory receptors? 2. How are individual tastes encoded? 3. What are the possible causes of synaesthesia?

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Summary Table 7.3: Major Features of the Chemical Sensory Systems Sensory Modality

Receptor Types

Pathways and Connections ●

Olfaction

Bipolar cells embedded in the olfactory epithelium

●

●

●

Gustation

Taste buds on the tongue and elsewhere in the mouth

● ●

●

Chapter Review T h ough t Qu est ion s 1. If you had to give up one of your senses, which one would it be, and why? 2. What steps can you take to reduce environmental causes of hearing loss? 3. Why does the representation of pain information in the CNS make it difficult to treat chronic pain with surgery? 4. How might the gradual loss of olfactory sensitivity affect the eating habits of seniors?

K e y Ter m s amplitude (p. 210) audition (p. 210) auditory nerve (cranial nerve VIII) (p. 215) basilar membrane (p. 215) cochlea (p. 214) decibel (dB) (p. 212) frequency (p. 211) gate theory of pain (p. 235) glomerulus (p. 241) gustation (p. 242) gustatory cortex (p. 244) hertz (Hz) (p. 212) infrasound (p. 212) intensity (p. 211) intralaminar nuclei (p. 235) mechanoreceptors (p. 227) medial dorsal nucleus (p. 241) medial geniculate nucleus (MGN) (p. 216)

Axons from the receptors synapse in the glomeruli of the olfactory bulbs. Axons from the olfactory bulbs form the olfactory tract and synapse in the olfactory cortex. The olfactory cortex sends information to the thalamus, limbic system, insula, and orbitofrontal cortex. Fibers serving the taste receptors join cranial nerves VII, IX, and X. These axons synapse in the gustatory nucleus of the medulla. Axons from the gustatory nucleus synapse in the ventral posterior medial (VPM) nucleus of the thalamus. VPM axons synapse in the gustatory cortex.

Meissner corpuscle (p. 228) Merkel cell (p. 228) nociceptor (p. 235) olfaction (p. 239) olfactory bulb (p. 241) olfactory cortex (p. 241) olfactory epithelium (p. 240) olfactory tract (p. 241) organ of Corti (p. 215) ossicle (p. 214) otolith (p. 225) otolith organ (p. 225) Pacinian corpuscle (p. 228) pain (p. 234) papilla (p. 242) pinna (p. 213) place theory (p. 219) primary auditory cortex (p. 218) primary somatosensory cortex (p. 226) Ruffini ending (p. 228) saccule (p. 225) semicircular canals (p. 225) somatosensory system (p. 224) spiral ganglion neuron (p. 215) substantia gelatinosa (p. 235) synaesthesia (p. 244) taste bud (p. 242) temporal theory (p. 219) tonotopic organization (p. 219) ultrasound (p. 212) umami (p. 242) utricle (p. 225) ventral posterior medial (VPM) nucleus of the thalamus (p. 244) ventral posterior (VP) nucleus of the thalamus (p. 226) vestibular system (p. 225)

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Chapter 8 Learning Objectives L01

L02

L03

Describe the physical structure of muscle fibers and explain the process of muscle fiber contraction. Explain the processes responsible for the initiation and control of muscle contractions. Differentiate among the structures and processes responsible for providing feedback from muscles to the central nervous system.

L04

Describe the major motor reflexes.

L05

Explain the initiation and control of movement.

L06

Identify the causes, symptoms, and treatments of major disorders of movement.

Movement Chapter Outline The Basal Ganglia The Motor Cortex

Muscles

Types of Muscles Muscle Anatomy and Contraction The Effects of Exercise on Muscle The Effects of Aging on Muscles

Interim Summary 8.2 Disorders of Movement

Toxins Myasthenia Gravis Muscular Dystrophy Polio Accidental Spinal Cord Injury (SCI) Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s Disease) Parkinson Disease Huntington Disease

Neural Control of Muscles

Alpha Motor Neurons The Motor Unit The Control of Muscle Contractions The Control of Spinal Motor Neurons

Interim Summary 8.1 Reflex Control of Movement

Reciprocal Inhibition at Joints The Flexor Reflex Central Pattern Generators Reflexes Over the Lifespan

Motor Systems of the Brain

Interim Summary 8.3 Chapter Review

Spinal Motor Pathways The Cerebellum

Thinking Ethically: Gene Doping by Athletes Connecting to Research: Intention to Move and Free Will Behavioral Neuroscience Goes to Work: Physical Therapy and the Neurologic Clinical Specialty Neuroscience in Everyday Life: How to Repair a Gene 247

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Muscles Muscles make up the majority of the human body’s tissues and are responsible for the movement of the body and the movement of materials within the body.

through the digestive tract, control blood pressure, and mix sperm with seminal fluid, among other tasks. The smooth muscles are controlled by the autonomic nervous system (refer to Chapter 2). Striated muscle, named after its striped appearance, can be further divided into two types, cardiac muscle and

Types of Muscles The muscles of the body, presented in Figure 8.1, can be divided into two types based on their appearance: smooth muscle and striated muscle. Smooth muscle is found in the lining of the digestive tract, within the arteries, and in the reproductive system. Smooth muscles move nutrients

smooth muscle A type of muscle found in the lining of the digestive tract, within arteries, and in the reproductive system; controlled by the autonomic nervous system. striated muscle A type of muscle named for its striped appearance; includes cardiac and skeletal muscles.

Figure 8.1 The Human Body Has Three Types of Muscle Muscle types are named after their appearance or location. (a) Smooth muscle is found in the digestive tract, blood vessels, and reproductive system. (b) Striated (striped) muscle gets its name from its striped appearance. There are two types of striated muscle. Cardiac muscle keeps our hearts beating. Skeletal muscles move our bones, eyes, and lungs.

Jose Luis Calvo/Shutterstock.com

Cardiac muscle

Tinydevil/Shutterstock.com

Science History Images/Alamy Stock Photo

Skeletal muscle

Intestinal smooth muscle

(a) Smooth Muscle

(b) Striated Muscle

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Muscles

skeletal muscle. Cardiac muscle produces the pumping action of the heart. The skeletal muscles attached to bones produce the majority of body movement. Other skeletal muscles are responsible for moving our eyes and lungs. The human body contains somewhere between 640 and 850 skeletal muscles, depending on which anatomist you ask. Our discussion of movement will focus on the skeletal muscles because these are responsible for the majority of our behavior.

Muscle Anatomy and Contraction Skeletal muscles, depicted in Figure 8.2, are made up of long, very thin cells referred to as muscle fibers. Human muscle fiber cells usually extend the length of the muscle

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and are up to 30 cm (11 in) long and from 0.05 mm (0.002 in) to 0.15 mm (0.006 in) wide. The Muscle Fiber The membranes encasing each muscle fiber are similar to the membranes of neurons. Like neural membranes, the muscle fiber membrane contains receptor sites, in this case for the neurochemical acetylcholine (ACh). When a molecule of ACh binds to a receptor site in cardiac muscle A type of striated muscle found in the heart. skeletal muscle A type of striated muscle that is attached to bones and is responsible for the majority of body movements. muscle fiber An individual muscle cell.

Figure 8.2 The Anatomy of a Muscle The building blocks of muscles are the sarcomeres, which contain filaments made of the proteins actin and myosin. Sarcomeres laid end to end make up the muscle fiber, and bundles of muscle fibers make up the muscle. Muscles are enclosed and attached to bones by tendons, a type of connective tissue.

Muscle Tendons

Bundle of fibers Axon of motor neuron

Muscle cell (fiber)

Neuromuscular junction Axon terminal of motor neuron

Muscle fiber membrane

Acetylcholine Muscle cell nuclei

Muscle fiber membrane

M line

Actin Myosin

Myosin Actin

Myofibril

Z line Z line

M line Sarcomere

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the muscle fiber membrane, sodium channels open. Sodium rushing into the muscle fiber depolarizes the cell and triggers an action potential. In Chapter 3, we observed that action potentials in neurons travel in only one direction—from the axon’s initial segment down the length of the axon. In contrast, the action potential in a muscle fiber spreads out in two directions on either side of the receptor site, which is located in the middle of the fiber. Each action potential produces a single contraction of the muscle fiber, known as a twitch. twitch The contraction of a single muscle fiber. myofibril A long fiber strand running the length of a muscle fiber that is responsible for contraction. sarcomere A myofibril segment bound on either side by a Z line and spanned by thin filaments. Z line A boundary line for each sarcomere within a myofibril. actin A protein that makes up the thin filaments of the myofibril. myosin A protein that makes up the thick filaments of the myofibril. M line The middle of the sarcomere where myosin fibers are anchored.

The Structure of Myofibrils The interior of the muscle fiber is made up of long strands of protein called myofibrils. The myofibrils run the length of the fiber and are responsible for producing fiber contractions. Single segments of a myofibril are called sarcomeres, which are arranged end to end. The boundary of each sarcomere is known as a Z line because the boundary looks like a Z shape under a microscope. Attached to each Z line are a number of thin filaments made up of the protein actin. Lying between each pair of thin filaments is a thick filament made up of the protein myosin. Myosin filaments are anchored at the middle of the sarcomere, known as the M line. Muscle Fiber Contraction Muscle contractions are caused by the movement of the thick myosin filaments along the length of the thin actin filaments. As the filaments slide by each other, the Z lines move closer together, and the sarcomere shortens. As the sarcomeres shorten, the muscle contracts. This process is presented in Figure 8.3.

Figure 8.3 Muscle Contraction Fully relaxed

M line

Partially contracted

Fully contracted

Fully relaxed

Sarcomere

Myosin filaments Actin filaments Z line

1 1. In the resting muscle, tropomyosin

prevents interaction between actin and myosin. 2. Action potential releases Ca2+, which binds with troponin. 3. Troponin displaces tropomyosin, allowing actin and myosin to interact.

2 1. Myosin binds to actin.

2. Myosin filaments rotate and move relative to actin, shortening the sarcomere.

3 1. Reuptake of calcium

frees troponin. 2. Tropomyosin blocks interaction of myosin and actin once again. 3. The filaments slide apart.

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Muscles

In a resting muscle fiber, actin binding sites are covered by the protein tropomyosin, which prevents actin from interacting with myosin. The arrival of an action potential at the muscle fiber is the catalyst for a series of events that allows actin and myosin to interact. The action potential triggers the release of calcium from internal organelles within the muscle fiber. Calcium, in turn, binds with another protein, troponin, which then displaces tropomyosin. Now unblocked, actin can bind with myosin. As a result of the binding of actin and myosin, the myosin molecules rotate, causing the thick myosin filaments to slide past the thin actin filaments. In a process requiring energy, the myosin molecules subsequently separate from the actin molecules. As long as calcium and energy are still present in the muscle fiber, the binding and unbinding process repeats itself, and the myosin filaments move step by step along the length of the actin filaments, pulling the Z lines closer to the M line. Consequently, the muscle fiber gradually contracts. In the absence of further action potentials, the muscle fiber will relax. Calcium is taken up again by the internal organelles in a process similar to the reuptake of a neurochemical by a presynaptic neuron. When troponin is no longer bound by calcium, tropomyosin once again blocks the interaction of myosin and actin, and the thin and thick filaments slide apart. The sarcomeres and the muscle fiber return to their resting length. If there is a shortage of energy in the cell, the detachment of myosin molecules from actin molecules can’t take place, and the muscle becomes locked in its contracted state. This process accounts for the muscle stiffness, or rigor mortis, that occurs after death. Fiber Types and Speed In humans, the thick myosin filaments in muscle fibers come in three varieties. Type I fibers are known as slow-twitch fibers, and types IIa and IIb are known as fast-twitch fibers. Type IIa fibers are also known as fast-twitch fatigue-resistant fibers, while type IIb are known as fast-twitch fatigable fibers. Type IIb fibers can contract up to 10 times faster than type I fibers. The contraction velocity of type IIa fibers falls somewhere between type I and type IIb (Scott et al., 2001). Most skeletal muscles contain mixtures of all three types of fibers but in different proportions. The postural muscles of the back, neck, and legs are dominated by slow-twitch fibers. The muscles of the arms and shoulders contain higher proportions of fast-twitch fibers. Fast- and slow-twitch fibers use energy differently. Slowtwitch fibers use aerobic metabolism, which requires oxygen, while the fast-twitch fibers use anaerobic metabolism, which occurs in the absence of oxygen. Endurance activities, such as distance running, rely primarily on aerobic slow-twitch fibers. Explosive, powerful movements, such as sprinting, jumping, and weightlifting, employ anaerobic fast-twitch fibers. Muscles dominated by fast-twitch fibers appear white (like the white meat of a turkey breast), and those containing slow-twitch fibers appear dark or red (like the dark meat of a turkey’s legs and thighs). The red color reflects the presence of myoglobin, an iron-based muscle protein that stores the

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oxygen necessary for aerobic metabolism, and the larger numbers of capillaries. Diving animals, such as seals and whales, owe part of their ability to remain submerged to the unusually high amounts of myoglobin contained in their muscles. The average adult human has approximately equal numbers of fast- and slow-twitch fibers in the quadriceps muscle on the front of the thigh. However, people vary widely in the composition of their muscles. Andersen et al. (2000) identified people with as few as 19 percent slow-twitch fibers in the quadriceps and other people with up to 95 percent slowtwitch fibers. This variation is heavily influenced by a single gene, ACTN3, which normally encodes a protein used by fasttwitch fibers (MacArthur & North, 2007). If people receive two copies of a common mutation of the ACTN3 gene, they will produce none of the fast-twitch protein at all. People with a particular allele of ACTN3 excel in speed and strength activities, recover faster from exercise, and are less prone to injury (Pickering & Kiely, 2017). The proportion of fast- and slowtwitch fibers in the quadriceps muscle of people engaged in different levels of activity is presented in Figure 8.4.

The Effects of Exercise on Muscle We know that exercise can build muscles. In many cases, muscle enlargement is desirable. However, enlargement of the cardiac muscle can result in life-threatening heart disease. Muscle enlargement occurs in response to muscle fiber damage. When fibers are damaged due to weightlifting or other strenuous activity, more actin and myosin filaments are produced. Lack of activity reverses this process quickly because filament proteins are either broken down faster or synthesized more slowly when muscles are not used. During space travel, in which lower gravity reduces the activity of major postural muscles, astronauts can lose as much as 20 percent of their muscle mass in as little as two weeks (Andersen et al., 2000). Changes in muscle fiber type can occur. People who are paralyzed because of a spinal cord injury experience a dramatic increase in fast-twitch fibers and a loss of slow-twitch fibers (refer to Figure 8.4). Neural input to the muscle, which is lacking in cases of spinal cord injury, is necessary for the maintenance of slow-twitch, but not fast-twitch fibers. tropomyosin A protein that covers actin binding sites in a resting muscle fiber, preventing actin from interacting with myosin. troponin A protein that, when bound by calcium, displaces tropomyosin, allowing actin to interact with myosin. slow-twitch fiber A muscle fiber containing type I myosin filaments and large numbers of mitochondria that contracts slowly using aerobic metabolism; primarily responsible for movement requiring endurance. fast-twitch fiber A muscle fiber containing type IIa or type IIb myosin filaments that contains few mitochondria, uses anaerobic metabolism, and contracts rapidly; primarily responsible for movement requiring explosive strength. aerobic metabolism A chemical process that requires oxygen. anaerobic metabolism A chemical process that does not require oxygen.

