Lateral Hypothalamic Control of Energy Balance (Colloquium Integrated Systems Physiology: From Molecule to Function to Disease) 9781615047659, 9781615047666, 9781615047673, 1615047654

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Lateral Hypothalamic Control of Energy Balance

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Colloquium Digital Library of  Life Sciences The Colloquium Digital Library of  Life Sciences is an innovative information resource for researchers, instructors, and students in the biomedical life science community, including clinicians. Each PDF e-book available in the Colloquium Digital Library is an accessible overview of a fast-moving basic science research topic, authored by a prominent expert in the field. They are intended as time-saving pedagogical resources for scientists exploring new areas outside of their specialty. They are also excellent tools for keeping current with advances in related fields, as well as refreshing one’s understanding of core topics in biomedical science. For the full list of available titles, please visit: colloquium.morganclaypool.com Each book is available on our website as a PDF download. Access is free for readers at institutions that license the Colloquium Digital Library. Please e-mail [email protected] for more information.

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Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease Editors D. Neil Granger, Louisiana State University Health Sciences Center Joey P. Granger, University of Mississippi Medical Center Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face of substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This eBook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the eBooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each eBook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material. Published titles (for future titles please see the website, http://www.morganclaypool.com/toc/isp/1/1)

Copyright © 2018 by Morgan & Claypool Life Sciences All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means—electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. Lateral Hypothalamic Control of Energy Balance Gizem Kurt, Hillary L. Woodworth, and Gina M. Leinninger www.morganclaypool.com ISBN: 9781615047659 paperback ISBN: 9781615047666 ebook ISBN: 9781615047673 hardcover DOI: 10.4199/C00159ED1V01Y201711ISP079 A Publication in the Colloquium Series on Integrated Systems Physiology: From Molecule to Function to disease Lecture #79 Series Editors: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of  Mississippi Medical Center Series ISSN ISSN 2154-560X

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ISSN 2154-5626

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Lateral Hypothalamic Control of Energy Balance Gizem Kurt Department of Physiology Michigan State University

Hillary L. Woodworth Department of Physiology Michigan State University

Gina M. Leinninger Department of Physiology Michigan State University

COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE #79

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ABSTRACT Food and water are necessary for survival, but can only be obtained via ingestive behaviors (feeding, drinking, and moving). Survival thus depends on the ability of the brain to coordinate the need for water and energy with appropriate behaviors to modify their intake as necessary for homeostasis. However, the balance of these behaviors also inherently determines body weight, and imbalances contribute to the development of weight disorders, such as obesity and anorexia nervosa. The lateral hypothalamic area (LHA) of the brain is anatomically positioned to coordinate the sensation of osmotic and energy status with goal-directed ingestive behaviors necessary to maintain homeostasis and body weight, and, hence, may hold insight into the potential treatment for energy balance disorders. This volume reviews the essential role of the LHA for the control of body weight, from its historical description as a “feeding center” to the current view of this LHA as a cellularly heterogeneous hub that regulates multiple aspects of physiology to influence body weight. Furthermore, we evaluate how specific LHA populations coordinate certain metabolic cues and behaviors, which may guide the development of pathway-specific interventions to improve the treatment of energy balance disorders.

KEYWORDS: lateral hypothalamic area, energy balance, body weight regulation, orexin, hypocretin, melanin concentrating hormone, neurotensin, ingestive behavior

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Contents 1. The Weighty Implications of  the Lateral Hypothalamic Area in Energy Balance................................................................................................1 1.1 Homeostasis and Body Weight............................................................................ 1

1.2 1.3 1.4 1.5

What Is Energy Balance and How Does It Relate to Health?................... 2 Obesity Is a Disease of Disrupted Energy Balance.................................... 4 The Brain Coordinates Energy Balance..................................................... 9 Discovery of a Role for the Lateral Hypothalamic Area (LHA) in Energy Balance.................................................................................... 10 1.6 “Lateral Hypothalamic Syndrome” Suggests an Essential Role for the LHA in Coordinating Behavior................................................... 12 1.7 Physiologic and Pharmacologic Regulation of the LHA......................... 14 1.8 Neuronal Diversity in the LHA and Implications for Energy Balance........................................................................................ 15 2.

Anatomy and Connectivity of the LHA .............................................................. 17 2.1 Location of the LHA and Implications for its Function.................................... 17 2.2 Molecularly Defined Populations of Neurons Within the LHA........................ 19 2.2.1 Overview of LHA Subpopulations......................................................... 19 2.2.2 Melanin-concentrating Hormone (MCH)............................................. 19 2.2.3 Orexin/Hypocrectin (OX)...................................................................... 22 2.2.4 Neurotensin (Nts)................................................................................... 23 2.2.5 Galanin (Gal)......................................................................................... 23 2.2.6 GABA.................................................................................................... 25 2.2.7 Glutamate............................................................................................... 25 2.2.8 Receptor Expressing Populations (LepRb, MC4R)............................... 25 2.2.9 Other Populations of LHA Neurons...................................................... 26 2.3 Afferents to the LHA......................................................................................... 26 2.3.1 Hypothalamic Arcuate Nucleus (ARC).................................................. 26

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2.3.2 Hypothalamic Ventromedial Nucleus (VMH)....................................... 27 2.3.3 Parabrachial Nucleus (PB)...................................................................... 27 2.3.4 The Bed Nucleus of the Stria Terminalis (BNST)................................. 28 2.3.5 Nucleus Accumbens (NA)...................................................................... 28 2.3.6 Regions Involved in Learning and Memory (Prefrontal Cortex, Amygdala, Hippocampus, and Septum)................................................. 29 2.3.7 Lamina Terminalis (LT)......................................................................... 29 2.4 Projections from the LHA................................................................................. 30 2.4.1 The Ventral Tegmental Area (VTA)...................................................... 30 2.4.2 The Nucleus Accumbens (NA).............................................................. 32 2.4.3 Lateral Habenula (LHb)........................................................................ 32 2.4.4 Regions Involved in Learning and Memory (Prefrontal Cortex, Amygdala, and Hippocampus)................................................................32 2.4.5 Lamina Terminalis (LT)......................................................................... 33 2.4.6 Preoptic Area (POA).............................................................................. 33 2.4.7 Hypothalamic Paraventricular Nucleus (PVH)...................................... 33 2.4.8 Local Projections Within the LHA....................................................... 34 2.5 Peripheral Regulators of LHA Neurons............................................................. 34 2.5.1 Leptin..................................................................................................... 34 2.5.2 Ghrelin................................................................................................... 35 2.5.3 Glucose................................................................................................... 35 2.5.4 Dehydration............................................................................................ 36 3.

Roles of LHA Neurons in Regulating Feeding..................................................... 39 3.1 Overview of the LHA in Control of Feeding..................................................... 39 3.2 Melanin-Concentrating Hormone (MCH) Neurons in Control of Feeding........................................................................................................... 40 3.3 Orexin (OX) Neurons in Control of Feeding..................................................... 41 3.4 Neurotensin (Nts) Neurons in Control of Feeding............................................. 43 3.5 Galanin (Gal) Neurons in Control of Feeding................................................... 45 3.6 Corticotropin Releasing Hormone (CRH) Neurons in Control of Feeding........................................................................................................... 45 3.7 GABA Neurons in Control of Feeding.............................................................. 46 3.8 Glutamate Neurons in Control of Feeding......................................................... 48

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Role of the LHA in Drinking Behavior................................................................ 49 4.1 Overview of the LHA in Control of Drinking.................................................. 49 4.2 Melanin-Concentrating Hormone (MCH) Neurons in Control of Drinking......................................................................................................... 50 4.3 Orexin (OX) Neurons in Control of Drinking................................................... 50 4.4 Neurotensin (Nts) Neurons in Control of Drinking........................................... 51 4.5 CRH Neurons in Control of Drinking............................................................... 52 4.6 GABA and Glutamate Neurons in Control of Drinking................................... 52

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Role of the LHA in Arousal, Physical Activity, and Energy Expenditure............... 55 5.1 Overview of the LHA in Control of Basal and Volitional Energy Expenditure........................................................................................................ 55 5.2 Melanin-Concentrating Hormone (MCH) Neurons in Control of Energy Expenditure........................................................................................... 56 5.3 Orexin (OX) Neurons in Control of Energy Expenditure.................................. 57 5.4 Neurotensin (Nts) Neurons in Control of Energy Expenditure......................... 58 5.5 Galanin (Gal) Neurons in Control of Energy Expenditure................................ 59 5.6 GABA and Glutamate Neurons in Control of Energy Expenditure.................. 59

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Role of the LHA in Human Physiology............................................................... 61 6.1 What Have 60 Years of LHA Studies in Animals Taught Us About Human Energy Balance?................................................................................................. 61 6.2 Role of Melanin-Concentrating Hormone (MCH) in Human Energy Balance and Disease............................................................................... 62 6.3 Role of Orexin (OX) in Human Energy Balance and Disease........................... 62 6.4 Role of Neurotensin (Nts) in Human Energy Balance and Disease................... 64 6.5 Role of GABA and Glutamate in Human Energy Balance and Disease........... 65