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Figure 8.4 Human Fiber Types (a) The proportion of fast- and slow-twitch muscles varies from person to person. People with spinal injuries lose most of their slow-twitch fibers. Athletes involved in power events, such as sprinting, usually have a higher proportion of fast-twitch muscles than athletes involved with endurance sports. (b) Because fast fibers produce muscle tension very quickly, they are useful for explosive movements such as sprinting and weightlifting. The slower fibers can produce equal tension but require a longer time to do so. Slower fibers are used in endurance activities such as long distance running and swimming. (a)

(b) Fast fiber

Person with spinal injury

Slow fiber

Tension

Elite sprinter Typical inactive person Typical active person Middle-distance runner Elite marathon runner Extreme endurance athlete

0

0

10

20

30 40 50 60 70 Percentage of total muscle

80

90

150 50 100 200 Time after activation (msec)

250

100

Slow twitch Type IIa Type IIb Fast twitch Source: Data from Anderson et al. (2000).

The Effects of Aging on Muscles The loss of muscle mass from aging begins as early as age 25 and accelerates through the remainder of the life span. By the age of 50, most people have lost at least 10 percent of the muscle mass they had at age 25, and that figure rises to 50 percent by the age of 80. The loss of muscle consists

of a reduction in the number of muscle fibers. This, in turn, results from a number of factors, including a sedentary lifestyle and chronic inflammation, but a key factor is age-related malfunctioning of mitochondria (Picca et al., 2018). Figure 8.5 demonstrates how the muscle fibers of young people presented in cross-section are angular, but in older

Figure 8.5 Aging Affects the Quantity, Shape, and Distribution of Muscle Fibers

Courtesy Jesper L. Andersen, Copenhagen Muscle Research Center

Courtesy Jesper L. Andersen, Copenhagen Muscle Research Center

As we age, we lose muscle fibers, which cannot be regrown. A comparison of the young muscle in the left photo with the aged muscle in the right photo shows other changes. The young muscle has angular-shaped fibers and a checkerboard distribution of fast (light) and slow (dark) twitch muscles. The aged muscle shows rounded fibers and clustering of fiber types.

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Neural Control of Muscles

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Thinking Ethically Gene Doping by Athletes & Bermon, 2013). The strong likelihood that athletes would manipulate combinations of genes, not single genes, would further complicate detection (van der Gronde et al., 2013). Myostatin is a protein that normally inhibits muscular growth. Inhibition of myostatin due to genetic mutation is associated with unusual musculature and strength. The remarkable musculature of Belgian blue cattle, like the one in Figure 8.6, results from a mutation in the myostatin gene. Researchers have already identified ways to use CRISPR gene-editing methods to knock out the myostatin gene in horse embryos (Moro et al., 2020). Increasing musculature on a frame that was not designed to support it, however, is risky. It is likely that athletes manipulating myostatin would suffer the same or even worse problems with damage to bones and connective tissue already experienced by those who use anabolic steroids to boost muscle growth.

Eric Isselee/Shutterstock.com

Athletics represents the nature of competition, and athletes appear to be willing to go to great lengths to achieve a “competitive edge.” The current use of performance-enhancing drugs, such as anabolic steroids, might be eclipsed in the near future by new, genetically based methods to get ahead. Gene doping refers to the use of nucleic acids (genetic material) to enhance sport performance. Gene doping is forbidden by the organizations governing human sports and horse racing, but with current technologies, it is difficult if not impossible to detect (Moro et al., 2020; Tozaki & Hamilton, 2022). Among the many targets for gene doping are myostatin, erythropoietin (EPO), insulin-like growth factor-1 (IGF-I), and growth hormone (GH) (Cantelmo et al., 2020). Genetic treatments targeting diseases such as muscular dystrophy (described later in this chapter) could potentially be hijacked by athletes (Fischetto

adults, the fibers are rounder. In addition, youthful muscles have a more even distribution of slow- and fast-twitch fibers. In the muscle of the older adult, the types cluster together. Older adults have a much higher proportion of hybrid muscles, neither slow nor fast, when compared with younger people, largely due to a selective atrophy of type II fibers. Age-related changes also occur in the neurons that control muscles. When older adults move a muscle, the firing rates of the associated neurons are lower than the rates observed in younger adults, resulting in slower and weaker muscle responses (Knight & Kamen, 2007). During adulthood, muscle fibers experience cycles of disconnection from the motor neurons that serve them followed by reconnection with either the original axon or a collateral from a nearby axon (Hepple & Rice, 2016). Eventually, these cycles of denervation–reinnervation take a toll on the structure of the neuromuscular junction. Fibers that are not reinnervated will atrophy. Although one cannot stop age-related

Figure 8.6 Myostatin and Muscle Development The replacement of typical genes with genes that enhance performance, or gene doping, might someday replace the use of anabolic steroids and other drugs to improve athletic performance. One candidate for genetic modification is the gene for myostatin, a protein that limits muscular growth. Belgian Blue cattle, like the 8-month-old bull in this image, have a mutation in the myostatin gene that produces unusual muscle development.

changes in muscle fibers and neural firing rates, remaining physically active can help offset this decline.

Neural Control of Muscles The contraction of skeletal muscles is directly controlled by motor neurons originating in either the spinal cord or in the nuclei of the cranial nerves in the brainstem. Just as skeletal muscles are not evenly distributed throughout the body, motor neurons are not evenly distributed throughout the spinal cord. As depicted in Figure 8.7, the ventral horns of the spinal cord, which contain the motor neurons, appear larger in segments C (Cervical) 3 through T (Thoracic) 1 and again in L (Lumbar) 1 through S (Sacral) 3. The enlargement of the ventral horns in these areas is due to the greater number of motor neurons required to innervate the muscles of the arms and legs, respectively.

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Figure 8.7 Distribution of Spinal Motor Neurons

The Motor Unit

A motor unit is made up of a single alpha motor neuron and all the muscle fibers it innervates. Although a single muscle fiber receives input from only one alpha motor neuron, alpha motor neurons can innervate many muscle fibers via their collaterals. Muscles used in fine movement (such as those in the hands and fingers) are controlled by motor neurons that innervate smaller numCervical enlargement bers (10–100) of muscle fibers. This allows (C3–T1) for the coordinated but individualized control of muscle fibers needed for precise movement. Muscles that are not involved with fine movement, like your back or thigh Midthoracic muscles, are controlled by motor neurons Larger ventral region serving 1,000 or more muscle fibers. horn area (T5–T9) A single motor unit includes either fastor slow-twitch fibers but not a mixture Lumbar of both. Motor neurons serving slow-twitch enlargement (L1–S3) muscles have smaller cell bodies and innerSmaller ventral vate fewer muscle fibers. Consequently, horn area these units generate relatively little force. In contrast, motor neurons serving the very fast IIb fibers have relatively large cell bodies and large-diameter axons, which are capable of rapid signaling. These motor units generate 100 times the force produced by Larger ventral horn area units made up of slow-twitch fibers (Loeb & Ghez, 2000). Motor units containing type IIa fibers fall between these extremes. The motor units innervating the fibers making up a single muscle, such as the quadriceps muscle of your thigh, are collectively known as a motor neuron pool. The cell bodies of motor Alpha Motor Neurons neuron pools form column-shaped nuclei in the spinal cord. The spinal motor neurons directly responsible for contracting muscles are known as alpha motor neurons. These are large, myelinated neurons capable of rapid sigFigure 8.8 The Neuromuscular Junction naling. The alpha motor neurons form highly efficient This image shows alpha motor neurons making contact connections with muscle fibers at a location called the with individual muscle fibers. The little dots at the end of neuromuscular junction, presented in Figure 8.8. Because each motor neuron fiber are individual axon terminals. of the efficiency of this connection, the arrival of a single action potential in the motor neuron terminal is capable of producing an action potential in the muscle fiber, leading to a single contraction, or twitch. alpha motor neuron A spinal motor neuron directly responsible for signaling a muscle fiber to contract. neuromuscular junction A synapse formed between an alpha motor neuron axon terminal and a muscle fiber. motor unit The combination of a single alpha motor neuron and all the muscle fibers that it innervates. motor neuron pool The collection of motor neurons that innervates a single muscle.

Kent Wood/Science Source

The spinal cord bulges in the segments that serve the arms and legs due to the large number of alpha motor neurons located in the ventral parts of those segments. In comparison, relatively few alpha motor neurons serve the torso.

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Neural Control of Muscles

The Control of Muscle Contractions As mentioned previously, a single action potential in the alpha motor neuron usually results in a single contraction in the associated muscle fiber. How, then, do we manage to produce muscular movements of different forces and durations? There are two methods for controlling the force of our movements. The first method, the rate code, is to vary the firing rate of motor neurons. Rapid firing by the motor neuron produces a sustained contraction in the muscle fiber. Contractions last longer than action potentials, allowing temporal summation to occur at the neuromuscular junction (refer to Chapter 3). The muscle fiber responds with increasing contraction. When the muscle cannot contract any farther, it has reached a state known as tetanus. This term is also used to describe the extreme muscle contraction resulting from infection by the bacterium Clostridium tetani and its neurotoxin, tetanospasmin, discussed in Chapter 3. The second method for varying muscle responses is known as recruitment, or the “size principle.” As an increased load is placed on a muscle, such as when you pick up a heavy object, more motor units are recruited to provide extra tension in the muscle. Recruitment proceeds according to the nature of the motor units. Smaller, slow-twitch units are recruited first, followed by the intermediate type IIa units, and finally, the largest, fastest type IIb units. The smaller neurons that innervate slow-twitch fibers are more easily excited by synaptic input, which explains why they are recruited first. Recruiting the smaller motor units first ensures that the body uses the least amount of force and energy to get a job done.

The Control of Spinal Motor Neurons The alpha motor neurons do not initiate movement on their own. Instead, these neurons react to information about the external environment and the current state of the body. To respond appropriately, alpha motor neurons require input from three types of neurons: neurons from muscle spindles and Golgi tendon organs, neurons of the brainstem and motor cortex, and spinal interneurons. Feedback From the Muscle Spindle Muscle spindles are specialized sensors that form part of a feedback loop from the muscle fibers to the spinal cord. If an object, a cup of coffee, for example, is placed in your outstretched hand, your hand might initially drop a bit in response to the weight of the cup before returning to its original position. You compensate for the added weight in your hand, which initially stretches the muscles of your arm, by increasing contraction in them. This adjustment requires a precise feedback loop that measures how much your muscles have stretched. The first element in the feedback loop is the muscle spindle. Muscle spindles are structures embedded in the muscle that serve as a source of information about muscle length. The spindle gets its name from its shape, which is similar to the spindle on a spinning wheel.

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Each muscle spindle contains approximately a dozen intrafusal muscle fibers. Fusal comes from the Latin word for “spindle,” so the intrafusal fibers are located “within the spindle.” Muscle fibers responsible for contraction, which have been the subject of our discussion up to this point, are extrafusal muscle fibers, or fibers “outside the spindle.” Muscle spindles lie parallel to the extrafusal fibers, so when the muscle stretches, so do its associated spindles. Muscles needed for fine motor movements, such as those in the hand, have more muscle spindles than do muscles used primarily for force, such as those in the torso and legs. Larger numbers of muscle spindles provide the more precise feedback required for fine movements. Figure 8.9 presents three types of muscle spindle fibers: nuclear chain fibers, static nuclear bag fibers, and dynamic nuclear bag fibers. The distinction between the

rate code Variations in the firing rate of motor neurons to meet the need for a certain amount of contraction. tetanus The point at which a muscle cannot contract farther. recruitment The process of gradually activating more motor units as an increasing load is placed on a muscle. muscle spindle A sensory structure that provides feedback regarding muscle stretch. intrafusal muscle fiber One of the fibers that makes up a muscle spindle. extrafusal muscle fiber One of the fibers outside the muscle spindle that is responsible for contracting the muscle.

Figure 8.9 Types of Muscle Spindle Fibers Three types of muscle spindle fibers are named after their shape (bag or chain) and their function (static or dynamic). The length of an unmoving muscle is signaled by the static nuclear bag fibers and the nuclear chain fibers. The rate of change in the length of a muscle (its velocity) is signaled by the dynamic nuclear bag fibers. Dynamic nuclear Static nuclear Nuclear bag fiber bag fiber chain fiber

la II g

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types is based on their structure and the type of information each communicates. Nuclear chain fibers and static nuclear bag fibers provide information about the length of a muscle. Dynamic nuclear bag fibers provide

information about the rate of change in the length of a muscle, or its velocity of change. Wrapped around the middle section of each type of spindle fiber are very large, very fast axons known as group Ia sensory fibers. Ia fibers are a type of the Aα fibers we mentioned in Chapter 7 (refer to Figure 7.17). These fibers generate action potentials every time the muscle nuclear chain fiber A type of muscle spindle fiber that provides spindle stretches. Because the Ia fibers interact with all information about muscle length. three types of muscle spindle fibers, they provide informastatic nuclear bag fiber A type of muscle spindle fiber that tion about both length and velocity. Contacting only the provides information about muscle length. static nuclear bag fibers and the nuclear chain fibers are dynamic nuclear bag fiber A type of muscle spindle fiber that group II sensory fibers (a type of Aβ fiber). Because these provides information about the velocity of change in the length of a muscle. fibers do not interact with the dynamic nuclear bag fibers, they provide information about length, but not velocity. Ia sensory fiber A large and fast sensory axon that connects a muscle spindle to neurons in the spinal cord. Group Ia fibers fire rapidly during the stretch of a muscle group II sensory fiber Sensory fiber that provides information (length plus velocity) but begin to fire more slowly at the about muscle length. end of the stretch (length only). In contrast, the group II myotatic reflex The contraction of a muscle in response to fibers fire rather steadily as a muscle is stretched. Within sensory information about being stretched. the spinal cord, the group Ia and group II fibers synapse on monosynaptic reflex A spinal reflex, such as the patellar reflex, interneurons and on the alpha motor neurons. that requires the action of only one synapse between sensory and motor neurons. Here’s how the system works. As the cup in our example patellar tendon reflex A spinal, monosynaptic, myotatic reflex in is placed in your hand, your arm muscle will stretch due to which stretching the quadriceps muscle results in the foot kicking the added weight. The stretching of your arm muscle will upward. also stretch the muscle spindle. The Ia and II fibers surrounding the muscle spindle fibers will sense the increased stretch and will excite the Figure 8.10 The Patellar Tendon (Knee-Jerk) Reflex alpha motor neurons in the The familiar patellar tendon or knee-jerk reflex tested by physicians during annual physicals spinal cord. Excitation of the is an example of a monosynaptic, myotatic reflex. Monosynaptic reflexes involve single alpha motor neurons will synapses between sensory and motor neurons. Myotatic reflexes occur when stretching cause the muscle to balance of a muscle initiates a compensating contraction. the stretch with further contraction. The cup is now safe. 3 The Ia sensory fibers stimulate Contraction in response alpha motor neurons in the spinal cord. to sensing stretch is known as Ia sensory fiber a myotatic reflex. Myotatic Spinal cord 2 The Ia sensory fibers in reflexes are examples of muscle spindles sense monosynaptic reflexes, in increased stretch. which only a single synapse Alpha between a sensory neuron motor neuron 1 Hammer tap stretches and a motor neuron is quadriceps muscle. 4 Alpha motor neurons cause involved. In addition to helpquadriceps muscle to contract. ing us hold a cup of coffee, myotatic reflexes allow us to Muscle spindle maintain a steady posture. Tilting to the side stretches Quadriceps muscle muscles, and the resulting Patellar tendon contractions from the myotatic reflex pulls you back to center. Another familiar 5 Foot kicks. type of myotatic reflex is the patellar tendon reflex (knee-jerk reflex) often performed as part of an annual physical (refer to Figure 8.10). The physician

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Neural Control of Muscles

taps the tendon located just below the knee, stretching the quadriceps muscle of the thigh. To compensate for the stretch, the quadriceps contracts, and the foot kicks out. This test helps to determine whether a person’s myotatic reflexes are in good working order. Reduced responses are often associated with peripheral nervous system damage while exaggerated responses are associated with central nervous system damage (Guertin, 2013). Some medical conditions, such as diabetes and Parkinson disease, reduce or eliminate the reflex. Other medical conditions, such as meningitis (discussed in Chapters 2 and 15), often produce exaggerated responses. We have mentioned previously that the alpha motor neurons provide input to the extrafusal fibers. The intrafusal fibers have their own set of motor neurons known as gamma motor neurons, depicted in Figures 8.9 and 8.11. Why would the intrafusal fibers need input when they do not

contribute to the overall contraction of a muscle? Without the gamma motor neurons, the intrafusal fibers could not provide accurate information. When the extrafusal fibers contract, the intrafusal fibers would become limp if they did not also contract. This would cause the Ia and II sensory fibers to stop signaling, and the brain and spinal cord would not know how long the muscle was. To solve this problem, gamma motor neurons and alpha motor neurons are activated simultaneously. The gamma motor neurons cause a small contraction of the spindle at nearly the same time that the alpha motor neurons contract the extrafusal fibers. In this way, the spindle matches the length of the muscle, and the Ia and II fibers can provide continuous feedback. gamma (γ) motor neuron A small spinal neuron that innervates the muscle spindles.

Figure 8.11 Muscle Spindles Provide Feedback About Muscle Stretch Alpha motor neuron

Ia or II sensory fibers

Gamma (g) motor neuron

Muscle spindle

Alpha motor neuron axon Intrafusal muscle fibers Ia or II sensory fibers Gamma (g) motor neuron axon Extrafusal muscle fibers 1 The Ia or II sensory fibers sense stretch of

muscle and activate alpha motor neurons, leading to extrafusal muscle contraction.

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Extrafusal muscle fibers Alpha motor neuron axon

Alpha motor neuron axon

Ia or II sensory fibers

Ia or II sensory fibers

Gamma (g) motor neuron axon

Gamma (g) motor neuron axon

2 Contraction of the extrafusal muscle

alone would make the intrafusal fibers limp. The Ia or II sensory fibers would fail to report any stretch.

3 Input from gamma (g) motor neurons

contracts the intrafusal fibers so that they match the length of the contracting extrafusal fibers. The Ia or II sensory fibers are now able to provide accurate reports about stretch.

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Feedback From Golgi Tendon Organs The Figure 8.12 Golgi Tendon Organs Provide muscle spindles do a good job of providing the brain and spinal cord with information about Feedback About Muscle Contraction muscle length, or the degree of stretch. However, we 1 The Ib sensory fiber carries information also need feedback regarding the degree of muscle Bone about muscle contraction from the Golgi contraction, or force. This information is provided tendon organ to the spinal interneuron. Golgi tendon by the Golgi tendon organs, which are located at organ the junction between a muscle and its tendon. Spinal interneuron Ib sensory fiber Like the muscle spindles, the Golgi tendon organs are innervated by sensory axons, the Ib sensory fibers. Ib fibers are a second type of Alpha-alpha (Aα) fiber but are smaller and slower than the Ia fibers that innervate the spindles. The Alpha motor Ib fibers from the Golgi tendon organs enter the neuron 2 Spinal interneuron spinal cord and form synapses with spinal interinhibits alpha motor neurons. In turn, these interneurons form inhibineuron; muscle relaxes. tory synapses on alpha motor neurons. 3 Now that the muscle is relaxed, the Golgi tendon To understand how the Golgi tendon organ organ reduces input to the inhibitory spinal feedback loop works, we return to the example of interneuron. Freed from inhibition, the alpha holding a coffee cup steady. The Ia and II fibers motor neuron signals the muscle to contract again. from muscle spindles in your fingers and arm sense the stretch resulting from holding the cup and activate the alpha motor neurons. The Golgi tendon organs respond to the resulting increase in muscle Interim Summary 8.1 tension by sending signals to the spinal interneurons via the Ib sensory fibers. In response to this input, the interneurons Summary Points 8.1 inhibit the alpha motor neurons, and muscle contraction 1. Muscles can be divided into three types: smooth is reduced. However, the reduced muscle contraction muscles, cardiac muscles, and skeletal muscles. results in less Golgi tendon organ activity, less input to the Together, the cardiac and skeletal muscles are spinal interneurons, and less inhibition of the alpha motor known as striated muscles. (LO1) neurons. The muscle contracts again. Not only does this 2. Skeletal muscles are made up of individual muscle system help prevent damage to the muscle fibers from too fibers surrounded by a membrane similar to that much contraction, but it also maintains the steady control of a neuron. Muscle fiber contractions result from over muscle tension that we need, particularly for fine motor the movement of myosin filaments relative to actin movements. This process is depicted in Figure 8.12. filaments. (LO1) Feedback From Joints In addition to receiving feedback 3. Alpha motor neurons in the spinal cord or cranial about muscle length and tension, we also receive informanerve nuclei produce muscle contraction through tion about position and movement from mechanoreceptors their activity at the neuromuscular junction. (LO2) in the tissues surrounding each joint. These mechanorecep4. Muscle spindles provide information about muscle tors, which we discussed in Chapter 7, respond primarily to stretch. Gamma motor neurons help the muscle movement of the joint, and they are relatively quiet when spindle match the length of the muscle, providing the joint is at rest. Receptors located in the skin near joints continuous feedback. (LO3) also supply information about movement and position. Free 5. Golgi tendon organs located in the connective nerve endings can signal pain resulting from extreme joint tissue between muscle and bone provide informapositions. It appears that joint receptors are not entirely nection regarding muscle contraction. Additional joint essary for judging the location of a joint. People who have receptors provide information regarding the moveundergone full hip or knee replacement surgery lose all ment of joints. (LO3) of their joint receptors in the procedure, yet they can still describe the position of their joint without looking. Review Questions 8.1 Golgi tendon organ A structure located in the tendons of muscles that provides information about muscle contraction. Ib sensory fiber A small, slower Alpha-alpha (Aα) sensory axon that connects the Golgi tendon organs to neurons in the spinal cord.

1. What is the sequence of events within the myofibril that leads to contraction? 2. What is a motor unit, and how do the units differ in terms of size, precision of movement, and muscle fiber type?

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Reflex Control of Movement

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Summary Table 8.1: The Control of Spinal Motor Neurons Cell Type

Location

Source of Input to These Cells

Alpha motor neurons

Ventral horns of the spinal cord, some cranial nerve nuclei

Motor cortex, brainstem, muscle spindles, spinal interneurons

Alpha motor neurons produce action potentials in muscle fibers leading to contraction.

Muscle spindles

Lie parallel to muscle fibers within a muscle

Respond to stretch of associated muscle fibers

Muscle spindles synapse with alpha motor neurons and spinal interneurons, allowing muscle contraction to adjust to muscle stretching.

Gamma motor neurons

Ventral horns of the spinal cord, some cranial nerve nuclei

Motor cortex, brainstem

Gamma motor neurons contract the muscle spindle to match spindle length to surrounding muscle fibers.

Golgi tendon organs

Junctions between muscles and tendons

Respond to tension in muscle

Golgi tendon organs synapse with spinal interneurons, inhibiting activity of alpha motor neurons, reducing contraction.

Reflex Control of Movement The spinal cord is responsible for a number of reflex movements designed to protect us from injury, to maintain posture, and to coordinate the movement of our limbs. Most of these reflexes are examples of polysynaptic reflexes, or reflexes requiring more than one synapse. In contrast, the myotatic reflexes discussed previously are monosynaptic, requiring only a single synapse between a sensory neuron and a motor neuron.

Reciprocal Inhibition at Joints Muscles can do only one thing: contract. The contraction of a single muscle can either straighten or bend a joint, but not both. As a result, a muscle is able to pull a bone in a single direction but is unable to push it back. Relaxing the muscle will not necessarily cause a limb to move back to its original position. To move a joint in two directions requires two muscles. Muscles are arranged at a joint in antagonistic pairs, as presented in Figure 8.13. Muscles that straighten joints are referred to as extensors, and muscles that bend joints are known as flexors. To bend the knee, the flexor muscles of the thigh must contract while the extensor muscles relax. To straighten the leg, the extensor muscles must contract while the flexors relax. Under most circumstances, flexors and extensors at the same joint are prevented from simultaneously contracting by a polysynaptic reflex known as reciprocal inhibition.

Fiber Type

Ia and II sensory fibers

Ib sensory fibers

Action Produced

Coordinating reciprocal inhibition requires inhibitory spinal interneurons. The Ia fibers associated with spindles branch in the spinal cord. As discussed previously, one branch communicates with the alpha motor neuron serving the muscle that is contracting to keep muscle tension steady. The other branch communicates with an inhibitory interneuron, which, in turn, synapses onto the alpha motor neuron serving the opposing muscle that needs to relax. Thus, information about contraction of the first muscle is transmitted by the Ia fiber to the inhibitory interneuron, which, in turn, prevents the contraction of the opposing muscle. In some circumstances, such as when we stiffen our elbows while catching a ball, the stability provided by simultaneous contraction of antagonistic muscle pairs is actually desirable. Achieving simultaneous contraction rather than reciprocal inhibition requires descending control from the brain, which acts by changing the firing patterns of the inhibitory spinal interneurons.

polysynaptic reflex A spinal reflex that requires interaction at more than one synapse. antagonistic pair Two opposing muscles, one a flexor and one an extensor, arranged at a joint. extensor A muscle that acts to straighten a joint. flexor A muscle that acts to bend a joint. reciprocal inhibition A polysynaptic reflex that prevents the simultaneous contraction of flexors and extensors serving the same joint.

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Figure 8.13 Muscles Form Antagonistic Pairs at Joints Each joint has at least one pair of antagonistic muscles, one flexor and one extensor. Contraction of the biceps muscle flexes (closes) the elbow joint, whereas the triceps muscle extends (opens) the joint. Try flexing and extending your elbow while touching the biceps and triceps muscles. You will be able to feel them working during their respective movements.

Bending a joint

Straightening a joint

Flexor (biceps) muscle contracts Flexor (biceps) muscle relaxes Extensor (triceps) muscle relaxes

Extensor (triceps) muscle contracts

more synapses than the previous simple reflexes. Across species, the rhythm of movements such as walking, flying, or swimming is governed by spontaneously active central pattern generators (CPGs) within the spinal cord (Guertin, 2013). Additional CPGs regulate breathing and swallowing. In primates, CPGs for locomotion are located in the lower thoracic and lumbar segments of the spinal cord. In some patients, like the one appearing in Figure 8.14, epidural stimulation of the CPGs of the spinal cord restored standing, voluntary movement, and assisted stepping in patients with spinal cord injury (Harkema et al., 2011; Mansour et al., 2022).

Reflexes Over the Lifespan

The Flexor Reflex Another familiar example of a polysynaptic reflex is the flexor reflex. We rely on flexor reflexes to protect us from further injury, such as when we jerk our hand away after touching a hot surface on the stove. It’s a good thing that the spinal cord, rather than the brain, manages this function. By the time the brain perceived the problem, generated solutions, evaluated solutions, and implemented solutions, your hand would be in bad shape. The flexor reflex begins as sensory neurons transmit information about the painful stimulus to interneurons in the spinal cord. The interneurons excite the alpha motor neurons serving the flexor muscles of the affected limb. At the same time, alpha motor neurons serving the opposing muscle, the extensor, are inhibited. As a result, your hand is successfully pulled back from the heat source.

The reflexes we have discussed so far are present throughout the human life span. Other types of reflexes are characteristic of young children but tend to diminish as the nervous system matures. These childhood reflexes are not lost by the nervous system, but they become inhibited or overwritten by other processes. When this normal inhibition of childhood reflexes fails due to brain damage or the use of alcohol and other drugs, the childhood reflexes will reappear.

Figure 8.14 The use of epidural stimulation to activate central pattern generators (CPGs) in the spinal cord has been used to restore some voluntary movement to patients with spinal cord injury.

Central Pattern Generators

flexor reflex A polysynaptic spinal reflex that produces withdrawal of a limb from a painful stimulus. central pattern generator (CPG) Circuit that produces rhythmic output spontaneously without needing rhythmic input.

University of Louisville

More complicated polysynaptic reflexes help coordinate the movement of several limbs at once. When we walk, we naturally balance our weight from side to side and swing our arms. These complex movements require many

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Figure 8.15 The Babinski Sign (a) Stroking the bottom of an infant’s foot causes the toes to spread and the big toe to point upward, a movement known as the Babinski sign. (b) Stroking the bottom of an adult’s foot results in the downward curling of the toes. In adults, the Babinski sign often indicates brain damage or damage to corticospinal pathways.

Among the normal childhood reflexes is the Babinski sign, a type of polysynaptic flexion reflex. When you stroke the bottom surface of the foot, infants will spread their toes with the big toe pointing up. The Babinski sign does not appear to confer any particular benefit to the infant. Instead, the reflex probably reflects the immaturity of the infant’s motor system. In typical adults, stroking the bottom of the foot causes the toes to curl down, not up. Adults with damage to either the motor cortex or corticospinal motor pathways will typically perform the infant’s version of the reflex. Figure 8.15 compares the typical adult reaction with the infant’s Babinski sign. A lack of movement has no clinical significance, and further tests will be needed to assess possible damage.

Motor Systems of the Brain The alpha motor neurons that contract muscle fibers are at the lowest end of a chain of command for initiating movement. In addition to input from interneurons and stretch receptors, the alpha motor neurons receive direction from neurons located in the cerebellum, basal ganglia, red nucleus, brainstem, and cerebral cortex. As we will discuss later, some of these motor pathways initiate voluntary movement, while others are responsible for subconscious, automatic movements. The central motor system is not strictly hierarchical, however. Multiple parallel pathways communicate from one level of the motor system to the next. As a result, we usually observe complete paralysis only as a result of damage to the lowest levels of the hierarchy in the spinal cord. Damage to the brain itself, for example, can definitely impact movement in a negative way, but moving is

still typically possible due to the ability of one pathway to compensate for damage to another.

Spinal Motor Pathways Motor neurons in the spinal cord can be located according to their roles as serving flexors and extensors and whether they serve proximal or distal parts of the body. Motor neurons associated with flexors are located dorsally to those associated with extensors. Motor neurons associated with distal structures, such as your hands, are located laterally to those than serve more proximal structures, like your torso. The brain manages movement of the head and neck through the corticobulbar tract, which connects the primary motor cortex with the brainstem nuclei serving the cranial nerves, and manages the rest of the body through connections with spinal alpha motor neurons. As presented in Figure 8.16, signals from the brain to the spinal alpha motor neurons travel along two routes. The first route, known as the lateral pathway, is located in the lateral part of the spinal column. This pathway originates in the cerebral cortex and in the red nucleus of the midbrain and is the pathway through which the brain controls voluntary fine movements of the hands, feet, and outer limbs.

Babinski sign A polysynaptic reflex present in infants and in adults with neural damage, in which stroking the sole of the foot causes the toes to spread with the big toe pointing upward. corticobulbar tract A pathway connecting the primary motor cortex with brainstem cranial nerve nuclei to manage movement of the head and neck. lateral pathway A large collection of axons that originates in the cerebral cortex, synapses on either the red nucleus or alpha motor neurons, and controls voluntary movements.