References.................................................................................................................. 67 Author Biographies................................................................................................... 105



chapter 1

The Weighty Implications of the Lateral Hypothalamic Area in Energy Balance 1.1

Homeostasis and Body Weight

Perhaps, the most fundamental theme of physiology is homeostasis: the maintenance of a relatively stable internal environment necessary to support life. Two essential components for homeostasis are adequate stores of energy (derived from caloric intake) and fluid (water), both of which are essential for cell, system, and bodily health. However, the very physiologic processes used to sustain life (e.g., respiration, thermogenesis, movement, digestion) constantly tap bodily reserves of energy and water so that they must be continually replenished. Because food and water cannot be synthesized within the body, they must be replaced via ingestion. Preservation of energy and fluid homeostasis, thus, requires that animals constantly assess their internal environment, detect need for energy and/or water, and then execute the appropriate feeding and/ or drinking behaviors to obtain these resources from the environment. The feelings of hunger and thirst serve to communicate the body’s need for food and water to the brain so that it can coordinate the appropriate ingestive behavior (feeding or drinking) to restore homeostasis. An important byproduct of this process is the regulation of body weight, which is a visible proxy for homeostasis and whether adequate resources are available to support bodily health. For example, fasting-induced hunger or dehydration-induced thirst increase the motivation to find and ingest food and water, respectively [1, 2]. Failure to obtain these resources results in acute weight loss that initially strengthens the drives to obtain them, and to avoid prolonged depletion of energy and fluid reserves that would compromise survival. Resource excess is coordinated with behavioral responses to limit intake: stomach fullness or increased body fat cue the cessation of feeding [3, 4], whereas plasma hypotonicity biases for salt versus water intake to restore fluid homeostasis [5]. Thus, individuals vigilantly monitor fluid and energy status and coordinate ap­ propriate ingestive behaviors that impact body weight and survival. Although work over the

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past decades indicates that the brain is crucial for orchestrating drive states, behavior, and body weight, the precise neural circuits underlying these processes remain incompletely understood. Herein, we will address the role of a particular part of the brain, the lateral hypothalamic area (LHA), in coordinating energy balance, homeostasis and, hence, in the physiology underlying health and survival.

1.2

What Is Energy Balance and How Does It Relate to Health?

Energy homeostasis is often referred to and illustrated as “energy balance,” to convey the inter­ dependent relationship between energy intake and expenditure that determines body weight and health (Figure 1A). Energy intake consists of calories consumed through food and caloricliquids, such as milk, juices, or sugar-laden sports drinks and soda. Energy expenditure refers to the calories that are consumed by the body to support basal metabolism and behavior, in the form of voluntary physical activity. For most individuals, energy expenditure is the sum of their resting metabolic rate (RMR), the thermic effect of feeding (TEF), and the thermic effect of activity (TEA) [6]. RMR comprises 60% to 75% of total energy expenditure and is the energy required by the body to perform basic physiologic functions, or more simply the “number of calories an individual would use if he/she stayed in bed all day.” The TEF accounts for 10% of energy expenditure and is the energy required for digesting food. The TEA can account for 15% to 30% of an individual’s energy expenditure and refers to the additional calories burned through volitional activity and exercise [6]. When energy intake exceeds expenditure, it creates a caloric surfeit, or “positive energy balance,” which can be stored in the body as fat and lead to weight gain (Figure 1B). Conversely, when energy expenditure exceeds caloric intake, the body experiences a caloric deficit or “negative energy balance”; as a result, calories required to support survival are obtained from adipose reserves, leading to weight loss (Figure 1C). At face value, energy balance appears to be a simple math equation, but its coordination is complex, requiring continuous communication between the periphery (to sense energy status) and the brain (to modulate energy intake and expenditure, as necessary). Energy balance is intimately tied to the idea of a body weight “set-point” wherein genetic and environmental factors determine an individual’s body weight, which is defended through homeostatic mechanisms that compensate for positive or negative energy balance [7]. For example, in controlled over-feeding studies, total energy expenditure increases and appetite decreases as the body attempts to deplete the caloric surplus [8, 9]. Similarly, weight loss leads to increased

Weighty Implications of  the Hypothalamic Area in energy balance  

Figure 1: Energy Balance. (A) The interdependent relationship between energy intake and expenditure that determines body weight. (B) Positive energy balance with increased energy intake and decreased energy expenditure leading to weight gain. (C) Negative energy balance with decreased energy intake and increased energy expenditure leading to weight loss.

  Lateral Hypothalamic Control of Energy Balance

appetite and reduced energy expenditure that drives recovery of lost body weight and indeed, most people who lose weight gain it back [10–14]. Cota et al. provide a salient example of just how tightly the body coordinates energy balance: the average adult male uses around 900,000 calories per year and only gains (on average) one pound or 3600 extra calories during that time, which amazingly amounts to >99% accuracy in matching food intake with energy expenditure [15].

1.3

Obesity Is A Disease of Disrupted Energy Balance

Although energy balance is exquisitely fine-tuned in the short-term, small, incremental weight gain over years is thought to contribute to obesity. As such, the body weight set-point slowly drifts upward with time [7], and losing weight after being overweight or obese for several years is extremely challenging because the body strives to defend a heavier set-point [12, 13]. A prime example of this physiology comes from study of obese participants on the TV show “The Biggest Loser”: contestants lost >120 pounds on average during the show, but 6 years later, individuals had regained approximately two thirds of the weight and their energy-expenditure was significantly decreased compared with what would be expected for their body weight [16]. Thus, overweight individuals who have lost weight are constantly battling increased hunger and reduced energy expenditure as their bodies defend their heavier weight set-point. This specific disruption of energy balance is a major health concern, as the worldwide prevalence of obesity and overweight has increased dramatically over the past decades [17, 18]. The United States of America (U.S.) is also experiencing an obesity epidemic [18, 19], with self-reported adult obesity rates exceeding 35% of the population in many states (Figure 2). Although geographic and socioeconomic factors may also play roles in the development of overweight and obesity [20], the incidence rates are high across demographics and regions of the U.S. Additionally, the growing occurrence of U.S. childhood and adolescent obesity (Figure 3) puts these individuals at risk for early development of chronic obesity-linked conditions (Figure 4), such as type-2 diabetes, cardiovascular disease, stroke, and cancer that require lifelong management and which can reduce lifespan [21, 22]. Despite the rising incidence of obesity and its negative impact on quality of life, there remain few medical strategies that have proven effective in maintaining long-term weight loss. The first-line prescription for weight reduction is diet and exercise, which has been capitalized by the U.S. weight loss industry, a market worth $60 billion in 2015 [23]. Although dieting in­ dividuals initially lose weight, most do not maintain the weight loss long-term [24]. A regimen

Weighty Implications of  the Hypothalamic Area in energy balance  

Figure 2: Self-Reported Obesity. CDC adult obesity prevalence maps1 obtained from CDC website on August 10, 2017, and available online at https://www.cdc.gov/obesity/data/prevalence-maps.html. (A) Prevalence of self-reported obesity among non-Hispanic white adults by state and territory 2013–2015. (B) Prevalence of self-reported obesity among non-Hispanic black adults by state and territory 2013–2015. (C) Prevalence of self-reported obesity among Hispanic white adults by state and territory 2013–2015. 1

 CDC. Adult Obesity Prevalence Maps (2017). Available at: https://www.cdc.gov/obesity/data/prevalence-maps .html. (Accessed: 10th August 2017). Image in the public domain.

  Lateral Hypothalamic Control of Energy Balance

Figure 3: Obesity in Students in Grades 9–12. CDC Nutrition, Physical Activity, and Obesity: Data,Trends and Maps 2 obtained from CDC website on August 10, 2017 and available online at https://www.cdc.gov/nccd php/dnpao/data-trends-maps/index.html. (A) Percent of students in grades 9 to 12 who have obesity by US states, 2011. (B) Percent of students in grades 9–12 who have obesity by U.S. states, 2015.

2

 CDC. Nutrition, Physical Activity, and Obesity: Data, Trends and Maps (2017). Available at: https://www.cdc .gov/nccdphp/dnpao/data-trends-maps/index.html. (Accessed: 10th August 2017). Image in the public domain.

Weighty Implications of  the Hypothalamic Area in energy balance  

Figure 4: Obesity Complications. CDC Medical Complications of Obesity3 obtained from CDC website on August 10, 2017, and available online at https://www.cdc.gov/vitalsigns/adultobesity/infographic.html

3

 CDC. Medical Complications of Obesity (2010). Available at: https://www.cdc.gov/vitalsigns/adultobesity/info graphic.html. (Accessed: 10th August 2017). Image in the public domain.