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Figure 8.16 Lateral and Ventromedial Pathways Provide Input to the Alpha Motor Neurons Input from the brain to the alpha motor neurons in the spinal cord travels over two routes. The lateral pathways originate in the motor cortex (corticospinal tract) or the red nucleus (rubrospinal tract) and control fine, voluntary movements of the outer limbs, hands, and feet. The ventromedial tracts (tectospinal, vestibulospinal, pontine reticulospinal, and medullary reticulospinal) control more reflexive movements such as posture and muscle tone. Forebrain Primary motor cortex

Thalamus

1

Midbrain Red nucleus

2

Midbrain Superior colliculus

2

Pons Pontine reticular formation

3

4

Medulla

4

Medulla Vestibular nucleus Medullary reticular formation

Spinal cord Corticospinal tract

5

5

Rubrospinal tract Tectospinal tract (a) Lateral Pathways 1

You use this pathway to write notes, drive your car, and type on your keyboard. ventromedial pathway A spinal motor pathway originating in the brainstem and carrying commands for subconscious, automatic movements of the neck, torso, and proximal portions of limbs.

(b) Ventromedial Pathways

Spinal cord Medullary reticulospinal tract Pontine reticulospinal tract Vestibulospinal tract

The second route, known as the ventromedial pathway, travels along the ventromedial part of the spinal column. Most of the neurons that supply axons to this pathway are located in the brainstem rather than in the cerebral cortex. As a result, the ventromedial pathway carries commands from the brain for automatic movements in the neck, torso, and portions of the limbs close to the body. You use

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Motor Systems of the Brain

the ventromedial pathway for behaviors such as maintaining posture and muscle tone and moving the head in response to visual stimuli. The functions of these two pathways are easier to remember if you think of the lateral pathway as a long-distance system serving more distal structures (hands, feet, distal portions of the limbs) and the ventromedial pathway as a relatively local system serving more proximal structures (neck, torso, proximal portions of limbs). Cell bodies giving rise to the axons of the lateral pathway are located either in the primary motor cortex of the frontal lobe (the corticospinal tract) or in the red nucleus of the midbrain (the rubrospinal tract). The first part of each term refers to the origin of the pathway (rubro refers to red), and the last part of the term refers to the pathway’s endpoint. The fibers of the corticospinal tract are some of the fastest and longest in the central nervous system (CNS). This tract is also one of the largest in the nervous system, featuring approximately 1 million axons in humans. This is the only descending system that makes direct synapses with alpha motor neurons. Humans and other primates have more of these directly synapsing corticospinal neurons than most other animals, and this feature probably accounts for our remarkable fine motor coordination of the hands and fingers. The rubrospinal tract connects the red nucleus of the midbrain to the alpha motor neurons of the spinal cord. The red nucleus receives substantial input from the motor cortex. Consequently, the motor cortex exerts both direct control (via the corticospinal tract) and indirect control (via the rubrospinal tract) on the alpha motor neurons of the spinal cord. However, the main source of input to the red nucleus is the cerebellum, so this pathway is probably one way that learned patterns of movement are communicated to the muscles. As these pathways travel from the brain to the spinal cord, they decussate, or cross, the midline. The rubrospinal tract decussates immediately in the midbrain, and the corticospinal tract decussates at the junction of the medulla and the spinal cord. Crossing the midline means that the right hemisphere’s motor cortex and red nucleus controls the left side of the body, and the left hemisphere’s motor cortex and red nucleus controls the right side of the body. Although the advantages of this organization remain a mystery, the results are most obvious when a person has damaged either the motor cortex or the descending lateral pathways due to a stroke or other accident. If the damage occurs in the right hemisphere, movement on the left side of the body will be affected. If the damage occurs in the left hemisphere, movement on the right side of the body will be affected. The four ventromedial pathways stimulate the alpha motor neurons to help maintain posture and carry out reflexive responses to sensory input, such as moving the head and torso in coordination with our eye movements. The ventromedial pathways also assist in behaviors such

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as walking, which are otherwise largely under cortical control. These pathways originate in various parts of the brainstem, including the vestibular nuclei of the medulla, the superior colliculi of the midbrain, and the reticular formation in the pons and medulla. Once again, you can use the names of these tracts to remember their points of origin. The tectospinal tract originates in the tectum of the midbrain, primarily in the superior and inferior colliculi (refer to Chapter 2). The vestibulospinal tract originates in the vestibular nuclei of the medulla, and the pontine and medullary reticulospinal tracts originate in the reticular formation at the levels of the pons and medulla, respectively. The reticulospinal tract ensures that the flexor reflex described earlier will result from painful stimuli but not other types of input.

The Cerebellum The cerebellum participates in the maintenance of balance and coordination as well as in the learning of motor skills (refer to Chapter 2). The cerebellum’s role in movement is probably its best understood function. Most of its output connects with other motor systems, but it would be inaccurate to conclude that its functions are restricted to movement. The cerebellum also participates in language and other cognitive processes, discussed further in Chapter 12. Although the cerebellum does not appear to initiate movement, it plays a very important role in the sequencing of complex movements. As you ride a bicycle or shoot a basket, your cerebellum is coordinating the contraction and relaxation of muscles at just the right time. To understand the value of the cerebellum, it’s helpful to observe what happens when the cerebellum is not working. One common example of poor cerebellar function occurs when a person drinks alcohol. The cerebellum is one of the first structures in the brain to show the effects of alcohol, leading to a lack of balance and coordination. As a result, law enforcement personnel check the function of the cerebellum to assess drunkenness. Most sobriety tests, such as walking on a straight line, are essentially the same

corticospinal tract A lateral pathway connecting the motor cortex to alpha motor neurons in the spinal cord. rubrospinal tract A lateral pathway connecting the red nucleus of the midbrain to the alpha motor neurons of the spinal cord. tectospinal tract A ventromedial pathway connecting the tectum of the midbrain to the alpha motor neurons in the spinal cord. vestibulospinal tract A ventromedial pathway that connects the vestibular nuclei of the medulla to the alpha motor neurons of the spinal cord. pontine reticulospinal tract A ventromedial pathway connecting the reticular formation in the pons to the alpha motor neurons of the spinal cord. medullary reticulospinal tract A ventromedial pathway connecting the reticular formation in the medulla to the alpha motor neurons of the spinal cord.

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as the tests a neurologist would use to diagnose lesions in the cerebellum. How does the cerebellum help us coordinate sequenced movements? It appears that the cerebellum is able to inform the motor cortex about such factors as the direction, force, and timing required to carry out a skilled movement. In many cases, this process requires learning. The cerebellum is constantly comparing the cortex’s intended movements with what actually happened in a trial-and-error manner. Adjustments are made as needed for future activity.

The Basal Ganglia Moving rostrally through the motor hierarchy toward the cerebral cortex, we come next to the basal ganglia, a collection of large nuclei embedded within the white matter of the cerebral hemispheres. The location of the basal ganglia is noted in Figure 8.17. Among their many tasks, only some of which involve motor activity, the basal ganglia

participate in the choice and initiation of voluntary movements and the inhibition of unwanted movements. As we discussed in Chapter 2, the basal ganglia consist of the caudate nucleus, the putamen, the globus pallidus, the subthalamic nucleus, and the nucleus accumbens. Some anatomists include the substantia nigra of the midbrain in their discussion of the basal ganglia due to the close linkages between these structures. Complex interactive loops connect the basal ganglia with the thalamus and with the motor cortex in the frontal lobe. The basal ganglia interact with the thalamus via two pathways, a direct excitatory pathway using glutamate and an inhibitory indirect pathway using GABA. When the thalamus receives excitatory input from the basal ganglia, it gives a “go ahead” message to the motor cortex and movement is initiated. In response to inhibitory input from the basal ganglia, the thalamus prevents the motor cortex from initiating unwanted movements. Input from the substantia nigra, which releases dopamine, modifies both the direct and indirect pathways to facilitate movement.

Figure 8.17 The Basal Ganglia Participate in Voluntary Movements The basal ganglia consist of the caudate nucleus, the putamen, the globus pallidus, the nucleus accumbens (not depicted in this view), and the subthalamic nucleus and are closely associated with the substantia nigra of the midbrain. The basal ganglia form complex loops with the cortex and thalamus and are involved with the initiation of voluntary movements.

Caudate nucleus Putamen

Globus pallidus Subthalamic nucleus

Thalamus Substantia nigra Basal ganglia: Caudate nucleus Putamen Globus pallidus Subthalamic nucleus

Substantia nigra

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Motor Systems of the Brain

These processes allow the basal ganglia to serve as a gate or filter for intentional activity. Motor programs associated with reward will be carried out, while competing motor programs unlikely to produce reward in the present circumstances are inhibited. In other words, the basal ganglia do not initiate movement, but without the “approval” of the basal ganglia, the cerebral cortex cannot send motor commands to lower levels of the system. As we will discuss later in the chapter, a number of disorders result from abnormalities in the basal ganglia, including Parkinson disease and Huntington disease. These conditions feature either reduced movement (Parkinson disease) or excessive movement (Huntington disease). The basal ganglia are also implicated in a number of psychological disorders, including obsessive-compulsive disorder and attention deficit hyperactivity disorder (refer to Chapter 16). Like the cerebellum, the basal ganglia participate in a number of important cognitive functions in addition to their motor responsibilities, such as operant learning and the formation and management of implicit or unconscious memories (refer to Chapter 12).

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tectospinal, and reticulospinal pathways discussed earlier. Also in the precentral gyrus, just rostral to primary motor cortex, we find additional motor areas, including the supplementary motor area (SMA) and the premotor cortex. The Organization of Primary Motor Cortex We can map the primary motor cortex in the precentral gyrus by observing which muscles respond when a particular part of the cortex is stimulated electrically. The resulting motor homunculus is found in Figure 8.18. In Chapter 7, we presented a similar map of the sensory cortex in the parietal lobe. The premotor and supplementary motor areas of the cortex also are organized as homunculi. The first thing you might notice is that the homunculus is upside down. Neurons controlling voluntary movement of the head are found in the most ventral portions of the precentral gyrus, and neurons controlling the feet are located in the opposite direction. Neurons serving the feet are found where the gyrus has actually curved across the top of the hemisphere into the longitudinal fissure that separates the two hemispheres.

The Motor Cortex The cortex located in the precentral (before the central sulcus) gyrus has been identified as the primary motor cortex (M1), the main source of voluntary motor control. The primary motor cortex not only forms direct connections with the spinal alpha motor neurons, but it also influences the activity of the other motor pathways, including the rubrospinal,

supplementary motor area (SMA) Motor area located in the gyrus rostral to the precentral gyrus; involved with managing complex sequences of movement. premotor cortex A motor area located in the gyrus rostral to the precentral gyrus; this area participates in holding a motor plan until it can be implemented; formerly referred to as the premotor area (PMA).

Figure 8.18 The Motor Homunculus Areas of the body requiring fine motor control have more than their fair share of cortical neurons. Large amounts of space in the human primary cortex are devoted to control of the hands, face, lips, jaw, and tongue, whereas relatively little space is given to the torso, arms, and legs. Compare this motor homunculus to the sensory homunculus in Figure 7.21. Trunk Hip Frontal lobe

Shoulder

Elbow

Wrist

Hand

Little

Ring Middle Index Thumb

Knee Ankle

Eye Eyelid and eyeball Face

Toes

Lips Jaw Temporal lobe

Tongue Pharynx

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As we observed in the case of the sensory homunculus (review Figure 7.21), the proportions of the homunculus are quite different from the proportions of our body. Once again, parts of the body that require delicate control are given a larger share of cortical territory. Face, lips, jaw, and tongue are given a great deal of space to manage the fine movements required by speech. Hands also get a disproportionate amount of cortical space, allowing for the many fine movements we need for tool use. In contrast, the torso gets very little space, especially considering the actual size of this body part. There isn’t much to do with torsos other than maintain posture, bend, lift, and twist. The Initiation and Awareness of Movement What happens when we decide to move? You might be thinking that this would be a good time to stop reading your text and take a snack break (which is fine as long as you also decide to come back and reopen the book). We might like to believe that we are consciously aware of our intent to move, but the brain makes a commitment to a choice of movement as many as 10 seconds before we become consciously aware of the decision (Soon et al., 2008). This delay is needed by higher level systems to prepare for an upcoming movement. It is possible that our conscious awareness of our movement might serve to “interpret” or make sense out of our own actions rather than actually guiding or initiating these actions (Gazzaniga, 2011). Other neuroscientists are still firmly convinced that we possess free will (Liljenström, 2022). Imaging technologies such as PET and fMRI have been used to track the initiation of movement in human volunteers (Deiber et al., 1999; Roland, 1993). As depicted in Figure 8.19, the first areas to show increased activity are the prefrontal cortex and parietal lobe. Before planning a movement, the system requires up-to-date information about the body’s current situation from the parietal lobe. Considering input regarding reward and current needs, the prefrontal cortex “thinks” about the movement and its consequences, leading to an intention to move. Activity in these two areas resulted in the early “commitment” observed by Soon et al. (2008) mentioned previously. Next, the prefrontal cortex informs the supplementary motor area (SMA) and premotor cortex of the intent to move. Coordinating with the cerebellum, the SMA and premotor cortex begin programming the sequence of movements required to carry out the plan. The anterior cingulate cortex (ACC) contributes information about an organism’s history of reward. Activity in these areas was reflected in an initial “readiness potential,” an EEG phenomenon preceding movement by about one half second recorded by Libet et al. (1982). pyramidal cell A large, pyramid-shaped neuron found in the output layers (Layers III and V) of the cerebral cortex, including the primary motor cortex. mirror neuron A special motor neuron that responds to a particular action, whether that action is performed or simply observed.

At this point, the system checks in with the basal ganglia, as described in an earlier section of this chapter, which, in turn, communicates with the thalamus. Inputs from the premotor cortex, SMA, and the thalamus converge on very large pyramidal cells, named for their shape, located in the output Layer V of the primary motor cortex. Pyramidal cell axons are an important source of input to the brainstem and to spinal motor neurons. Once the motor cortex is activated, information flows down the lateral pathways to the spinal cord, either directly or through the red nucleus of the midbrain. The axons from the lateral pathways then synapse on the alpha motor neurons, which initiate the muscle contractions needed to carry out the descending commands. Simultaneously with the “go” message to the primary motor cortex, a copy of the command returns to the prefrontal cortex, parietal lobe, and cerebellum (Virameteekul & Bhidayasiri, 2022). As soon as the movement is carried out, results and intent are compared by these structures. When intent and results match, we experience a sense of agency, or control. If they do not match, we might perceive the movement to be generated by external causes rather than our own “free will.” The Coding of Movement In vision, single-cell recording techniques have been used to discover the precise type of stimulus to which a particular cell will respond. Similar efforts to identify the responsibilities of single neurons in the primary motor cortex have produced curious results. Even though our movements are generally very precise, individual primary motor cortex neurons seem to be active during a wide range of movements. It appears that movement is encoded by populations of motor neurons rather than by single cells (Georgopoulos et al., 1986; Georgopoulos et al., 1993). To investigate the role of cell populations in movement, activity in single cells in the primary motor cortex of monkeys was recorded as the monkeys moved an arm in one of eight possible directions. Single cells responded to a wide range of movement, but they responded most vigorously to a single preferred direction. The best predictor for whether the monkey’s arm would move in a particular direction was a population vector, or the sum of the activity of the entire population of neurons in the area being observed. An example of the population vectors computed by Georgopoulos et al. (1993) is presented in Figure 8.20. This finding predicts that large numbers of motor cortex cells, rather than a small group, should be active during any type of movement. It also suggests that the direction of a movement represents the averaging of all inputs from the entire population of neurons. Mirror Neurons Mirror neurons, discovered by accident, appear to fire during either the execution of a movement by the self or the observation of the same movement by another (Di Pellegrino et al., 1992). When discussing mirror functions in humans, we generally refer to them as mirror systems rather than mirror neurons (Fabbri-Destro & Rizzolatti, 2008).