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of both diet and exercise is more likely to provide long-term benefit [24]; however, adherence to such lifestyle modifications is notoriously challenging. Given the high likelihood of weight re-gain, many dieters enter a vicious cycle of weight cycling or “yo-yo dieting” which increases risk of heart disease, stroke, and diabetes [25]. Thus, not only are lifestyle modifications largely ineffective, but repeated dieting and weight cycling imposes adverse health effects. A handful of pharmacologic agents have been developed to aid weight loss, but most have side effects and not all are approved for long-term use [26]. The effectiveness of obesity medications is typi­ cally modest, with most agents achieving 5% loss of body weight at 1 year [27, 28]. Although 5% weight loss can reduce risk of obesity-related complications, it is not enough to achieve a healthy body mass index (BMI) for most patients. Additionally, few studies have examined outcomes including potential weight regain after patients stop taking the medication, thus the long-term effectiveness of anti-obesity drugs is largely undetermined. Currently, the most effective obesity treatment is bariatric surgery, with the Roux-en-Y gastric bypass procedure (RYGB) producing an average loss of 5 BMI points at 5 years [29, 30]. In addition to substantial weight loss, bariatric surgery also alleviates obesity-related type 2 diabetes, hypertension, and joint pain [29], plus patients report increased quality of life after surgery [31]. The major drawbacks of  bariatric surgery include the risk of complications and the cost which averages $15,000 to $25,000 [32, 33]. Because of this, surgery is usually reserved as a last resort for the morbidly obese (BMI, >40 kg/m2), which comprise less than 10% of overweight or obese adults. Thus, moderately overweight or obese individuals who are still at risk for developing obesity-related complications have limited options for weight control (diet and exercise or pharmacotherapy), which provide only modest benefit. Therefore, there is a clear need to develop better strategies to promote weight loss and prevent weight gain to improve health outcomes for overweight and obese individuals. It is also vital to understand why the surge in overweight and obesity has occurred, as this may suggest design of interventions to manage body weight. Average caloric intake has increased by around 240 kcals/day since 1970, with most of the increase attributed to carbohydrates [34]. Interestingly, fat intake decreased over the same period as obesity rates continued to rise, suggesting that excess caloric intake, not high dietary fat consumption, potentiates weight gain. Furthermore, occupational-associated energy expenditure has progressively declined since 1960 [35] and only 1 in 5 adults fulfills the recommend amount of daily physical activity [36]. Thus, one would speculate that the obesity epidemic is fueled by excess caloric intake combined with reduced physical activity, and hence disruptions to both arms of energy balance. Although this certainly explains what causes obesity, it does not explain why individuals overeat and move less. The increasing availability of palatable, calorie-rich, and inexpensive food has

Weighty Implications of  the Hypothalamic Area in energy balance  

fueled obesity rates [37], but what permits caloric intake in excess of metabolic demands? Under normal circumstances, energy intake is exquisitely coordinated with energy expenditure in an effort to defend body weight from both loss and gain [7, 15]. However, these mechanisms are not completely understood and are impacted by numerous variables (i.e., food palatability, genetics, sedentary lifestyle) that contribute to the development of obesity.

1.4

The Brain Coordinates Energy Balance

Energy balance strongly relies on behavioral output, namely, feeding and volitional activity that are controlled by the brain. Interestingly, most genes implicated in obesity have enriched expression in the nervous system [38], supporting the role of the brain as a master regulator of  body weight. In particular, sub-regions of  the hypothalamus have been implicated in regulating energy balance, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and the lateral hypothalamic area (LHA). The hypothalamus is found at the base of the brain near the third ventricle and is well positioned to intercept circulating energy cues from the periphery. Important hormonal cues detected by the hypothalamus include the anorectic hormone leptin and the orexigenic hormone ghrelin. Leptin is secreted from adipose cells as a signal of long-term energy storage and acts on hypothalamic nuclei to suppress food intake [39]. Ghrelin, by contrast, is secreted from the stomach as hunger increases and acts on the hypothalamus and other brain areas to promote food intake [40]. The ARC is a key site for energy integration and has been extensively studied in energy balance. The ARC contains two discrete neuronal populations expressing either agouti-related peptide (AgRP) or proopiomelanocortin (POMC), which exert opposing actions on feeding and body weight [41]. AgRP neurons are activated by physiologic hunger and promote food intake while reducing energy expenditure [42, 43]. AgRP neurons also express neuropeptide Y (NPY) and GABA, and the contribution of each individual neurotransmitter has been shown to increase feeding [44]. AgRP neurons are active in a fasted state, which is potentiated by ghrelinmediated excitatory input [45, 46]. After a meal, ghrelin levels fall and leptin becomes a dominant circulating signal of energy status, which inhibits AgRP neurons to reduce food intake [47]. By contrast, neighboring POMC neurons are activated during satiation and suppress food intake while increasing energy expenditure [48–50]. POMC is a precursor protein that is cleaved into distinct fragments, including alpha melanocyte stimulating hormone (α-MSH), which exerts anorectic effects by binding the melanocortin-4 (MCR-4) receptors at key brain sites. Rodents deficient in MCR-4 signaling are hyperphagic and obese [51, 52] and MCR-4 mutations are the

10  Lateral Hypothalamic Control of Energy Balance

most common monogenic cause of  human obesity [53, 54], underscoring the importance of mela­ nocortin signaling in energy balance. Although the ARC is a critical center for direct sensing of peripheral energy cues, POMC and AgRP neurons likely feed into a variety of downstream circuits that fine-tune feeding behavior and energy expenditure, such as the LHA. Indeed, POMC neurons project heavily to the LHA which expresses MCR-4 [55, 56], which may contribute to sympathetic regulation of glucose tolerance that can have beneficial effects for energy balance [57, 58]. However, the ARC and other mediobasal hypothalamic nuclei (e.g., the VMH and DMH) do not account for all central regulation of energy balance, and in particular do not explain how the brain coordinates the “motivated” feeding and moving behaviors that modify energy balance. This has led to the view that medial hypothalamic nuclei are primarily important for homeostatic feeding and energy expenditure, but that other hypothalamic sites might influence body weight via engaging the dopamine system that is well known to modify the motivation to eat and move [59].

1.5

Discovery of a Role for the Lateral Hypothalamic Area (LHA) in Energy Balance

The first study to suggest a function for the LHA resulted from an experimental accident, and serves as a reminder to let the data (not a preconceived hypothesis) lead understanding of the underlying physiology. Scientists had been studying animals with brain lesions in specific hypothalamic sub-regions, reasoning that the observed deficits in “lesioned” animals indicate what behavior and physiology is normally controlled via the site. Lesions within the ventromedial hypothalamus (VMH) caused striking overeating and subsequent development of obesity, and as a result of these experiments the VMH was declared a “satiety center” whose intact function is necessary for normal body weight (Figure 5). Anand and Brobeck sought to further define the VMH mechanisms that coordinate energy balance, so they generated a cohort of “VMH-lesioned” rats. They expected to observe the hyperphagia and obesity characterized in prior VMH lesion studies, but their experimental rats unexpectedly exhibited such severe, self-imposed aphagia that they died of starvation unless they were force-fed by the experimenters [60]. Subsequent examination of the brains from these rats revealed the source of the discrepancy: the lesions were not targeted to the VMH as intended, but instead were within the LHA. This serendipitous experiment promoted a view of LHA as the “feeding center” [60], thought to counteract the effects of the VMH “satiety center.” LHA lesions were subsequently made in cats [61, 62] and monkeys [62] and produced similar feeding suppression as those made in rats. By contrast, electrical stimulation of the LHA increases feeding [61], exploratory behaviors,

Weighty Implications of  the Hypothalamic Area in energy balance  11

Figure 5: Impact of the VMH and LHA Lesions on Body Weight in Rodents. Coronal brain section as modified from the Paxinos and Franklin (2001) mouse brain atlas.4 Rodent illustrations5 were modified from Smart Servier Medical Art on October 24, 2017, available online at http://smart.servier.com/category/general -items/animals/

and intestinal motility in cats [63]. In rats, electrical stimulation of the LHA not only increased feeding but also the motivation to obtain food, determined by the rats willingness to press a le­ ver and cross an electrical shock grid to obtain food [64]. Similarly, activating the LHA of goats triggered feeding and locomotion [65], which might reflect the fact that movement is necessary for these animals to procure food. 4

 Paxinos, G. & Franklin, B. The Mouse Brain in Stereotaxic Coordinates (Academic Press, 2001). Used with permission.  Smart Servier Medical Art. Animals. (2017). Available at: http://smart.servier.com/category/general-items/ani mals/. (Accessed: 24th October 2017). CC-BY 3.0 license. 5

12  Lateral Hypothalamic Control of Energy Balance

Taken together, the early lesion and activation studies were interpreted to support a “dual center hypothesis” in which the LHA and VMH exert antagonistic control of feeding. These descriptions are now recognized as oversimplifications, because the LHA and VMH are now accepted to contribute to many aspects of physiology beyond just feeding. Nonetheless, these loss and gain-of-function manipulations provided the first clue that specific hypothalamic subregions control strikingly different behaviors, and that there must be different, brain regionspecific mechanisms to regulate feeding and energy balance.

1.6

“Lateral Hypothalamic Syndrome” Suggests an Essential Role for the LHA in Coordinating Behavior

The LHA was initially deemed a “feeding center” because animals with LHA lesions will not voluntarily consume food [66, 67]. Less emphasized, but equally important, is that LHA-lesioned animals also lose the motivation to drink water, and their resulting dehydration causes death well before starvation [66, 67]. However, rats with LHA lesions can be kept alive if they are administered food and water via stomach tubes [66–68]; this indicates that loss of action via the LHA impairs coordination of the need for resources and the motivation to ingest them, but it does not compromise the body’s ability to utilize ingested resources. Intriguingly, the forcefed and force-hydrated LHA-lesioned rats termed as having “lateral hypothalamic syndrome” eventually recovered sufficient ingestive behavior to maintain survival via four distinct stages [67] reviewed below and in (Figure 6). • •

•

•

Stage 1: LHA-lesioned rats exhibited total aphagia and adipsia, and their survival depended on experimenter-administered food and water via stomach tubes. Stage 2: Rats ate small amounts of moistened, palatable food, so were considered to exhibit anorexia as opposed to aphagia. Rats remained adipsic and required experimenteradministered fluids. Stage 3: Rats voluntarily consumed some dry food as long as they were kept hydrated and would eat enough moistened palatable foods to support regulation of body weight without experimenter-administered nutrition. However, rats still did not voluntarily drink water. Stage 4: Rats were considered “recovered” because they accepted dry food and drank water, thus they no longer required force feeding/hydration to live. The recovered animals maintained sufficient body weight for survival, but their weight was lower compared with those with intact LHA action [67, 69, 70].