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Figure 8.19 The Initiation of Voluntary Movement The intent to move is processed in the prefrontal cortex in consultation with the parietal lobe. The supplementary motor area (SMA) and premotor cortex develop a plan for the intended movement with input from the cerebellum and circuits connecting the basal ganglia and thalamus. Instructions to move are then sent to the primary motor cortex, which will then implement the movement through connections with spinal alpha motor neurons. A “copy” of the plan is sent to the posterior parietal lobe, providing a sense of control or agency. The plan is compared to the outcome of the movement, providing the ability to make needed corrections. Copy of motor plan

Drive to move (Intention)

Sense of agency

Decision to move

Somatosensory feedback Motor plan

Motor execution

Prefrontal cortex Supplementary motor area Premotor cortex Primary motor cortex Posterior parietal cortex Basal gangia Thalamus Cerebellum Brainstem

The concept of mirror neurons captured the imaginations of scientists and the public, leading to sensational claims about the cells’ being the basis of mind-reading, language, and empathy. Autism spectrum disorder was said to result from a “broken mirror.” Subsequent research has called for a calmer, more reasoned approach. Although mirror neurons contribute to the processing of observed action, they do not support interpretation of those observations, such as figuring out the intent of another person (Heyes & Catmur, 2022). Unlike early reports, further investigation showed that mirror neurons respond when observing both non-biological and biological movements (Albertini et al., 2021). Biological and non-biological movements can be represented with very limited input, such as the movement of a few point lights. Biological movement is typical of living things, while on-biological movement is

typical of inanimate objects, such as a propeller or vehicle. Mirror neurons are not some built-in feature of the brain. Instead, it is likely that they develop through associative learning (refer to Chapter 12; Cook et al., 2014). Not only do people with autism spectrum disorder have perfectly functional mirror systems (Schulte‐Rüther et al., 2016), but under some circumstances, they actually outperform neurotypical individuals on tasks related to mirror system functions (Heyes & Catmur, 2022). Does this mean that mirror neurons are now irrelevant? Not at all. Mirror neurons play important roles in imitation, or the copying of a body movement. Further research can illuminate the contributions of mirror neurons to understanding how body movements are categorized, how some aspects of speech are perceived, and how imitation is learned and performed.

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Figure 8.20 The Direction of Movement Is Encoded by Populations of Neurons (a) Monkeys were trained to move a joystick in response to a small light moving around a circle. (b) Although single-cell recordings indicated that neurons responded most vigorously to a preferred direction, they also indicated that cells would respond to directions that varied as much as 45 degrees from the preferred direction. (c) Responses of single cells can be combined into population vectors. (d) The summed response of each population of neurons accurately predicts the direction of the monkey’s movement. In other words, the population of cells essentially tallies up individual cell “votes” on the best direction to move.

Direction of lever

2258

1808

1358

908

458

08

3158

2708

Rate of firing Direction vector (b) Responses of a Single Cell Movement Response Response Population vector direction of Cell 1 of Cell 2 (sum of two responses)

Population vector

908 (a) The Monkey and Apparatus 08 908 (c) Individual Direction Vectors and Population Vectors from Two Neurons

(d) Vector Representing Summed Activity from a Population of Neurons

Connecting to Research Intention to Move and Free Will Imagine that I’m telling you right now to raise either your right hand or your left hand. Which would you choose? What activity might be going on in your brain as you make that choice? We like to think that we make such choices consciously, but perhaps that is not always the case. A study by Chun Siong Soon and his colleagues (2008) suggests that such choices are made long before we are consciously aware of them. The Question: How is the timing of conscious

awareness related to decisions to move?

Methods While participants were scanned using fMRI, they viewed a sequence of letters presented one at a time every half second on a screen. At a time of their choosing, they were to carry out two tasks: 1) decide whether to press a button with their left or right hand, and 2) note the letter that was present when they made their decision. They were then shown an array with four letters, including the one that had been present as they became aware of their decision, and they pressed another button to (continued)

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Connecting to Research Intention to Move and Free Will (Continued) indicate the correct letter. This second press allowed the researchers to pinpoint the time at which the decision became conscious (refer to Figure 8.21).

Results The first brain region to show activity that was predictive of the later movement was the prefrontal cortex, followed by activity in the parietal lobe. The frontal lobe activity preceded the conscious awareness of the decision by 7 seconds. As you might recall from Chapter 1, one of the weaknesses of fMRI is temporal resolution, or the ability to localize responses in time. The researchers suspected that due to the sluggish response of blood flow, the frontal lobe activity might precede the conscious decision by as many as 10 seconds.

Conclusions Does this mean you have to abandon the concept of free will? Did you have any conscious control over which hand you raised? If not, what factors would determine such a decision? While some neuroscientists argue that studies like Soon et al. (2008) make it difficult to believe in free will, others are not so certain. Making a decision to move one finger rather than another might be a very different process than deciding which school to attend or which car to buy. Soon et al. also note that their ability to predict the participants’ movements was very good, but not perfect. Perhaps at the last moment, some bit of free will intrudes to determine our actions.

(a) Participant decides to push the left or right button and notes which letter is displayed when the choice is made.

500 ms

s

v

d

m

p

k

Choice R

(b) Participant pushes the appropriate button to identify the letter present when the choice was made.

s

d

m

k

Interim Summary 8.2 Summary Points 8.2 1. Monosynaptic reflexes, such as the myotatic reflex, require the interaction of only one sensory and one motor neuron. Polysynaptic reflexes involve more than one synapse. (LO4) 2. The lateral pathways connect the primary motor cortex and red nucleus with the spinal motor neurons and are responsible for voluntary movements. The ventromedial pathways originate in the brainstem and are responsible for reflexive movements. (LO5)

Procedure from Soon et al. (2008)

L

Figure 8.21 Comparing Recorded Brain Activity and Conscious Intent to Move (a) To “timestamp” participants’ intent to move, Soon et al. (2008) displayed a sequence of single letters for one half second each while they underwent fMRI. Participants were instructed to make note of the letter that was present when they were consciously aware of their choice of pushing the right or left button. (b) Subsequently, an array of four letters containing the one that was chosen earlier was presented. The participant pushed another button to indicate the one that had been present when they became consciously aware of their decision to move.

3. The cerebellum is involved with the timing and sequencing of complex movements. The basal ganglia form complex loops with the cortex and the thalamus and serve as a gate or filter for intentional activity. (LO5) 4. Cortical areas involved in the control of voluntary movement include the primary motor cortex, the supplementary motor area (SMA), the premotor cortex, and the anterior cingulate cortex (ACC). (LO5) 5. The initiation of voluntary movement is correlated with sequential activity in the prefrontal cortex

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and parietal cortex, followed by activity in the premotor cortex and SMA. Incorporating input from the basal ganglia and thalamus, commands are finally issued by the pyramidal cells of the primary motor cortex. These primary motor neurons control movement as a function of cell population activity rather than as a function of single-cell activity. (LO5)

a basis for imitation. It is unlikely that mirror neurons are responsible for higher-order cognitions such as understanding the behavioral intentions of others. (LO5)

1. What motor functions are carried out by reflexive or involuntary processes?

6. Mirror neurons or systems are active during both observation and execution of movements, forming

2. What steps lead to the initiation of a voluntary movement?

Review Questions 8.2

Summary Table 8.2: Central Motor Systems Structure or Pathway

Location

Principal Connections

Functions

Lateral pathways

Lateral spinal cord

Motor cortex and red nucleus to spinal motor neurons

Voluntary fine movements of hands, feet, and outer limbs

Ventromedial pathways

Ventromedial spinal cord

Brainstem to spinal motor neurons

Maintain posture; carry out reflexive responses to sensory input

Cerebellum

Hindbrain

Spinal motor neurons, forebrain motor systems

Sequencing of complex movements, muscle tone, balance, and coordination

Basal ganglia

Forebrain

Motor cortex, thalamus

Choice and initiation of voluntary movements

Primary motor cortex

Precentral gyrus of the frontal lobe

Other cortical areas, basal ganglia, brainstem, spinal motor neurons

Initiation of voluntary movements

Premotor cortex

Rostral to the primary motor cortex

Thalamus, primary motor cortex

Managing movement strategies

Supplementary motor area (SMA)

Rostral to the primary motor cortex

Thalamus, primary motor cortex

Managing movement strategies

Anterior cingulate cortex

Rostral portion of the gyrus dorsal to the corpus callosum

Red nucleus and spinal motor neurons

Selection of voluntary movement based on prior reward

Disorders of Movement We can learn a great deal about the neural control of movement by observing what goes wrong when the system is damaged. Because movement disorders obviously cause enormous human suffering, our further understanding might also lead to more effective treatments.

Toxins A variety of toxic substances interfere with movement. Many of these toxins affect the neurochemical ACh, which is used by alpha motor neurons to communicate with muscle fibers at the neuromuscular junction.

Toxins that are cholinergic agonists boost the activity of ACh at the neuromuscular junction, affecting muscle tone. For example, black widow spider venom overstimulates the release of ACh from the alpha motor neuron, causing the muscles to spasm in painful convulsions (review Chapter 4). In unusually severe cases, the alpha motor neuron runs out of ACh and can no longer signal the muscles to contract, leading to paralysis and possibly death. Although large doses of cholinergic agonists are capable of producing death, cholinergic antagonists are generally far more dangerous and potent. These substances paralyze muscles, including those required for respiration. We observed the deadly actions of the cholinergic

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Behavioral Neuroscience Goes to Work Physical Therapy and the Neurologic Clinical Specialty

antagonists curare and botulinum toxin in Chapter 4. The venom of the Taiwanese cobra also binds tightly to the nicotinic ACh receptor and is nearly impossible to dislodge, leading rapidly to paralysis and death. Sarin, a synthetic chemical used as a bioweapon, is a colorless, tasteless, odorless liquid that can evaporate into a gas (refer to Figure 8.22). Sarin acts as a neurotoxin by inhibiting acetylcholinesterase (AChE), the enzyme that normally breaks down ACh in the synaptic gap. In the presence of sarin, ACh continuously stimulates muscle fibers, which remain contracted and unable to relax. This can result in respiratory failure due to paralysis of the diaphragm muscles.

Association [APTA], 2022). The course of study is broad, from biomechanics to neuroscience to psychology and communication. Neuroscience, and in particular its contributions to the understanding of pain (review Chapter 7), has played an increasingly important role in the physical therapy profession. Physical therapists specializing in neurological physical therapy focus on helping people with nervous system damage. Neurologic clinical specialists already hold licenses as physical therapists, which means that they have completed a bachelor’s degree plus a 3 year doctoral program in physical therapy. In addition, they must demonstrate either 2,000 hours of patient care in the area of their specialty or the completion of an accredited internship. Applicants must pass a standardized exam that covers foundational science, professional roles, patient management, and relevant medical conditions. With an aging population, physical therapists trained to treat neurological disorders and injury are likely to remain in demand. In particular, there is a need for African-American and Hispanic physical therapists, as these populations are underrepresented within the profession (APTA, 2020).

Figure 8.22 Neurotoxins Often Affect the Neuromuscular Junction Members of the Syrian community of Adelaide, Australia, protest the use of sarin gas in Syria. Syria’s use of chemical weapons against primarily non-combatants took many lives between 2012 and 2018.

Amer ghazzal/Alamy Stock Photo

Management of rehabilitation in movement disorders is primarily the domain of the physical therapist (PT). Physical therapists assess movement issues and administer remediation in the form of special exercises, education, manipulation, and other similar techniques. Some physical therapists are board certified as Neurologic Clinical Specialists by the American Board of Physical Therapy Specialties. Although the idea of treating movement problems with exercise dates back to ancient times, events occurring in the twentieth century promoted the rapid acceptance of this practice. Polio outbreaks at the beginning of the twentieth century led to the use of massage and remedial exercise as treatments. Soldiers recovering from injuries in World Wars I and II benefited from physical therapy techniques. Today, physical therapists not only treat patients with existing movement disorders but also attempt to prevent the development of movement disorders in vulnerable populations. Physical therapists typically hold either a Doctor of Physical Therapy (DPT) or Master of Physical Therapy (MPT) degree and are licensed on a state-by-state basis in the United States (American Physical Therapy

Myasthenia Gravis Myasthenia gravis is an autoimmune disease in which a person’s immune system, for reasons that are not well understood, produces antibodies that bind to the nicotinic ACh receptor. Over time, the ACh receptors degenerate and become less efficient, leading to extreme muscle weakness and fatigue. The degeneration usually affects the muscles of the head first, resulting in droopy eyelids and slurred speech. As the degeneration proceeds, the patient might experience difficulty swallowing and breathing.

myasthenia gravis An autoimmune condition caused by the degeneration of acetylcholine (ACh) receptors at the neuromuscular junction, resulting in muscle weakness and fatigue.

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Chapter 8

Movement

Myasthenia gravis can be treated with medications that suppress the immune system. This approach slows the production of the troublesome antibodies. In other cases, medications inhibit AChE, the enzyme that deactivates ACh at the synapse. As we observed in the case of sarin gas, when the ability of AChE to break down ACh is reduced, more ACh remains active in the synaptic gap. For obvious reasons, the effects of these medications are monitored very closely. Some cases benefit from the surgical removal of the thymus gland, a part of the lymphatic system located in the upper chest. Lymphocytes (white blood cells) mature in the thymus gland, so removing the gland reduces the overall immune response. While there is no cure, these treatments allow most people with myasthenia gravis to live full, active lives.

Figure 8.23 Cellular Changes in Muscular Dystrophy Healthy muscle cells appear on the left, while cells unable to produce the protein dystrophin are presented on the right. Recent breakthroughs in gene therapy might eventually provide relief from some forms of muscular dystrophy.

Patrick Landmann/Science Source

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Muscular Dystrophy Muscular dystrophy is not a single disease but rather a group of about 30 inherited diseases characterized by progressive muscle degeneration. These diseases are caused by abnormalities involving the protein dystrophin, which makes up part of the muscle fiber membrane. Dystrophin protects the membrane from injuries due to the force that occurs during normal movement. Muscular dystrophy is a sex-linked disorder, more frequently affecting males, because the gene responsible for encoding dystrophin is located on the X chromosome (review Chapter 5). In the most severe type of muscular dystrophy, Duchenne muscular dystrophy, dystrophin is not produced at all (refer to Figure 8.23). Faulty dystrophin is present in cases of Becker muscular dystrophy. Without the protective action of dystrophin, muscles are damaged during normal activity. The muscle turns to scar tissue before gradually wasting away. This disorder eventually reduces mobility and results in a shortened life span. Currently, there are no effective treatments for muscular dystrophy. However, gene therapy, in which faulty dystrophin genes are replaced with functioning genes, has produced improvement in animal models of muscular dystrophy. However, avoiding adverse immune responses elicited by gene therapy remains challenging (Dowling, 2022).

muscular dystrophy A group of diseases characterized by muscle wasting due to abnormalities in the protein dystrophin. polio A contagious viral disease that attacks the spinal motor neurons, producing paralysis.

In April 2022, Pfizer received permission to restart clinical trials of their gene therapy product following the death of a young boy in an initial testing phase in December 2021.