Weighty Implications of  the Hypothalamic Area in energy balance  13

FIGURE 6: Lateral Hypothalamic Syndrome. Hallmarks of the lateral hypothalamic syndrome stages.6 Modified from Teitelbaum, P. & Epstein, A. N. (1962). The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychological Review 69(2), 74–90.

These data suggested that the LHA is important for energy and fluid balance, but that other brain sites can, in time, sufficiently regulate ingestive behavior to permit survival. However, upon careful study, even the rats that had “recovered” from lateral hypothalamic syndrome remained unable to appropriately respond to altered energy or fluid status with appropriate intake behavior. For example, normal rats respond to peripheral cues of insufficient energy status (e.g., low blood sugar or fasting) by eating more food, but the recovered lateral hypothalamic rats did not adjust feeding in response to these stimuli [71]. Likewise, recovered lateral hypothalamic rats did not counter dehydration with increased drinking behavior, and in fact only exhib­ ited prandial drinking (e.g., water intake to facilitate chewing and swallowing of food) [67, 72, 73]. Similarly, they did not respond to dipsogenic stimuli (i.e., thirst-inducing treatments such as hypertonic saline or polyethylene glycol) with appropriate drinking behavior, and hence also exhibited abnormal urinary water output [74, 75, 76]. Fascinatingly, if these rats had the choice of receiving water through stomach tubes or the mouth they preferred it via the stomach [77], suggesting a pervasive, diminished motivation to voluntarily drink. The phenotype of lateral hypothalamic syndrome was similar in young and adult rats [78, 79], but recovery was impaired in 6

 Teitelbaum, P. & Epstein, A. N. The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychol. Rev. 69, 74–90 (1962). Used with permission of the American Psychological Association (APA).

14  Lateral Hypothalamic Control of Energy Balance

juvenile rats compared with adults, emphasizing the importance of an intact LHA for development and survival [78, 80] At face value, these data suggest that the LHA is important for the physiologic motivation to consume. However, perhaps, a more parsimonious interpretation is that the LHA is necessary to coordinate changes in metabolic and fluid status with appropriate ingestive behavior to resolve them. This also makes the LHA unique from other mediobasal hypothalamic sites with documented roles in energy balance, but not for fluid intake. Thus, the LHA is distinctive because it adaptively modifies both ingestive behaviors necessary for homeostasis and survival.

1.7

Physiologic and Pharmacologic Regulation of the LHA

Experimental lesions and electrical stimulation implicated the LHA in motivated ingestive behavior, but the activity of LHA neurons is also regulated by endogenous and exogenous stim­ uli relevant to maintaining energy and fluid balance. For example, early studies hinted that the LHA might modify peripheral glycemic control in response to alterations in plasma insulin and glucagon levels [81, 82]. Indeed, central treatment with glucose [83, 84], free fatty acids [85], and insulin [84] does modify the activity of some LHA neurons. These peripheral cues convey ample energy status to the brain, and presumably, the LHA detects these signals and modifies output ingestive behavior accordingly. Moreover, the LHA was also implicated in coordinating the motivation to obtain food, including willingness to work for it. Surveillance of LHA neurons in monkeys shows that their activity changes during a lever pressing-task to obtain food [86]. These data suggest that some LHA neurons are regulated as part of the process of harmonizing resource need and behavior. Indeed, electrical stimulation of the LHA increases rats’ motivation to learn, which mimics the impact of food deprivation upon neural activity [87]. Consistent with a role for the LHA in water intake, osmolality changes are also detected within the LHA [83, 88], and may serve to couple thirst with drinking behavior needed to resolve it. Intriguingly, pharmacological data suggest that feeding and drinking might be regulated via ligands acting upon distinct subsets of LHA neurons. For example, administration of adrenergic reagents into the LHA of sated rats induces feeding [89, 90], whereas the injection of a cholinergic reagent into the LHA resulted in drinking behavior [89, 90]. Cholinergic reagents also trigger drinking when in­jected into the preoptic area [91] and lateral septal nucleus [92], but fail to do so if administered to recovered LHA-lesioned rats. These data suggest that LHA-mediated control of drinking in the LHA occurs via a distinct mechanism compared with that via other brain areas.

Weighty Implications of  the Hypothalamic Area in energy balance  15

1.8

Neuronal Diversity in the LHA and Implications for Energy Balance

Initial studies of the LHA manipulated the entire region, but such bulk regulation is unlikely to occur physiologically because of the cellular heterogeneity of this region. Indeed, it is now recognized that the LHA contains many molecularly distinct populations of neurons, which are differentially implicated in control of feeding, drinking, locomotor activity, goal-directed behaviors, sleep/arousal or responses to stress or inflammation [93–103]. As a result of these findings, the early designation of the LHA as a “feeding center” has fallen out of favor because it vastly under-represents the myriad ways in which the LHA can modify behavior to contribute to energy and fluid homeostasis. However, the molecular phenotyping of subsets of LHA neurons has enabled development of genetic methods to specifically identify LHA populations and study their contributions to physiology. Subsets of LHA neurons also receive information concerning energy status that may be important for appropriately coordinating feeding and other motivated behaviors. Some LHA neurons express receptors for the orexigenic hormone ghrelin [104, 105], whereas separate LHA neurons express receptors for the feeding suppressing hormone leptin [106, 107], indicating that the LHA directly intercepts circulating cues with opposing results upon energy balance. The LHA also receives dense input from the ARC [55], and thereby receives indirect information regarding peripheral energy status. Taken together, this work suggests that the LHA is uniquely positioned to integrate specific peripheral energy cues with appropriate motivated behaviors to adapt resource intake. Given that the LHA responds to anorectic, orexigenic and dipsogenic cues, there are likely distinct neural mechanisms by which the LHA can coordinate motivated behaviors and homeostasis. Indeed, several populations of neurons have been described in the LHA that vary in neurotransmitter and neuropeptide content, projection targets and function. The connectivity of key LHA neuronal populations will be discussed in Chapter 2, and Chapters 3 to 5 will provide the current understanding of how these LHA neurons contribute to feeding, drinking and movement behaviors related to energy balance. Similar to the underlying premise of lesion studies, understanding how disruption of specific LHA populations or pathways compromises homeostasis will inherently reveal how they coordinate normal physiology. These findings may suggest the development of novel strategies to promote weight loss and maintenance of healthy body weight necessary to overcome the obesity epidemic. • • • •

17

chapter 2

Anatomy and Connectivity of the LHA 2.1

Location of the LHA and Implications for Its Function

The architecture of the hypothalamus has been well described in rodents, per the rat and mouse brain atlases generated by Paxinos and Watson [108, 109]. The rodent hypothalamus, much like in primates or humans, primarily consists of nuclei (sub-regions containing-densely populated neurons) distributed along the rostral-caudal and dorsal-ventral aspects bordering the third ventricle (3V). These “mediobasal hypothalamic nuclei” are grouped into the more ventral hypothalamic nuclei [the arcuate (ARC), ventral premammillary (PMV) and ventromedial (VMH) nuclei] and the more dorsal nuclei [the dorsomedial nucleus (DMH) and more rostrally the paraventricular nucleus (PVH)]. In contrast to the mediobasal structures, the LHA is considered an “area” rather than a nucleus because it spans across nearly the entire rostralcaudal continuum of the hypothalamus, with no easily definable cyto-architectural borders (Figure 7). In lieu of clear boundaries, the LHA is differentiated from the mediobasal nuclei by being generally dorsal to the PMV and VMH, but lateral to the DMH and PVH. The LHA is bordered dorsally by the zona incerta (ZI) and medially by the mammillothalamic tract (mt), which serves as an approximate landmark to visually differentiate the LHA from the DMH and PVH. The fornix (f ) is roughly considered be within the medial-ventral extent of the LHA, and the portion of the LHA that lies just above and around the fornix is often referred to as “the perifonical hypothalamic area” (PFA). There is no observable boundary or tract between the LHA and the most rostral extent of the hypothalamus, the preoptic area (POA), making it particularly difficult to distinguish the precise margins of the LHA and the adjacent lateral preoptic area (LPOA). Perhaps the most defining architectural feature of the LHA is that, in contrast to the mediobasal hypothalamic nuclei, it is not positioned adjacent to the 3V. This has important ramifications for the LHA in detecting peripheral stimuli. Because the 3V adjoins the median eminence, the permissive portion of the blood-brain barrier, it contains peripheral hormonal and nutrient cues that are thus easily and quickly accessed via the cells of

18  Lateral Hypothalamic Control of Energy Balance

Figure 7: The Localization of the LHA and Mediobasal Nuclei. Mouse coronal brain section at Bregma –1.58 mm.7 Arcuate nucleus (Arc), ventromedial nucleus (VMH), dorsomedial nucleus (DMH), lateral hypothalamic area (LHA), 3rd ventricle (3V), fornix (f ), mammillothalamic tract (mt), lateral ventricle (LV), dorsal 3rd ventricle (D3V).

the adjacent mediobasal nuclei. Because of its distant position from the 3V, the LHA lacks such “first-line,” direct access to these peripheral cues. The LHA does have the capacity to directly respond to some circulating energy balance cues, such as leptin, ghrelin, insulin and glucose, but this occurs at a slower time course compared with that of mediobasal nuclei, presumably via transfer from capillaries reaching into the LHA [110]. However, the LHA also receives sig­ nificant neural inputs from other brain areas, including from areas that may be more quickly or directly regulated by systemic signals. This had led to the idea that the LHA is an important coordinating center, receiving afferent input concerning energy status and sending projections 7

 Paxinos, G. & Franklin, B. The Mouse Brain in Stereotaxic Coordinates (Academic Press, 2001). Image used with permission of Elsevier Inc.