Polio Polio, or poliomyelitis, occurs only in human beings and is caused by a contagious virus that specifically targets and destroys spinal alpha motor neurons. Polio comes from the ancient Greek word for “gray” and refers to damage to the gray matter of the spinal cord. Symptoms can include muscle weakness and paralysis, usually of the legs. If the infection affects higher levels of the CNS, breathing can be compromised. This situation leads to the patient’s reliance on assisted respiration, such as an “iron lung.” Following the development of effective vaccines, worldwide rates of polio have fallen dramatically. War, travel, and the upheaval of the Covid-19 pandemic have complicated eradication efforts. Long absent from the United States and Europe, surveillance of sewage in New York City and London indicated the presence of the polio virus again in 2022. Wild variety cases continue in Afghanistan and Pakistan, while some other countries experience vaccine-derived cases. Vaccine-derived cases result from the use of attenuated live virus in the oral version of the vaccine. While the oral vaccine has made remarkable contributions to the reduction of polio cases, it poses a risk in populations that are sparsely vaccinated. Ideally, all polio vaccines would be the injectable variety, which contains virus killed by formalin, but this version is more expensive and more difficult to administer.

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Disorders of Movement

Accidental Spinal Cord Injury (SCI)

273

Figure 8.24 Christopher Reeve: A Tireless Advocate for Research Into Accidental Spinal Injury Treatments

Richard Ellis/Alamy Stock Photo

The spinal cord can be accidentally damaged when the protective vertebrae surrounding the cord are Following his spinal cord injury in a horseback riding accident in broken and compress or sever the cord itself. These 1995, actor Christopher Reeve of Superman fame pushed for more tragic accidents generally result in permanent paralresearch funding for spinal injury treatments. Along with his wife, ysis of the muscles served by neurons below the he founded the Christopher and Dana Reeve Foundation. level of damage. Worldwide, approximately 250,000 to 500,000 people per year experience spinal cord injury, usually from traffic accidents, falls, or violence (World Health Organization [WHO], 2022c). The most common spinal injury occurs in the cervical, or neck, region of the spinal cord, resulting in quadriplegia, or the loss of movement in both arms and legs. Damage in the lumbar region of the lower back results in paraplegia, or the loss of movement in the legs. As we discussed in Chapter 3, a number of factors interfere with the regeneration of spinal cord axons. The blood-brain barrier is typically damaged at the site of injury, and the resulting ability of immune system cells to enter the CNS promotes further inflammation. This inflammation causes a “secondary injury” involving the death of more neurons and oligodendrocytes. The surviving astrocytes fight back by constructing a stiff glial scar to protect remaining neural tissue. These responses motor cortex. The muscles served by these motor neurons make it difficult to deliver therapies aimed at promoting degenerate when their input ceases. Patients experience regeneration in the spinal cord. Nanoparticles are being muscle weakness, and about 15 percent experience froninvestigated as a possible solution for reducing inflammatotemporal dementia (refer to Chapter 15). The median tion and delivering therapeutic drugs (Chakraborty et al., lifespan after diagnosis is two to three years (Westeneng 2021). et al., 2018). Hawking’s more than 50 years as an ALS patient Actor Christopher Reeve (star of the 1978 film was highly unusual. ALS affects about 30,000 people in the Superman and the 1980 film Superman II; depicted in United States and is about as common as multiple sclerosis Figure 8.24) suffered a spinal cord injury in a horseback (refer to Chapter 15) and about five times more common riding accident in 1995. Until his death in 2004, Reeve lobthan Huntington disease. bied for additional research funds for spinal cord damage The causes of ALS are still somewhat mysterious, but and its treatment. Although a cure is still years away, progscientists are beginning to identify genes that predict risk ress is taking place. Earlier, we discussed the use of epiof the disease. Approximately 10 percent of the cases run dural stimulation coupled with training as a method for in families. About 15 to 25 percent of patients with familial regaining some mobility. Other researchers are investigatALS (FALS) had an abnormal version of a gene known as ing technologies that bypass the injury altogether by transSOD-1 (Rosen et al., 1993). SOD-1 codes for superoxide lating brain signals into spinal commands (Hejrati & Fehdismutase copper/zinc, a key enzyme in oxidative metabolings, 2021). Insertion of stem cells remains an active area lism. The mutant forms of SOD-1 cause damage to motor of research. Artificial scaffolds supporting neural regrowth neurons in multiple ways, including interference with the might also become routine in the future. normal functions of mitochondria. A relatively small set of abnormal genes, including SOD-1, account for the majority of familial cases (Newell et al., 2022). Amyotrophic Lateral Sclerosis Most cases of ALS, however, are not purely genetic, leading to investigations of possible environmental causes. (ALS; Lou Gehrig’s Disease) Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig’s disease after the outstanding baseball player of the 1930s whose life was ended by the disease. Physicist Stephen Hawking was diagnosed with a rare, early onset and slowprogressing form of ALS. ALS results from the degeneration of motor neurons in the spinal cord, brainstem, and

amyotrophic lateral sclerosis (ALS) A disease in which motor neurons of the spinal cord, brainstem, and motor cortex progressively deteriorate, leading to death.

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Among the environmental toxins associated with ALS are BMAA (a neurotoxin produced by microorganisms and aggregated in seafood), formaldehyde (also released during smoking), manganese, mercury, and zinc (Newell et al., 2022). Possible protective factors include caffeine, tea, and dietary fiber. Currently, there are no cures for people with the disease (refer to Figure 8.25). Research continues in the effort to identify effective treatments. The 2014 social media phenomenon of the ALS “ice bucket” challenge raised more than $115 million in one 8-week period, accelerating research into potential cures. Two medications have been approved to treat ALS in the United States. Riluzole (Rulitek ©) reduces the activity of glutamate in the brain and extends life an average of two to three months (Miller et al., 2012). Edaravone, initially developed to treat strokes, appears to act as an antioxidant and slows loss of function in some patients with ALS. Stem cell therapies are a particularly promising approach for ALS (Liu et al., 2022). Advances in methods that differentiate stem cells into motor neurons (refer to Chapter 5) and enhance their survivability are bringing stem cell therapies for ALS closer to reality.

Figure 8.25 Steve Saling and ALS Residences When Steve Saling, (below, right) a successful landscape architect, learned that he had ALS at age 38, he went to a conference to learn about his future living options. He connected with Barry Berman (below, left) of the Leonard Florence Center for Living in Boston. Steve used his design skills to help build a facility that allowed residents the most independence possible. The facility uses PEAC, a comprehensive automation system that opens doors and operates elevators and other equipment using any wireless device.

Parkinson disease is characterized by a progressive difficulty in all movements, muscular tremors in the resting hand, and frozen facial expressions. These symptoms were first observed and described by the English physician James Parkinson in the early 1800s. Patients with Parkinson disease experience enormous difficulty initiating even the simplest voluntary movements, such as standing up from a chair. The disease produces a characteristically stooped posture and reduces innervation to the heart. Patients’ reflexive movements are also impaired, and they fall easily if they lose their balance. Parkinson disease is often associated with drops in blood pressure, dizziness, and other symptoms of autonomic nervous system disorder. Eventually, the condition leads to premature death. Typically, Parkinson disease affects people after the age of 50 years. Women enjoy a slight protection from Parkinson disease compared to men, possibly due to higher dopamine levels in the basal ganglia, which, in turn, is the result of estrogen activity (Haaxma et al., 2007). The direct causes of Parkinson disease are quite clear. This disease occurs when the dopaminergic neurons of the

Parkinson disease A degenerative disease characterized by difficulty in moving, muscular tremors, and frozen facial expressions.

ALS Residence Initiative (ALSRI)

Parkinson Disease

substantia nigra in the brainstem begin to degenerate. As we discussed previously, the substantia nigra forms close connections with the basal ganglia in the cerebral hemispheres. The end result of degeneration in the substantia nigra is a lack of typical dopaminergic activity in the basal ganglia. Recall from earlier in this chapter that the basal ganglia are intimately involved with the production of voluntary movements. In addition to the degeneration of neurons in the substantia nigra, Parkinson disease features Lewy bodies, which are pathological clumps formed from alpha synuclein protein. These are also present in cases of Lewy Body disease, discussed in Chapter 15. The factors that initiate degeneration of the substantia nigra and the formation of Lewy bodies remains somewhat

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Disorders of Movement

mysterious. Parkinson disease probably involves some genetic vulnerability, but genetics alone do not predict most cases. In particular, genes involved with the functioning of mitochondria have been implicated (Cardoso et al., 2005). Environmental toxins definitely participate in the development of Parkinson disease. Support for this hypothesis originated from an unfortunate accidental experiment involving young people addicted to heroin who suddenly developed symptoms of Parkinson disease (Langston, 1985). They had shared a homemade synthetic heroin, which contained a chemical known as MPTP. When MPTP binds with the enzyme monoamine oxidase, found in large quantities in the substantia nigra, it forms a very toxic substance known as MPP+. MPP+ is attracted to the pigment neuromelanin, which is also found in large quantities in the substantia nigra. You may recall that substantia nigra means “black substance” and that the structure is named in part because of its pigmentation. The affinity between MPP+ and neuromelanin results in the accumulation of MPP+ in the substantia nigra, leading to degeneration of the neurons. Obviously, the vast majority of people with Parkinson disease have never been exposed to heroin, synthetic or otherwise. However, toxins that act like MPTP, such as the herbicide paraquat, are present in the environment. People who report having applied insecticides and herbicides on their home gardens or farms are significantly more likely to develop Parkinson disease than relatives who do not have any direct pesticide exposure (Ritz et al., 2016). Exposure to commonly used solvents such as toluene differentiated between identical twins with and without Parkinson disease (Goldman et al., 2012). The gut-brain axis might provide a mechanism by which environmental toxins can lead to Parkinson disease. Many patients with Parkinson disease experience gastrointestinal disturbances prior to experiencing motor symptoms. Lewy bodies have been discovered in areas of the gastrointestinal system served by the vagus nerve (cranial nerve X). Environmental toxins in the gut could promote the formation of abnormal alpha synuclein, which, in turn, could travel by retrograde transport via the vagus nerve up to the brain (Nunes-Costa et al., 2020). High levels of caffeine intake and blood levels of urate are negatively correlated with Parkinson disease, suggesting these chemicals are protective (Bakshi et al., 2020). Protection might occur due to caffeine’s ability to block adenosine receptors and urate’s antioxidant capabilities. However, these findings should not inspire you to head immediately for your nearest coffee shop. These correlational data do not allow us to say that the reduced risk for Parkinson disease was caused by coffee consumption. It is also possible that the physiology of people who can tolerate larger amounts of caffeine makes them resistant to Parkinson disease. However, the caffeine as a protector model is supported by findings that a person’s ability to metabolize

275

caffeine, which is mostly genetic, does not interact with the effects of caffeine intake on Parkinson risk (Chen & Schwarzschild, 2020). The traditional treatment for Parkinson disease is the medication levodopa, usually combined with carbidopa. Carbidopa does not cross the blood-brain barrier but acts peripherally to reduce the breakdown of levodopa. Levodopa is a precursor in the synthesis of dopamine (review Chapter 4), so additional levodopa should help the neurons in the substantia nigra manufacture more of the neurochemical. Levodopa crosses the blood–brain barrier, while dopamine itself does not. However, levodopa loses its effectiveness as the numbers of substantia nigra neurons decrease and feedback loops inhibit the further production of dopamine. Because levodopa affects all dopaminergic systems, not just those originating in the substantia nigra, it produces multiple undesirable side effects. Dyskinesia, or involuntary movements, eventually is experienced by the vast majority of patients treated with levodopa. Increasing overall dopamine activity often results in psychotic behavior, including hallucination and delusional thinking. As we noted in Chapter 4, the increased activity of dopaminergic neurons associated with schizophrenia and with the abuse of dopamine agonists such as amphetamine can produce similar types of psychotic behaviors. Observations of caffeine’s possible protective effects have led to investigations of caffeine and other adenosine antagonists as treatments for Parkinson disease. The results of animal research have been very promising, but clinical trials in humans have lagged behind. The adenosine antagonist istradefylline was approved by the United States FDA in 2019 after two decades of testing (Chen & Cunha, 2020). Istradefylline is not used alone, but in conjunction with levodopa/carbidopa. Surgery as a treatment for Parkinson disease has become more common. In a procedure known as a pallidotomy, a part of the globus pallidus of the basal ganglia is destroyed. Another surgical approach to Parkinson is the thalamotomy, in which a small area of the thalamus is destroyed. Pallidotomy and thalamotomy do not require invasive surgery but instead are conducted with ultrasound and gamma knife technologies. These procedures, when successful, generally reduce unwanted muscle tension and tremor. Deep brain stimulation, demonstrated in Figure 8.26, involves surgically implanted electrodes in the thalamus, globus pallidus, or subthalamic nucleus that are connected to two pulse generators implanted near the patient’s collarbone. The generators maintain a steady electrical signal that interferes with signals that lead to tremor. Transplantation of stem cells as a treatment for Parkinson disease has a history of over 30 years. Recent advances in the development of induced human pluripotent stem cells from skin or blood dodges many of the ethical concerns over the earlier use of fetal cells and make cell replacement strategies more practical (Parmar et al., 2020).

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Figure 8.26 Deep Brain Stimulation Treatment for Parkinson Disease To date, thousands of patients with Parkinson disease have been treated with this electricity-based technique that requires the insertion of two generators under the skin, usually near the collarbone. The generators, each about 2 in in diameter, emit tiny electrical pulses that pass along wires, also under the skin, through electrodes implanted in select areas of the brain. Some patients experience a tingling sensation, but typically, the stimulation pulses go unnoticed.

Implanted electrode

Generators

Gene therapy might also lead to effective treatments, as initial experiments in human patients appear promising and relatively safe (Merola et al., 2021). More work needs to be done before this type of treatment is widely available, but the outlook is optimistic.

Huntington Disease Huntington disease is a genetic disorder that usually strikes in middle age and produces involuntary, jerky, dance-like movements. As the disease progresses, cognitive symptoms Huntington disease A genetic disorder beginning in middle age that results in jerky, involuntary movements and progresses to psychosis and premature death.

Images provided courtesy of Sanjiv Sam Gambhir, M.D., Ph.D., Stanford University.

Thalamus

such as depression, hallucination, and delusion occur. Fifteen to 20 years after the onset of symptoms, the patient dies. There is no known cure for this disease, which affects about one person out of 10,000. The disease was first identified by George Huntington, a doctor in Long Island, New York, in 1872. Eventually, Huntington’s original patients were found to be part of one extended family going back to a pair of brothers who came to America from England in 1630. A number of family members were burned as witches in Salem in 1693, probably due to the odd behaviors associated with the disease (Ridley, 1999). The cause of Huntington disease is simple and well understood. The huntingtin (HTT) gene on Chromosome 4, named after George Huntington, encodes the brain protein huntingtin. The HTT gene contains a codon, or sequence that encodes an amino acid, that can repeat between six and over 100 times (refer to Figure 8.27). Most people have between 10 and 15 repeats of this sequence. A person with 37 or more repeats will develop Huntington disease. Higher numbers of repeats are correlated with an earlier onset of symptoms (Gusella et al., 1996). To make matters worse, this gene is one of the few examples of a dominant gene for a disease. It doesn’t help at all to have one normal HTT gene. If you have one disease gene, you will have the disease. If one of your parents has the disease, then you have a 50 percent chance of developing the disease yourself. The identification of the HTT gene in 1993 made genetic testing possible for those who are at risk for the disease (Gusella & MacDonald, 1993). How does the mutant huntingtin protein produce the symptoms of Huntington disease? The huntingtin protein produced by the disease gene appears to accumulate, particularly in the cells of the basal ganglia. This accumulation of disease proteins forms a sticky lump in the cells and triggers cellular suicide (apoptosis; review Chapter 5). Currently, there are no effective treatments for Huntington disease, despite the fact that the responsible gene has been recognized for quite a few years. Brain imaging shows that changes in brain volume begin to occur long before the appearance of symptoms leads to diagnosis (Ross et al., 2014). Investigation of these changes might lead to treatments that delay the onset of symptoms or slow the progression of the disease. Most current treatments are aimed at managing symptoms to improve patients’ quality of life. However, novel approaches like gene silencing might someday alleviate symptoms altogether (Testa & Jankovic, 2019). Theoretically, the genetic testing of all offspring of patients with Huntington disease and their subsequent use of assisted reproduction, selecting out all affected embryos, would end the disease for all time in one generation. But this is a highly complex psychosocial decision that is unlikely to be chosen by all concerned.