Anatomy and Connectivity of the LHA  19

to brain sites capable of modifying behavior. Furthermore, it is now clear that there are many distinct types of neurons contained within the LHA, which appear to have different connectivity and contributions to physiology. We will thus briefly review the current understanding of molecularly defined neuronal populations in the LHA (section 2.2), which will be important for contextualizing how their connections (sections 2.3–2.4) impact control of energy balance (Chapters 3–5).

2.2

Molecularly Defined Populations of Neurons within the LHA

2.2.1 Overview of LHA Subpopulations Given the expansive reach of the LHA, it is perhaps not surprising that this area is cellularly heterogenous, containing numerous different populations of neurons as well as resident glia. Subsets of LHA neurons have been described via their molecular signature, and although all of these populations have yet to be fully understood, it is clear that these neurons also differ in connectivity and function. A wealth of evidence supports the idea that subsets of LHA neurons coordinate unique aspects of energy and fluid balance, hence requiring systematic testing of each population and its projections to determine their function. Hence, any understanding of how the LHA contributes to physiology, and in particular energy balance, must separately evaluate the role of the molecularly specified LHA subpopulations. To date, LHA neurons have been defined via their neuropeptide expression, classical transmitter signaling and expression of specific receptors. We will briefly introduce the major neurochemically defined populations in the LHA (summarized in Figure 8), and their specific contributions to feeding, drinking and movement are reviewed in Chapters 3 to 5. Then, we will use this neural framework to review the current understanding of the inputs to the LHA and its outputs (summarized in Figure 9), which is relevant for understanding how this brain region senses resource need and organizes appropriate ingestive and motor behavior to resolve that need and modify body weight.

2.2.2 Melanin-concentrating Hormone (MCH) The first documented molecular marker of a population of LHA neurons was melanin concentrating hormone (MCH), a 19 amino acid cyclic neuropeptide [111]. MCH expression is primarily confined to cell bodies within the LHA but also a few within the bordering ZI [112]. Although this population is most generally referred to as “MCH neurons,” MCH-containing neurons can be further subdivided into subsets that differ in their co-expression of nesfatin,

20  Lateral Hypothalamic Control of Energy Balance

Figure 8: LHA Heterogeneity. Schematic description of the major neurochemically-defined populations in the LHA. Co-localized dots indicate reported co-localizations of the neurotransmitters and neuropeptides. Orexin (OX), melanin-concentrating hormone (MCH), neurotensin (Nts), gamma-amino butyric acid (GABA), glutamate, corticotropin-releasing hormone (CRH), Galanin.

Anatomy and Connectivity of the LHA  21

Figure 9: Inputs and Outputs of the LHA. Main peripheral and central inputs and central outputs of the LHA are presented. Color coding: feeding associated cues and pathways (physiological feeding – orange; mo­ tivational aspects of feeding – red), drinking associated cues and pathways (blue), cues and pathways associ­ ated with both feeding and drinking (purple). Arcuate nucleus (ARC), ventromedial nucleus (VMH), prefron­ tal cortex (PFC), hippocampus (HP), bed nucleus of the stria terminalis (BNST), parabrachial nucleus (PB), lamina terminalis (LT), locus coeruleus (LC), nucleus accumbens (NA), ventral tegmental area (VTA), lat­ eral habenula (LHb), preoptic area (POA), hypothalamic paraventricular nucleus (PVH).

22  Lateral Hypothalamic Control of Energy Balance

the neuropeptide cocaine-amphetamine-regulated transcript (CART) or proteins to support synthesis and release of the classical neurotransmitters GABA or glutamate [113–115]. Although the CART-containing MCH neurons may differ somewhat in projections from other MCH neurons, the projections and functions of the MCH-containing subpopulations have yet to be systematically parsed [116]. MCH itself plays important roles in control of arousal and en­ ergy balance (reviewed in Chapters 3–5) via actions on the G protein–coupled receptors MCH Receptor-1 (MCHR-1) and -2 (MCHR-2), though the latter isoform has only been described in humans, primates, cats, and dogs (but not rodents) [117–119]. MCH neurons may also contribute to aspects of physiology relevant to body weight and health, such as glucose tolerance and arousal [120–123].

2.2.3 Orexin/Hypocretin (OX) The next major population of LHA neurons discovered were those that express the orexigenic neuropeptides orexin (OX)/hypocretin (HCRT) -A and/or -B, and these neurons are separate from the MCH neurons. The dual nomenclature for the peptides is because they were simultaneously reported by two independent groups who alternately named them OX or HCRT; both reports were later found to describe the same neuropeptides, which are only expressed within cell bodies of the LHA [93, 124]. The “OX” name was adopted to describe the orexigenic effect of this neuropeptide, and we will use it throughout this volume. OX also plays a critical role in wakefulness and arousal, such that loss of OX neurons or OX signaling causes narcolepsy [125, 126]. The presiding view of OX neurons is that they promote arousal necessary to support goaldirected behaviors, including feeding and moving, and do so via their broad projections throughout the brain. Consistent with this, experimental activation of OX neurons increases arousal along with feeding, locomotor activity, and energy expenditure [127]. OX neurons are most activated during awake/alert periods, but are also activated by cues of energy depletion including fasting, ghrelin, and low glucose, which may serve to promote arousal necessary to obtain food and restore homeostasis when peripheral energy stores are low. OX neurons project broadly throughout the brain, but released OX can only exert effects via target neurons expressing the G protein–coupled OX receptor-1 (OXR-1) or -2 (OXR-2). OX-A preferentially acts via OXR-1, whereas OXR-2 binds OX-A and OX-B with similar affinity [93, 128]. Although generally referred to as “OX neurons,” in addition to containing OX, they also contain and release glutamate, dynorphin, and neuronal pentraxin (NARP/Nptx2), that could differentially modify downstream neurons [129–132]. There is some evidence to suggest that the relative release of these substances varies by synaptic target, allowing for differential regulation. Furthermore,

Anatomy and Connectivity of the LHA  23

at least two subpopulations of OX neurons have been described with distinct electrophysiologic properties and responses to glucose, yet molecular markers differentiating these OX subpopulations have yet to be described [133, 134].

2.2.4 Neurotensin (Nts) A large population of LHA neurons expresses the neuropeptide, neurotensin (Nts), and these are distinct from the MCH or OX-containing populations [105, 113] (Figure 10A). Unlike MCH and OX neurons that are specific to the LHA, Nts-expressing neurons are found in many sites throughout the brain; thus, Nts is a marker of a subset of LHA neurons, but is not a specific LHA marker [135–138]. LHA Nts neurons also appear to be neurochemically heterogeneous, with subsets that co-express the long form of the leptin receptor (LepRb) and/or GABA [99, 105, 139]. Some Nts neurons also co-express galanin, and these may project locally within the LHA to inhibit neighboring OX neurons [140, 141]. Nts neurons may also be projection specified, because non-galanin containing Nts neurons project to the VTA, where pharmacologic Nts administration produces anorexia and locomotor activity [99, 139, 142]. Because Nts is an established modulator of DA signaling [143–145], the LHA may provide an endogenous source of Nts input to the VTA that impacts motivated behaviors. Nts signals via binding to the G protein–coupled receptors Nts receptor-1 (NTSR-1) or -2 (NTSR-2). Pharmacologic Nts suppresses feeding and promotes weight loss [88-92] via an NTSR-1–dependent mechanism, however the functional role of LHA Nts neurons, and Nts signaling from them, has not been completely defined. Study of Nts neurons, including those in the LHA, has been somewhat hampered by the fact that immunoreagents do not reliably detect Nts-expressing soma without the use of colchicine treatment to inhibit axonal transport and concentrate the Nts within the cell bodies. This technical limitation may account for why characterization of the extensive population of LHA Nts neurons lagged behind that of MCH and OX neurons, which are readily detectable via standard immunolabeling methods. The development of mice that express Cre recombinase within Nts neurons (NtsCre mice) enables the facile detection and manipulation of Nts neurons using Cre-lox technology, and have begun to reveal how Nts neurons contribute to physiology [146].

2.2.5 Galanin (Gal) Galanin (Gal) is an orexigenic neuropeptide that is widely distributed throughout the brain, including within a population of LHA neurons. Gal expression in the LHA overlaps with several

24  Lateral Hypothalamic Control of Energy Balance

Figure 10: Distinct LHA Neurons. Immunofluorescent labeling of LHA neurons from NtsCre;GFP reporter mice (A) Modified from Brown et al. 2017 Figure 1.8 A large LHA Nts expressing neural population is distinct from OX and MCH expressing ones, and a subpopulation of LHA Nts neurons express LepRb. (A`) MCH (blue), OX (red), and Nts-EGFP (green).The small panels are the enlarged version of the dashed-box area, showing the individual staining for each neuronal population and the merged image. (A``) Nts-EGFP neurons (green) and pSTAT3, a marker for LepRb activation (blue). Filled arrows, Nts-EGFP neurons that colocalize with pSTAT3 and are Nts­LepRb neurons. Unfilled arrows, LepRb neurons that do not express Nts (A```). The relative size and distribution of the MCH, OX, Nts, Nts LepRb, and LepRb neuronal populations in the LHA. ARC, arcuate nucleus; DMH, dorsomedial hypothalamus; f, fornix; VMH, ventromedial hypothalamus. (B) From Stuber & Wise 2016 Figure 3.9 LHA GABA­ergic neurons do not overlap with MCH and OX neurons. Vesicular GABA transporter (vgat)-indicator of GABAergic neurons. (B`) Vgat neurons (green) and MCH neurons (red) in the LHA. (B``) Vgat neurons (green) and OX neurons (red) in the LHA. (c) VGat-target LHA neurons are a distinct population of LHA neurons.

other marker-populations, including subsets of MCH, OX, Nts and LepRb-expressing neurons [113, 140, 147, 148]. However, like Nts, immunohistochemical detection of Gal-expressing soma also requires colchicine treatment to suppress axonal transport and concentrate the Gal within cell bodies, or use of mice that express Cre recombinase selectively within Gal-expressing cells [147]. 8

 Brown, J. A. et al. Loss of action via neurotensin-leptin receptor neurons disrupts leptin and ghrelin-mediated control of energy balance. Endocrinology 158, 1271–1288 (2017). Used with permission of OUP. 9  Stuber, G. D. & Wise, R. A. Lateral hypothalamic circuits for feeding and reward. Nat. Neurosci. 19, 198–205 (2016). Used with permission of SpringerNature.

Anatomy and Connectivity of the LHA  25

2.2.6 GABA Gamma-amino butyric acid (GABA) is the principle inhibitory neurotransmitter of the central nervous system, and is found extensively throughout the brain. A sizeable population of LHA neurons express markers for the synthesis and vesicular packaging and release of GABA, hence referred to as LHA GABA neurons. Study of LHA GABA neurons or their function was limited by the fact that neither GABAergic markers or GABA itself can be detected via immunolabeling, but the establishment of Cre-recombinase lines for the vesicular GABA transporter-2 (vGAT2) and glutamate decarboxylase-2 (GAD2) have allowed multiple groups to visualize and interrogate the function of LHA GABA neurons [149, 150]. There is considerable heterogeneity within the LHA GABA population, raising the possibility that specified subsets of LHA GABA neurons coordinate specific aspects of physiology. For example, some of the previously mentioned LHA neural populations co-express GABA, and in these cells the GABA likely serves to mediate fast inhibitory synaptic regulation of target neurons in addition to more modulatory roles exerted via co-released neuropeptides. However, LHA GABA neurons do not appear to overlap with MCH or OX [149, 150] (Figure 10B), though they may overlap with some Gal and/or Nts cells [99, 148].

2.2.7 Glutamate Glutamate is the principle excitatory neurotransmitter of the nervous system. The advent of Cre driver mouse line permitting identification of neurons expressing vesicular glutamate transporter-2 (vGLUT2) has been an important step for determining how specific populations of glutamate neurons mediate physiology, and was instrumental for revealing a modest population of LHA glutamate neurons. OX neurons co-express glutamate, as may some MCH neurons, but there are also LHA glutamate neurons that lack any currently recognized neuropeptide or receptor markers [151, 152]. Hence, like the LHA GABAergic neurons, the LHA glutamatergic subset is neurochemically diverse.

2.2.8 Receptor Expressing Populations (LepRb, MC4R) The long form of the leptin receptor (LepRb) is expressed in a group of LHA neurons, hence, referred to as LHA LepRb neurons. The adipose-derived hormone leptin signals via LepRb to modify energy balance, and the essential function of this signaling system is demonstrated by the severe obesity in animals and humans that results from lacking functional leptin or LepRb [153–155]. At least some portion of leptin action is mediated via LHA LepRb neurons, including subsets that co-express Nts and/or Gal [104, 140]. LepRb neurons that co-express Nts vs.

26  Lateral Hypothalamic Control of Energy Balance

Gal appear to have differences in projection targets and leptin-mediated function, suggesting that they may be functionally distinct populations. Additionally, some LHA neurons express another receptor implicated in the control of energy balance, the melanocortin-4 receptor (MC4R). These LHA MC4R neurons are also neurochemically diverse: some of them contain Nts, others do not. Although MC4R within the PVH is vital for regulation of feeding, including in part via leptin regulation, melanocortin action via the LHA MC4R cells does not alter feeding but may instead contribute to regulation of blood glucose levels, another important aspect of homeostasis [57, 58].

2.2.9 Other Populations of LHA Neurons Compared with the sizable neurochemically defined LHA populations discussed above, there are a few additional marker-defined populations within the LHA though their functions are largely unknown. CART is expressed in the LHA, though it largely overlaps with MCH neurons (as addressed above). Corticotropin-releasing hormone (CRH) is also expressed in the LHA and is modulated by stress or dehydration, suggesting targeted roles for CRH in specific physiology [156, 157]. Neurons expressing thyrotropin releasing hormone (TRH), urocortin 3 (UCN3), tyrosine hydroxylase (TH), encephalin and parvalbumin have also been described within the LHA, but their contributions to energy balance have yet to be defined [158].

2.3

Afferents to the LHA

2.3.1 Hypothalamic Arcuate Nucleus (ARC) The ARC is positioned above the median eminence (ME) and near the 3V, and so can directly intercept circulating cues that convey the energy status of the body [159]. ARC neurons detecting such cues project to other hypothalamic regions to coordinate metabolic actions and behavior, and one important ARC projection site is the LHA [55, 160]. Some ARC POMC neurons innervate the LHA [161–163], and because LHA administration of the POMC cleavage product MSH suppresses food intake in rodents [164], this circuit is likely anorexigenic in nature. Immunohistochemical labeling in rodents indicates that at least two populations of LHA neurons receive dense projections from ARC AgRP/NPY neurons: those containing orexin/hypocretin (OX) or melanin concentrating hormone (MCH) [163]. Given the orexigenic nature of AgRP/NPY, these ARC projections likely translate feeding-inducing messages to the LHA neurons, and OX neurons (which themselves have been implicated in promoting

Anatomy and Connectivity of the LHA  27

arousal and feeding) are especially densely targeted [165]. ARC POMC and AgRP/NPY projections to LHA neurons have been validated via multiple methods [166, 163], and because these ARC neurons are leptin responsive [55], it suggests that they mediate indirect leptin-control of the LHA. A subset of LHA neurons express MC4R, hence they should be able to bind and respond to released melanocortins from ARC POMC and AgRP neurons [167, 159]. However, although leptin regulates the activity of LHA neurons expressing MC4R, the MC4R agonist MTII does not, calling into question the role of direct orexigenic actions via the LHA. Similarly, optogenetic activation of ARC AgRP neuron terminals in the LHA promotes feeding behavior [161], but direct administration of AgRP into the LHA does not [164]. One hypothesis compatible with these data is that ARC melanocortin input to the LHA does not regulate homeostatic feeding behavior, but instead modifies motivation to eat palatable or calorically dense foods [168]. Indeed, AgRP signaling in the LHA suppresses weight gain in mice on a high-fat diet, but neither stimulation of ARC AgRP → LHA terminals, LHA MC4R-positive neurons or AgRP within the LHA modifies feeding and body weight of mice on a regular chow diet [168, 169]. It is also possible that ARC AgRP/NPY neuronal projections to the LHA primarily act via release of NPY, which has been shown to reverse dehydration-induced anorexia and promote feeding [170]. It will be important to clarify which signals released from the numerous ARC afferents to the LHA modify intake behavior, and whether this depends on homeostatic or motivational status.

2.3.2 Hypothalamic Ventromedial Nucleus (VMH) Lesion studies established a role for the VMH in feeding, though subsequent work also suggests a role for the VMH in modifying drinking behavior [171, 172]. The VMH provides some afferents to the LHA, as established via tract tracing experiments [166, 173]. In particular, VMH neurons regulated by bone morphogenetic protein 8B (BMP8B) may engage LHA OX neurons, thereby inducing brown adipose tissue thermogenesis and browning of white adipose tissue [174]. Given the existence of  VMH → LHA circuits, and the important yet complex roles of both regions in ingestive behavior and metabolism, it will be important to further define how these two hypothalamic areas coordinate to influence homeostasis.

2.3.3 Parabrachial Nucleus (PB) The parabrachial nucleus (PB) is involved in the sensation of taste and conditioned taste aversion, and the PB sends afferents to the LHA as well as receives projections from it. The PB

28  Lateral Hypothalamic Control of Energy Balance

consists of two regions conveying distinct physiology: a medial portion in which gustation sensitive neurons reside and a lateral part containing viscerosensory neurons [175]. Taken together, tract tracing methods [176] and LHA electrical stimulation experiments [177] suggest that both the gustation and viscerosensory populations of the PB send inputs to the LHA. In return, the LHA sends feedback to PB neurons that sense sodium and acidity, which may serve to decrease their excitability and modify sour and bitter sensation [177].

2.3.4 The Bed Nucleus of the Stria Terminalis (BNST) The bed nucleus of the stria terminalis (BNST) is a structure near the nucleus accumbens that is implicated in the regulation of anxiety, stress, motivated behaviors and autonomic function [178, 179]. Some BNST GABAergic neurons synapse onto glutamatergic LHA neurons, and activation of this circuit promotes food intake even in well-fed mice [152]. By contrast, inhibition of the BNST GABAergic projections to the LHA suppressed feeding even in hungry mice [152]. These data argue for the BNST in providing inhibitory tone to the LHA that modifies feeding, but the specific LHA neurons targeted via this circuit remain to be characterized.