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Figure 8.27 Huntington Disease Results From Excess Codon Repeats People with more than 37 codon repeats in a segment of the huntingtin (HTT) gene on chromosome 4 will have Huntington disease. Greater numbers of repeats are correlated with earlier onset. The disease gene is unusual in that it is dominant. Even with one healthy HTT gene on the other copy of chromosome 4, a person with a disease gene will develop the disease.

Protein

CAGCAGCAG...

Healthy Gene 10–26 repeats

CAGCAGCAGCAGCAGCAGCAGCAGCAG...

Huntington’s Disease Gene 37–80 repeats

Protein

National Institute of Standards and Technology

Triplet Repeat

Source: https://en.wikipedia.org/wiki/Huntington%27s_disease#/media/File:Huntington’s_disease_(5880985560).jpg

Neuroscience in Everyday Life How to Repair a Gene Many of the movement disorders described in this chapter could benefit from gene therapy, but this technology is still considered experimental and risky. While a thorough description of gene-editing methods is beyond the scope of this book, we can highlight some of the promises and challenges. Many current gene-editing methods involve CRISPR (pronounced “crisper” and standing for Clustered Regularly Interspaced Short Palindromic Repeats). CRISPR genetic sequences were discovered in bacteria, where they provide a defense against invading viruses. CRISPR consists of an enzyme that cuts DNA and a segment of guide RNA that helps the enzyme know where to cut. This basic unit can be combined with a replacement piece of DNA that fits into the area of the cut. At this point, the cell’s natural repair mechanisms take over and complete the edit. CRISPR technologies might eventually help people with Huntington disease and similar conditions by

replacing the disease gene with a healthy one, but this process is not without risk. In 1999, 18-year-old Jesse Gelsinger died during a clinical trial for gene therapy at the University of Pennsylvania. He reacted to the adenovirus vector used to deliver a replacement gene with a massive inflammatory response, leading to organ failure. Ironically, Jesse’s condition had been managed effectively with medication and a special diet, but he wanted to help others with more serious versions of his disease. His death was a huge setback to gene therapy efforts. Safer vectors have been developed now, but additional risks remain. CRISPR is not perfect. It is capable of producing unwanted mutations and effects away from the target site. However, progress continues to be made. One research group has demonstrated that by targeting a single strand of DNA (a “nick”) rather than the usual targeting of strands on both relevant chromosomes (complete cut), they could improve the rate of (continued)

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Movement

Neuroscience in Everyday Life How to Repair a Gene (Continued) which there are the least treatment options. In these cases, the risks and potential benefits might be better aligned.

Science History Images/Alamy Stock Photo

successful repairs and avoid mutations and unwanted effects elsewhere in the genome (Roy et al., 2022). As the field of gene therapy moves forward, it is likely to be focused on the most serious conditions for

Interim Summary 8.3 Summary Points 8.3 1. A number of toxins interfere with movement due to their action at the cholinergic neuromuscular junction. (LO6) 2. Myasthenia gravis is an autoimmune disease that produces extreme muscle weakness and fatigue due to the breakdown of ACh receptor sites at the neuromuscular junction. Muscular dystrophy is a collection of diseases that produces muscular degeneration. Polio is a contagious viral disease that attacks spinal motor neurons, causing some degree of paralysis. Accidental spinal injury results in the loss of voluntary movement produced by nerves below the level of injury. (LO6)

Figure 8.28 CRISPR The CRISPR gene-editing process begins with the attachment of a CRISPR enzyme (the purple structure) to the DNA of a cell using a guide RNA (in orange) that matches the DNA sequence to be modified. This separates the double helix of the DNA strand. The DNA is cut at the area in green. After the cut has been made, the DNA sequence can be disabled, replaced, or silenced. The cell’s normal repair machinery then finalizes the process automatically.

3. Amyotrophic lateral sclerosis (ALS) is a degenerative condition resulting from the progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. (LO6) 4. Parkinson disease produces difficulty moving, tremor in resting body parts, frozen facial expressions, and reduced heart innervation. (LO6) 5. Huntington disease is a genetic disorder characterized by involuntary movement and cognitive decline. (LO6) Review Questions 8.3 1. What effects can toxins have on the neuromuscular junction, and how does this affect movement? 2. What physical changes underlie the symptoms of Parkinson disease?

Summary Table 8.3: Major Disorders of the Motor Systems Disorder

Symptoms

Causes

Treatments

Myasthenia gravis

Muscle weakness, fatigue

Autoimmune damage to the nicotinic ACh receptor

Medications that inhibit the immune system or AChE

Muscular dystrophy

Progressive muscle degeneration

Abnormalities in the gene that encodes for the protein dystrophin

None currently approved; gene replacement and muscle cell replacement under investigation

Polio

Damage to spinal motor neurons leading to mild to severe muscle paralysis

Virus

Prevented by immunization (continued)

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Chapter Review

279

Disorder

Symptoms

Causes

Treatments

Accidental spinal cord injury

Paralysis in muscles served by the spinal cord areas below the point of damage

Compression or laceration of the spinal cord

None currently approved; stem cell therapy and methods for promoting axon regrowth are under investigation

Amyotrophic lateral sclerosis (ALS)

General weakness, muscle atrophy, cramps, muscle twitching

Possible genetic inheritance; exposure to environmental toxins

Medications slow the progression of the disease

Parkinson disease

Progressive difficulty initiating movement

Genetic risk and exposure to toxins

Deep brain stimulation, surgical removal of sections of the basal ganglia or thalamus, medication; gene therapy and stem cell implants under investigation

Huntington disease

Involuntary, jerky movements; depression, hallucinations, delusions

Abnormalities in the gene that encodes for the protein huntingtin

Experimental gene replacement, stem cell implants, and medications under investigation

Chapter Review Tho u g h t Q u e st ion s 1. What advice would you give an older adult who wanted to maintain or improve muscle strength? 2. Why do you think we evolved three types of muscle fibers? 3. Damage or abnormalities in the prefrontal cortex and basal ganglia might be responsible for some impulsive behavior. Using your knowledge of the initiation of movement, explain why abnormalities in these areas might lead to impulsivity. 4. If you had a parent with Huntington disease, would you undergo the available genetic screening? What factors would influence your decision? 5. At what levels of the motor system do we treat fine motor activities, such as speech and the movement of our fingers and hands, differently from gross motor activities, such as posture?

Key Ter ms actin (p. 250) alpha motor neuron (p. 254) amyotrophic lateral sclerosis (ALS) (p. 273) central pattern generator (CPG) (p. 260) corticospinal tract (p. 263) extensor (p. 259) extrafusal muscle fiber (p. 255) fast-twitch fiber (p. 251) flexor (p. 259) flexor reflex (p. 260) gamma motor neuron (p. 257) Golgi tendon organ (p. 258)

Huntington disease (p. 276) Ia sensory fibers (p. 256) Ib sensory fiber (p. 258) intrafusal muscle fiber (p. 255) lateral pathway (p. 261) M line (p. 250) mirror neuron (p. 266) monosynaptic reflex (p. 256) motor unit (p. 254) muscle fiber (p. 249) muscle spindle (p. 255) muscular dystrophy (p. 272) myasthenia gravis (p. 271) myofibril (p. 250) myosin (p. 250) myotatic reflex (p. 256) neuromuscular junction (p. 254) nuclear chain fibers (p. 256) Parkinson disease (p. 274) polio (p. 272) polysynaptic reflex (p. 259) premotor cortex (p. 265) rate code (p. 255) reciprocal inhibition (p. 259) recruitment (p. 255) rubrospinal tract (p. 263) sarcomere (p. 250) slow-twitch fiber (p. 251) smooth muscle (p. 248) striated muscle (p. 248) supplementary motor area (SMA) (p. 265) tropomyosin (p. 251) troponin (p. 251) twitch (p. 250) ventromedial pathway (p. 262) Z line (p. 250)

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Chapter 9 Learning Objectives L01

Differentiate between the terms homeostasis, set point, and motivation.

L02

Identify the behavioral and physical adaptations organisms use to regulate body temperature.

L03

Explain the mechanisms used to initiate and cease drinking.

L04

Describe the mechanisms leading to the initiation of feeding and to satiety.

L05

Differentiate between healthy eating and disordered eating.

L06

Assess the biological correlates of feelings of reward and pleasure.

Homeostasis, Motivation, and Reward Chapter Outline Homeostasis and Motivation Regulating Body Temperature

Adaptations Maintain Temperature Endothermic Responses to Heat and Cold Disruptions to Human Core Temperature Brain Mechanisms for Temperature Regulation

The Pancreatic Hormones The Initiation of Eating Satiety Healthy and Disordered Eating

Defining Healthy Weight Obesity Disordered Eating

Interim Summary 9.2

Thirst: Regulating the Body’s Fluid Levels

Pleasure and Reward

Interim Summary 9.1

Interim Summary 9.3

Hunger: Regulating the Body’s Supply of Nutrients

Chapter Review

Intracellular and Extracellular Fluid Compartments Osmosis Causes Water to Move The Kidneys The Sensation of Thirst

Classical Research in Self-Stimulation Multiple Facets of Reward Reward Pathways The Neurochemistry of Reward Cortical Processing of Reward

Digestion and Storage of Nutrients

Neuroscience in Everyday Life: Understanding the Benefits of Fever Behavioral Neuroscience Goes to Work: Nutritional Neuroscience Thinking Ethically: How Dangerous Is It to Be Overweight or Obese? Connecting to Research: Working for Brain Stimulation 281

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Chapter 9

Homeostasis, Motivation, and Reward

Homeostasis and Motivation Without much conscious awareness or effort on our part, our bodies maintain homeostasis. Homeostasis, a term coined by psychologist Walter Cannon (1932), refers to the active maintenance of a constant internal environment. Homeostasis frees organisms to some extent from the constraints of the external environment, which, in turn, enables them to inhabit a wider range of habitats. Early research suggested that regulatory systems actively defend certain values, or set points, for variables such as core body temperature, fluid levels, and body weight. The defense of these set points is similar to the thermostat of your home’s heating system (refer to Figure 9.1). If the air temperature drops below the setting, the furnace is turned on. Once the desired temperature is reached, the furnace turns off again. Deviations from set points are rapidly assessed by the nervous system. Once discrepancies are recognized, the nervous system makes appropriate internal adjustments and motivates behavior designed to regain the ideal state. While this model has provided useful research guidance, it cannot account for phenomena like the current obesity epidemic. It might be more useful to think of body weight as having a moderately stable “settling point” influenced by internal hunger and satiety mechanisms as well as context and the palatability of available food (Kringelbach & Berridge, 2016). We are clearly capable of eating without being in the presence of a homeostatic deficit. The process of motivation both activates and directs behavior toward a goal. Behavioral drive theories suggest that when homeostasis has been compromised, the nervous system first activates behavior by generating tension and discomfort in the form of drive states such as thirst or hunger. Drive states arise in response to physiological needs and disappear, usually with a sense of relief, when those needs are met. Once the organism is activated by a drive state, it will initiate behavior to solve the specific problem. The action chosen to reestablish homeostasis will not be random. We do not respond to hunger cues by getting a drink of water. Instead, the activity of the nervous system ensures that we will be motivated specifically to seek out food. Drive theories of motivation are also known as “push” theories because the organism is pushed toward a goal to reduce tension and discomfort. Not all motivated behavior works this way. In other cases, organisms are “pulled” toward a goal by the anticipation of rewards or incentives. While it is true that we will seek food when we feel hungry, the anticipation of feeling pleasure while eating something

homeostasis The active maintenance of a constant internal environment. set point A value that is defended by regulatory systems, such as core temperature. motivation The process of activating and directing behavior.

Figure 9.1 Set Points Set points for some physiological systems, like core body temperature, work much like the setting on the thermostat of your home. Deviations from the set point initiate behaviors (turning the heat or air conditioning on) that return the system to homeostasis or equilibrium. In other cases, like hunger, it is more accurate to say we have a “settling” point combining internal factors and context. We definitely have the ability to eat without being in a deficit situation.

© BSteve Cukrov/Shutterstock.com

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truly delicious will also motivate us to eat, even when we really don’t need more food. Humans possess a wide range of motivated behavior, from basic needs such as hunger and thirst to more cognitive motives for achievement and affiliation. This chapter will focus on model systems involved with the regulation of body temperature, thirst, and hunger. We will also explore the general mechanisms of reward and pleasure. In upcoming chapters, we will investigate the sexual motive (Chapter 10) and the influence of reward on learning (Chapter 12) and decision making (Chapter 13).

Regulating Body Temperature Temperature regulation involves all of the major features of a homeostatic system that we have discussed so far: a precisely defined set point, mechanisms for detecting deviations away from the set point and, finally, internal and behavioral elements designed to regain the set point. Animals inhabit niches that vary dramatically in external temperature, from the frozen Arctic to steamy equatorial jungles. Some bacteria exist in the hot volcanic vents in the ocean floor. Extreme temperatures limit life through their impact on the chemical properties of living cells. If temperatures are too low, ice crystals form within cells and damage the cell membrane. In high temperatures, the proteins necessary for carrying out cell functions become unstable. No matter where they live, animals

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Regulating Body Temperature

must maintain an internal temperature that is ideal for the normal activity of their bodies’ cells.

Adaptations Maintain Temperature Two solutions have evolved to help animals maintain an optimal body temperature in a varying environment. Mammals and birds are referred to as endotherms (endon is the Greek word for “within”) due to their ability to maintain body temperature through internal metabolic activity. Amphibians, reptiles, and fish are referred to as ectotherms (ektos is the Greek word for “outside”) because they rely on external factors, such as basking in the sunlight or retreating to the shade below a rock, to maintain ideal body temperature. Endotherms usually maintain a steady internal temperature, but the internal temperature of the ectotherm will vary more widely in response to changes in the external environment. The common terms warmblooded and cold-blooded are misleading. The body temperature of so-called cold-blooded animals will become very warm indeed if they are in a warm environment. The maintenance of body temperature is influenced by an animal’s surface-to-volume ratio. The larger the overall

283

volume of the body, the more heat is produced by metabolic activity. Heat is lost to the surrounding environment as a function of the animal’s surface area. As demonstrated in Figure 9.2, smaller animals have more surface area relative to their overall body volume than larger animals do, so small animals require more energy to maintain a constant body temperature. Within a species, populations of animals evolve features that fit a particular environmental niche. In cold climates, surface area and heat loss are reduced in animals that have compact, stocky bodies and short legs, tails, and ears. To promote heat loss in warm climates, animals have greater surface area in the form of slim bodies and long appendages (refer to Figure 9.3). This trend can be observed among human beings as well, although there are obviously many exceptions.

endotherm An animal that can use internal methods, such as perspiration or shivering, to maintain body temperature. ectotherm An animal that relies on external methods, such as moving into the sun or shade, for maintaining body temperature.