2.3.5 Nucleus Accumbens (NA) The nucleus accumbens (NA) can be anatomically subdivided into its shell and core regions. The NA is predominantly composed of GABAergic medium spiny neurons that express ei­ ther dopamine receptor-1 (D1R) or dopamine receptor-2 (D2R). Tract tracing studies suggested that NA neurons in the medial shell region project to the LHA [180]. This NA → LHA connection was first linked to feeding via pharmacological studies, in which inhibiting the NA shell induced both robust feeding and markers of activation within the LHA [181–185], but these were blunted if a GABAergic receptor agonist was infused into the LHA [182, 186]. Together these studies suggested that an inhibitory NA → LHA circuit led to disinhibition in the LHA, thereby releasing a brake on feeding. It is now clear that most of the LHA input from the NA arises from the D1R-experssing population, and these project to the lateral portions of the LHA rather than the perifornical area. Optogenetic modulation of the NA D1R → LHA projection confirms that activation of this inhibitory input to the LHA promotes feeding, whereas inhibition of the circuit ceases feeding behavior even in animals who are actively consuming food [187]. However, there may be additional heterogeneity of NA → LHA circuits, because they have been shown to regulate the activity of LHA OX neurons and

Anatomy and Connectivity of the LHA  29

of separate GABAergic neurons, both of which are implicated in promoting feeding behavior but via distinct mechanisms (see Chapter 3). Furthermore, glutamatergic NA shell neurons also send projections to the LHA that may function in feedback regulation of sugar intake [188].

2.3.6 Regions Involved in Learning and Memory (Prefrontal Cortex, Amygdala, Hippocampus, and Septum Animal behaviors are not only directed by evolutionary drives (e.g., hunger, thirst), but are also shaped by individual experiences, cognition, memories and emotions. Sites of the brain involved in decision making and memory/emotion processing thus also may impact energy balance behaviors, such as those of the prefrontal cortex (PFC) [189–191], amygdala [189], hip­pocampus (HP) [192–194], and septum [195], and these regions and the LHA are reciprocally con­nected [190, 191, 194–197]. The dorsal LHA receives projections from the central amygdala and the whole dorsoventral and rostrocaudal medial PFC. By contrast, in rats, the ventral LHA receives inputs from the basolateral aspect of the amygdala and part of the ventrocaudal medial PFC [191, 197], and these projections may specifically control learned appetitive cues that influence feeding [190, 191]. Similarly, in humans, learned taste cues engage the basolateral amygdala → hypothalamus circuit, and this circuit may predict weight change because of non-homeostatic intake [198]. Furthermore, amygdala neurons may exert regulation of  LHA OX neurons to modify cue-induced feeding, though it has yet to be determined if they also engage other types of LHA neurons [199]. The HP is associated with memory and conditioned-meal anticipation [192, 193], and so may act to coordinate peripheral cues of energy balance with prior learning and memory. Some ventral hippocampus (vHP) neurons respond to the hunger-hormone ghrelin and project to LHA OX neurons, and this circuit is required for ghrelin-induced hyperphagia and conditioned appetite [194]. The septum has also been shown to act on the LHA to control feeding behavior. Specifically, activation of septal GABAergic neurons or their projections to the LHA suppresses feeding, but inhibition of these GABAergic inputs to the LHA increases feeding [195]. Intriguingly, modulation of the septum → LHA circuit selectively alters feeding, but not locomotor or anxiety behavior, suggesting this circuit is specified for modulating ingestive behavior [195].

2.3.7 Lamina Terminalis (LT) The lamina terminalis (LT) is essential for water homeostasis, and consists of the organum vasculosum of the LT (OVLT), the median preoptic nucleus (MnPO) and the subfornical organ

30  Lateral Hypothalamic Control of Energy Balance

(SFO). The SFO and OVLT lie outside of the blood-brain barrier and directly detect plasma osmolality or the hormone angiotensin II [44, 45]. Although LT neurons are first-line detectors of need for water [200–204], they do not directly modify physiologic processes to restore fluid homeostasis. Instead, LT afferents to the supraoptic and paraventricular nuclei coordinate release of the hormone arginine vasopressin (AVP), which modifies peripheral fluid handling via the renal and cardiovascular systems [205–207]. Additionally, the LHA receives projections from the osmolality-detecting LT [208–212], so it is anatomically positioned to respond to homeostatic imbalance. Stimulation of GABAergic neurons in the MnPO/OVLT suppresses water consumption in dehydrated mice but does not affect feeding, whereas experimental activation of the resident glutamatergic neurons induces voracious drinking behavior [204]. The LHA is one of the densest projection targets of MnPO and OVLT neurons, with both GABA­ergic and glutamatergic afferents [204], and hence indirectly receives osmosensory input. Although the SFO has been extensively in regulating water intake, and it projects to the LHA, the functional connection between the SFO and the LHA neurons for drinking behavior remains incompletely understood. Some evidence suggest that there is an adrenergic mechanism linking SFO → LHA signaling in angiotensin II-stimulated drinking [213–215], but a specific circuit mediating these effects has yet to be established. For example, injection of the dipsogenic angiotensin II into the SFO of rats that lack access to water causes LHA noradrenalin levels to increase, but this effect is suppressed when drinking is allowed [215]. Moreover, blocking α1 and β2 adrenergic receptors in the LHA suppresses drinking induced by angiotensin II injection into the SFO, whereas α2 adrenergic receptor suppression promotes drinking [213, 214]. Given the well-documented inputs from the LT to the LHA, and evidence that the LHA itself is implicated in modifying drinking behavior [216, 217], it is highly plausible that the LHA may coordinate osmosensory LT afferents with output behaviors to modify water intake and restore homeostatic fluid balance.

2.4

Projections from the LHA

2.4.1 The Ventral Tegmental Area (VTA) Neuroanatomical tracing studies reveal that the LHA projects widely throughout the brain, but it provides particularly dense efferents to the ventral tegmental area (VTA). The VTA is largely composed of neurons that express the catecholamine neurotransmitter dopamine (DA) that is essential for movement and motivation [218], raising interest in how LHA neurons might modulate such DA-dependent behaviors to influence energy balance. Two major projection

Anatomy and Connectivity of the LHA  31

targets of VTA DA neurons are the NA and associated ventral striatal sructures (termed the mesolimbic pathway) and the prefrontal cortex (referred to as the mesocortical pathway), where DA release controls the motivation to obtain pharmacological and natural rewards (e.g., food, physical activity and sex) [219]. Hence, LHA projections to the VTA presumably modify DA­ ergic signaling and motivation for natural rewards, such as food, water, and physical activity, that may impact energy balance. Indeed, electrical stimulation of the LHA increases DA release into the ventral striatum, and notably within the NA [220–222]. VTA DA neurons are direct synaptic targets of at least some LHA neurons [223]. Additionally, some LHA neurons synapse upon the modest VTA population of GABAergic neurons, which may act locally to inhibit adjacent DA neurons [224, 225]. Thus, the LHA synaptically modulates the VTA DAergic system that controls motivated behaviors, which provides an explanation for why lesion of the LHA abolishes the motivation to eat and move. Subsequent work has begun to refine which of the many subpopulations of LHA neurons project to the VTA, and which ones target resident DA neurons vs GABA neurons, to clarify the mechanisms by which they modify DA signaling and behavior. These data confirm that some, but not all, LHA neurons project to the VTA. For example, LHA neurons expressing OX project widely throughout the brain, including to the VTA [129, 226], where their release of OX, dynorphin and glutamate may have opposing regulation upon VTA DA targets that pro­ ject to the NA or amygdala [130, 131, 227, 228]. LHA neurons containing Nts [105, 142] and GABA also project to the VTA [151, 229, 230]. Recent interest has been invested in understanding how neuropeptides modulate VTA DA neurons, and hence, how they coordinate behaviors relevant to energy balance. For example, pharmacological and electrophysiologic studies suggest that VTA DA neurons express receptors for the neuropeptides, OX, CRH, and Nts, which all have the capacity to regulate DA neuronal function and motivated behaviors (reviewed in [231–233]). The specific importance of neuropeptides in directing neuronal signaling is just beginning to be appreciated (as recently reviewed by van den Pol [234]). Neuropeptides are often co-expressed along with classical amino acid neurotransmitters (glutamate or GABA), however, the properties of neuropeptides vary greatly from classical transmitters. First, glutamate and GABA are released from the pre-synaptic terminal and travel mere nanometers across the synapse, where they act rapidly on ion channels to activate or inhibit the post-synaptic neuron. By contrast, neuropeptides released form presynaptic terminals can diffuse microns outside the synapse and thus can bind to both the post-synaptic neuron and neighboring neurons that do not make direct synaptic contact. Although classical transmitters can gate ligand-gated ion channels to rapidly alter membrane potential, neuropeptides bind to G protein–coupled receptors that change gene transcription or intracellular Ca++, and

32  Lateral Hypothalamic Control of Energy Balance

hence mediate long-term signaling changes in target neurons. Furthermore, in addition to release at the presynaptic terminal, some neuropeptides can be released from the dendrites or anywhere along the axon, which further increases the number of neurons that are influenced by neuropeptide release. Thus, although classical transmitters and neuropeptides may be released from the same neuron, they mediate very distinct and temporally dissociable effects on target cells. Furthermore, the distribution of different neuropeptide receptors on target neurons allows for further refinement of signal transduction and physiologic regulation, and these may be selectively targeted via pharmacological means. Understanding the role of neuropeptide and neuropeptide receptor systems that engage the DA system thus holds promise for selective, long-term control of DA-mediated behaviors that impact body weight.