Figure 9.2 Surface-to-Volume Ratios Affect Temperature Regulation

12

6

3

Rat—1:6.67

Black Morion/Shutterstock.com

(a) The higher an animal’s surface-to-volume ratio, the harder it must work to maintain core temperature. The amount of heat loss is a function of the body surface area, and body volume determines the amount of heat generated by metabolic activity. Because smaller animals have larger surface-to-volume ratios, maintaining core temperature is harder for them than for larger animals such as humans. (b) Rats have larger surface-to-volume ratios than humans or elephants. Consequently, rats must work much harder than humans or elephants to maintain core temperature.

Human—1:35.3

Surface area

54

216

864

Volume

27

216

1,728

Surface-tovolume ratio

2:1

1:1

1:2

Elephant—1:150 (a)

(b)

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Figure 9.3 Adaptations to Climate Occur Within Species

© Karla Freberg

Animals in warm climates disperse heat by having slim bodies and long appendages. Animals in cold climates conserve heat by having compact, stocky bodies and short legs, tails, and ears. These foxes are found in (left) warm, (center) temperate, and (right) Arctic climates.

sympathetic nervous system responds to cold by stimulating greater metabolic activity in brown fat cells. Brown fat cells are located primarily in the torso, close to the vital organs. The fat cells appear brown due to large numbers

Endotherms demonstrate a variety of automatic internal responses to deviations from the temperature set point. Humans defend a temperature set point of approximately 37°C (98.6°F), but this can Figure 9.4 Raynaud’s Disease Produces an range from 36.1°C (97°F) to 37.2°C (99°F). When the internal temperature drops Extreme Reaction to Cold below this set point, we shiver. Shivering Blood vessels normally constrict in response to cold. In Raynaud’s disease, results from muscle twitches, which can be this constriction becomes extreme, leading to a lack of circulation in the so intense that teeth chatter together. The affected digit. People with Raynaud’s disease are cautioned to avoid sudmuscle activity involved in shivering proden cold and to use gloves when removing food from their freezers. duces heat, but at the cost of a high expenditure of energy. Blood vessels constrict, keeping most of the blood away from the surface of the skin, where heat loss is greatest. In some cases, blood vessel constriction is too extreme, leading to a condition known as Raynaud’s disease, depicted in Figure 9.4. If cold conditions persist despite shivering, the thyroid gland increases the release of thyroid hormone. Higher levels of thyroid hormone are associated with greater overall metabolic activity, which warms the body. Thyroid disease is often diagnosed based on the patient’s lower-than-normal body temperature. In human infants and small animals, the

Medical Images/BOB TAPPER

Endothermic Responses to Heat and Cold

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Regulating Body Temperature

of mitochondria, the organelles responsible for energy production. Very warm temperatures produce their own set of responses. Perspiration cools the skin through evaporation. Blood vessels near the surface of the skin dilate in hot environments, allowing more heat loss to the external environment. As a result, people often become red-faced in warm temperatures.

Disruptions to Human Core Temperature The body’s core temperature refers to the temperature maintained for vital organs within the head and torso. Although we can survive drastic changes in the temperature of the body’s outer shell, much smaller deviations in our core body temperature can have severe consequences. Hot flashes are a frequent disturbance of core temperature homeostasis affecting nearly 80 percent of women in the months or years surrounding menopause. Hot flashes last seconds to minutes and are characterized by sweating, flushing, heart palpitations, and a subjective feeling of being very warm. Hot flashes result from changes in sympathetic nervous system activation and reduced estrogen levels. Core body temperature increases slightly, and the temperature range between shivering and sweating thresholds becomes quite narrow. Frequent hot flashes can affect a woman’s quality of life, particularly since these episodes are correlated with poor sleep (Freedman, 2014). Temperature homeostasis is also affected by fevers associated with illness. We all know how miserable a fever of only a few degrees feels, and very high fevers (in excess of 41°C/105.8°F) can cause brain damage. Fevers due to illness result when chemical byproducts of bacteria or

285

viruses known as pyrogens enter the brain, causing the brain to increase the core temperature set point from 37°C to 39°C (98.6°F to 102.2°F). We’ll discover exactly how this occurs in the next section on brain mechanisms controlling temperature. Body temperature will rise gradually until the new set point is reached. Although uncomfortable, fever does have beneficial effects in fighting disease (Singh et al., 2021). A fever represents a carefully monitored increase in the body’s temperature set point. In contrast, heat stroke, or hyperthermia, occurs when the body’s normal compensations (such as sweating and dilating the blood vessels close to the skin) cannot keep the core temperature within normal limits. If the core temperature rises above 40°C/104°F, a person can become confrontational, faint, and confused. Sweating stops, compounding the problem of overheating. Hyperthermia is a life-threatening condition and requires immediate medical assistance. Hyperthermia often results from engaging in strenuous physical activity or wearing heavy clothing in hot, humid environments, conditions that limit the body’s ability to get rid of excess heat (refer to Figure 9.5). People with alcohol abuse problems and older adults, especially those with infections and cardiovascular problems, are at greater risk of dying from hyperthermia (Hall et al., 2021).

fever A carefully controlled increase in the body’s thermal set point that is often helpful in ridding the body of disease-causing organisms. hyperthermia A life-threatening condition in which core body temperature increases beyond normal limits in an uncontrolled manner.

Neuroscience in Everyday Life Understanding the Benefits of Fever Not only are fevers uncomfortable, but also, from an evolutionary point of view, they are expensive. Raising the core body temperature requires a significant increase in metabolism, which in turn requires more energy from food. To support this cost across many different types of species, fever must provide substantial benefits. Many disease-causing organisms can tolerate a much narrower temperature range than the infected animal or person. Viruses have survival rates at 37°C/98.6°F that are 250 times higher than at 40°C/104°F. Raising the host’s set point kills many of the invading organisms, assisting the immune system in its task of ridding the body of disease. Prevention of fever through the use of sodium salicylate, a chemical similar to aspirin, increased the

death rate of animals infected with bacteria (Bernheim & Kluger, 1976; Cann, 2021). Among the pathogens that are reduced by fever are the viruses responsible for many upper respiratory diseases and the bacteria responsible for gonorrhea and syphilis. Prior to the discovery of antibiotics, patients with syphilis were deliberately infected with malaria to induce fever (Bruetsch, 1949). Because of the potential benefits of fever, current medical practice suggests using medication to reduce a fever only if other health risk factors are present or when discomfort is excessive. Even though SARS-CoV-2, the virus responsible for Covid-19, produces higher fevers than most coronaviruses, experts are questioning the common practice of using medication right away to reduce fever (Cann, 2021).

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Low core temperatures are also life threatening. Hypothermia (low core body temperature) has Heat stroke is a risk whenever people experience physical activity, warm weather, and killed many stranded hikers and heavy clothing. Military personnel often wear heavy protective gear that retains heat. ocean swimmers. Hypothermia This soldier is attempting to cool off while on duty. occurs when the core body temperature drops below 35°C/95°F. Uncontrolled, intense shivering, slurred speech, pain, and discomfort occur. At core temperatures below 31°C/87.8°F, the pupils dilate, behavior resembles drunkenness, and consciousness is gradually lost. Deliberately inducing mild hypothermia has become a common method of reducing brain damage following cardiac arrest, traumatic brain injury, neonatal encephalopathy, stroke, or open-heart surgery. Cooling can be achieved using a special mattress, intravenous fluids, or applications of ice. Although the mechanism by which cooling prevents damage is not completely understood, it is likely that cooling Many recreational and therapeutic drugs are capable counteracts typical negative reactions to an interruption of producing hyperthermia. Drugs can either increase in the blood supply to the brain, such as the increased the production of heat, interfere with heat dissipation, or activity of free radicals, excitatory neurochemicals, and both. Stimulant drugs, including amphetamine, cocaine, calcium. and MDMA (Ecstasy), are particularly likely to interfere with normal temperature regulation. Antidepressants, Brain Mechanisms for Temperature including selective serotonin reuptake inhibitors (SSRIs), Regulation monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants, can also disrupt body temperature. Temperature regulation is too important for survival to Serotonin syndrome, which produces muscular rigidity be left to a single system. Instead, temperature regulation and hyperthermia, can result from the use of multiple results from the activity of a structural hierarchy, begintypes of antidepressants at the same time, overdose with ning with the spinal cord and extending through the antidepressants, or gradual increases in antidepressants brainstem to the hypothalamus. Sensitivity to temperature intended to achieve therapeutic effects. With nearly one change increases from the lower to the higher levels of this in eight adults in the United States taking antidepressant hierarchy. Lower levels, such as the spinal cord, do not medications, the frequency of serotonin syndrome is respond to heat or cold until an animal’s core temperature expected to increase. The highest risk of severe serotonin is as much as two to three degrees away from the set point. syndrome is associated with taking an MAOI (refer to Patients with spinal cord injury, which prevents temperaChapter 4) in conjunction with another drug affecting ture regulation of the body by the brainstem and hypothalserotonin (Scotton et al., 2019). amus, frequently complain about their inability to manage temperature control of their arms and legs. Higher levels of the hierarchy act as much more precise thermostats. The hypothalamus initiates compensation whenever core temserotonin syndrome A life-threatening condition characterized perature deviates as little as 0.01° from the ideal set point by hyperthermia and muscular rigidity caused by excess serotonin activity due to the use of therapeutic or recreational drugs. (Satinoff, 1978). hypothermia A potentially fatal core body temperature below Sensory neurons that respond to changes in tempera35°C/95°F. ture are known as thermoreceptors. Thermoreceptors thermoreceptor A sensory neuron that responds to changes in possess ion channels that open in response to temperatures temperature. within a narrow range. Some thermoreceptors respond STAN HONDA/AFP/Getty Images

Figure 9.5 Heat Stroke

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Regulating Body Temperature

more vigorously to warming and reduce their response during cooling. Others do the opposite. Thermoreceptors in the skin consist of free nerve endings and travel along the same routes as pain fibers, as discussed in Chapter 7. Cooling within the spinal cord can activate cold-sensitive skin thermoreceptors as their axons ascend to the brain (Brock & McAllen, 2016). Warmth within the spinal cord changes the neurochemical release by warm-sensitive skin thermoreceptors, activating other spinal neurons in the “warm” pathway. Core temperature is monitored by sensory neurons in the hypothalamus itself. The preoptic area (POA) of the hypothalamus, presented in Figure 9.6, along with adjacent areas of the anterior hypothalamus and septum, manages appropriate responses to higher core temperatures, such as panting, sweating, and the dilation of blood vessels. The posterior hypothalamus is responsible for initiating responses to cooler core temperatures, such as shivering and blood vessel constriction. The POA contains three types of neurons that contribute to the temperature set point: warm-sensitive, cold-sensitive, and temperature-insensitive neurons. Warmsensitive neurons make up about 30 percent of the POA. In addition to receiving input from the skin and spinal

Figure 9.6 The Hypothalamus Controls Temperature Regulation The preoptic area (POA) of the hypothalamus, along with adjacent areas of the anterior hypothalamus and septal area, manages appropriate responses to higher core temperatures such as panting, sweating, and the dilation of blood vessels. The posterior hypothalamus is responsible for initiating responses to cooler core temperatures such as shivering and blood vessel constriction.

Thalamus Preoptic area (POA) Septal area

Optic chiasm Pituitary gland

Posterior hypothalamus

287

cord, warm-sensitive neurons have receptors embedded in their membranes similar to those in the mouth that are sensitive to capsaicin, the ingredient in peppers that gives us the sensation of heat (refer to Chapter 7). These receptors respond directly to changes in the temperature of the brain and blood in their vicinity. Warm-sensitive neurons maintain a background level of activity that increases sharply when core temperatures surpass 37°C (98.6°F). Output from the warm-sensitive neurons travels to the paraventricular nucleus (PVN) and lateral nucleus of the hypothalamus, which, in turn, initiate parasympathetic activity designed to dissipate heat, such as sweating. Cold-sensitive neurons make up about 5 percent of the POA, but larger numbers are found in the posterior hypothalamus. These neurons receive input from thermoreceptors in the skin. However, unlike the warm-sensitive neurons, the cold-sensitive neurons do not have any special membrane receptors for sensing coldness in the nearby brain and blood. Instead, cold-sensitive neurons receive inhibitory input from the warm-sensitive neurons. As core temperature drops below 37°C (98.6°F), the reduced activity of the warm-sensitive neurons results in less inhibition of the cold-sensitive neurons, allowing them to increase their activity. Output from the cold-sensitive neurons to the PVN and the posterior hypothalamus results in activation of the sympathetic nervous system. Sympathetic activity generates and conserves heat by raising the metabolism and constricting blood vessels at the surface of the skin. Temperature-insensitive neurons make up about 60 percent of the POA and are also found in the posterior hypothalamus. These neurons maintain a fairly steady rate of response under all temperature conditions, yet they do have a role to play in thermoregulation. Input from the temperature-insensitive neurons provides a baseline of activity in the cold-sensitive neurons that is modified by the amount of inhibition provided by the warm-sensitive neurons. As mentioned earlier, pyrogens entering the brain act to gradually increase the body’s temperature set point, causing fever. Not surprisingly, the pyrogens’ target in the brain is the hypothalamus. The blood–brain barrier is relatively weak near the POA, which allows pyrogens to exit the blood supply and enter the brain tissue. Once in the POA, pyrogens stimulate the release of prostaglandin E2, which, in turn, inhibits the firing rate of warm-sensitive neurons. As demonstrated in Figure 9.7, reduced activity in the warm-sensitive neurons disinhibits the cold-sensitive neurons and increases their activity, which fools the system into thinking the body is too cold. The hypothalamus responds by raising the temperature set point. Activity in the cold-sensitive neurons leads to greater production and retention of heat, increased heart rate, shivering, and the other unpleasant symptoms of fever. preoptic area (POA) A part of the hypothalamus involved in a number of regulatory functions, including temperature control.

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Chapter 9

Homeostasis, Motivation, and Reward

Figure 9.7 Pyrogens Reset the Temperature Set Point in Fever Pyrogens stimulate the release of prostaglandin E2 (PGE2), which binds to surface receptors on the warm-sensitive neurons (W) of the POA, lowering their activity. In response to reduced inhibition from the warm-sensitive neurons, cold-sensitive cells (C) increase their output, which results in a higher temperature set point. Temperature-insensitive neurons (I) provide a baseline of activity in the C cells, which is modified by varying levels of inhibition provided by the W cells.

W

Intracellular and Extracellular Fluid Compartments The body has three major compartments for storing water, as presented in Figure 9.8. About two-thirds of the body’s water is contained within cells as intracellular fluid or cytoplasm. The remaining third is found in extracellular fluid, which is further divided into the blood supply (about 7 percent of the body’s water total) and the interstitial fluid surrounding the body’s cells (about 26 percent of the body’s water total). Cerebrospinal fluid makes up an additional tiny fraction of a percentage of the extracellular fluid. As we discussed previously in Chapter 3, the composition of extracellular and intracellular fluids is quite

Pyrogens W Warm receptors C Cool receptors

To posterior hypothalamus and PVN.

I Legend: W = Warm sensitive neuron C = Cold sensitive neuron I = Temperature-insensitive neuron

Figure 9.8 The Body’s Fluids Are Held in Three Compartments About two-thirds of the body’s fluid is stored as intracellular fluid (cytoplasm). The remaining third is stored as extracellular fluid, divided between the interstitial fluid surrounding cells (26 percent) and the blood supply (7 percent). The cerebrospinal fluid, also a type of extracellular fluid, accounts for less than 1 percent of the body’s fluids. Cerebrospinal fluid