2.4.2 The Nucleus Accumbens (NA) LHA neurons that express melanin-concentrating hormone (MCH) project directly to GABA­ ergic medium spiny neurons of the NA that themselves provide tonic inhibitory input on food intake [235, 236]. Thus GABAergic MCH neurons may disinhibit the NA, removing the “brake” on feeding to promote food intake [106]. It is possible that MCH neurons could disinhibit NA neurons that project back to the LHA to promote feeding [187], but this has yet to be tested.

2.4.3 Lateral Habenula (LHb) The LHb suppresses rewarding [237–240] and addictive behaviors [241, 242], in part via LHb inhibitory projections onto VTA DA neurons [243, 244]. Tract tracing and immunolabeling confirm that glutamatergic LHA neurons synapse with LHb neurons, which in turn target the VTA—rostromedial tegmental nucleus (RMTg) in rats [245]; thus, glutamatergic LHA neurons act via the LHb to indirectly modify VTA DA signaling and DA-dependent behaviors. Indeed, optogenetic suppression of the LHA glutamatergic → LHb circuit has been shown to elevate palatable calorie-dense liquid reward intake [151].

2.4.4 Regions Involved in Learning and Memory (Prefrontal Cortex, Amygdala, and Hippocampus) There is a bidirectional physical circuit between these regions and the LHA [191, 196]. Thus far, both LHA MCH and Orexin neurons have been shown to project to the hippocampus as

Anatomy and Connectivity of the LHA  33

well as the septum [166, 246], which might orchestrate cognitive and motivational aspects of conditioned feeding [189, 190].

2.4.5 Lamina Terminalis (LT) The three regions that compose the LT all send projections to the LHA, but of these, the SFO appears to also receive input from the LHA. A probable LHA → SFO circuit is implied by the observation that both angiotensin II administration into the LHA and electrical stimulation of LHA induced excitation of SFO neurons that in turn modulated the activity of vasopressinsecreting neurons in PVN [247, 248]. To date, the connections between the SFO and LHA have not been functionally tested, but given that both of these brain regions are implicated in regulating drinking behavior, they may act in concert to direct physiologic drinking and fluid balance.

2.4.6 Preoptic Area (POA) The preoptic area (POA), with its lateral, ventrolateral, median, medial and periventricular subdivisions, is linked to many ingestive and sexual behaviors, including drinking [76, 249, 250], arousal [251–253], social reward circuits [146], and thermoregulation [251]. Most studies about the coordination of the LHA and the POA have been focused on sleep-wake behaviors. For example, the ventrolateral preoptic area (VLPO), which is an important regulator of sleep, receives input from some LHA OX, MCH, and other uncharacterized LHA neurons [254]. In return, sleep promoting GABAergic POA neurons directly inhibit the activity of the LHA OX neurons, presumably to facilitate switching between sleep and arousal states [255, 256]. Some leptin responsive and GABAergic LHA neurons send projections to the rostral POA [257], though the function of these connections is yet to be understood.

2.4.7 Hypothalamic Paraventricular Nucleus (PVH) The hypothalamic paraventricular nucleus (PVH) is another brain region involved in the control of ingestive behaviors [258]. Although the PVH and LHA functional connection has not been extensively studied, some GABAergic LHA neurons send efferents to the PVH, and optogenetic activation of this LHAGABA → PVH circuit promotes feeding via a GABAA receptordependent mechanism [94]. In addition to feeding however, LHA → PVH circuits might also modify drinking, as neurons in both regions are strongly activated upon dehydration [97] and are involved in dehydration-induced anorexia [170].

34  Lateral Hypothalamic Control of Energy Balance

2.4.8 Local Projections Within the LHA Some LHA neuronal populations project within the LHA itself, and may serve to antagonistically control other LHA populations. For example, some LHA neurons containing Gal, Nts or the long form of the leptin receptor (LepRb) project within the LHA. However, at least some Nts and LepRb neurons also project outside of the LHA, and it remains clear if these neurons simultaneously project within the LHA and externally or if there are projection-specified subpopulations. LHA Gal neurons that project locally to OX neurons appear to modify nutrient intake via an inhibitory mechanism [140]. There are also local “LHA microcircuits” between OX and MCH neurons that modulate arousal [121, 259].

2.5

Peripheral Regulators of LHA Neurons

2.5.1 Leptin Leptin is made by white adipocytes, secreted into the blood, and this circulating pool of leptin can access the brain to act at neurons expressing LepRb. Leptin thus delivers the message of peripheral energy status to the brain, such that the more fat/leptin produced the more negative feedback should be induced (e.g., suppression of feeding, induction of energy expenditure) [260, 261]. Intact leptin signaling via LepRb is essential for regulation of body weight, evidenced by the profound hyperphagia and obesity caused in mouse and man due to lacking the gene products for leptin (ob/ob [262, 263] mice and humans [262, 264, 265]) or LepRb (db/db mice [266, 267]). Leptin effects have been well characterized within the ARC, where leptin activates the anorectic POMC neurons that express LepRb, and inhibits the activity of LepRb-expressing AgRP/ NPY neurons to mitigate their orexigenic actions [268]. However, leptin actions within the ARC or other mediobasal hypothalamic regions do not explain the entirety of leptin regulation. The discovery of LepRb-expressing cells within the LHA, first via in-situ hybridization [269] and later using leptin receptor reporter mice [104, 270], suggested that leptin might exert specific actions via the LHA as opposed to mediobasal sites. Indeed, peripheral leptin [260] or leptin infusion into the LHA suppresses feeding and promotes weight loss that depends on action via LHA LepRb neurons [104]. Intriguingly, LepRb expression in the LHA overlaps with GABA [104], Nts [139] and Gal [140, 141] expressing neurons, but not with OX or MCH neurons [104]. However, leptin acts via LHA LepRb neurons that synapse onto OX neurons, thereby indirectly inhibiting OX neurons [104] and regulation of  OX expression [139, 271–273]. Leptin function may differ via LHA LepRb neurons expressing Nts vs. Gal [139, 141] and GABA­ ergic neurons [133]. Leptin modifies preference for sucrose and fat consumption via LHA Gal

Anatomy and Connectivity of the LHA  35

neurons [140]. Leptin acts via LHA Nts neurons to inhibit OX neurons and also acts via projections to the VTA to modify DA signaling and motivated locomotor activity [99, 105, 141]. Leptin is also involved in the metabolic stress response mediated by OX neurons [102], and leptin indirectly suppresses the activity of LHA MCH neurons that may help to counteract orexigenic tone [274, 275]. Together these data suggest that leptin acts via LHA LepRb neurons that in turn modify activity of  key LHA populations and the DA system to modify behaviors relevant to energy balance. Loss of leptin action via the LHA promotes weight gain and dysfunction in target systems, demonstrating the unique yet vital role of leptin action via the LHA and its necessity for normal energy balance [105, 139, 140, 148].

2.5.2 Ghrelin The “hunger” hormone ghrelin is made by the stomach in response to energy deficit and released to the circulation. Ghrelin levels are thus elevated during hunger states before a meal, but diminish upon feeding and restoration of circulating energy levels [276]. The ghrelin receptor (growth hormone secretagogue receptor, GHSR) is expressed in many brain regions, including the LHA [277], and circulating ghrelin can both access and modify the activity of the LHA [278]. Ghrelin acts in the brain to promote feeding, and in rodents it also triggers feeding associated foraging and hoarding behaviors [276], which are mediated, in part, via midbrain DA signaling [279, 280, 281]. Ghrelin may act specifically via LHA OX neurons that project to the VTA, thereby indirectly modifying DA signaling. Indeed, ghrelin increases the firing frequency and overall number of activated LHA Ox neurons [272, 282]. Furthermore, ghrelin-induced regulation of feeding and the motivation to obtain palatable food (especially fat rich food) is partially mediated by LHA OX neurons [283, 284]. Although there may be minimal GHSR expression on OX neurons [113], ghrelin may still exert effects via GHSR-expressing ventral hippocampal (vHP) and ARC neurons that project to LHA OX neurons, and which have been demonstrated to modify feeding behavior [194, 285]. Nonetheless, ghrelin action is primarily mediated via OX neurons, as it does not alter the activity of other major LHA populations, including MCH or Nts neurons [105, 282, 286].

2.5.3 Glucose Similar to leptin and ghrelin, circulatory glucose levels inform the brain about the energy status of the body. Although increased circulating glucose and leptin both indicate energy surplus, glucose levels fluctuate rapidly and serve as an acute signal of immediate energy status, leptin

36  Lateral Hypothalamic Control of Energy Balance

communicates long-term energy status and is modulated in a more gradual manner. Given that these peripheral signals convey distinct information, it stands to reason that they may be detected by, and directly modulate, different sets of LHA neurons. Within the cellularly heterogeneous LHA, some neurons are glucose sensitive whereas others are unresponsive to changes in glucose [83]. Distinct LHA neural populations expressing OX [272, 287, 288], MCH  [287, 288], and markers of GABA synthesis [149] have been shown to be glucose sensitive. Elevated glucose strongly inhibits a subpopulation of OX neurons via a tandem-pore-K+ channel mechanism [288]. The glucose sensitive OX neurons in the LHA regulate depolarization of other LHA neural populations under hypoglycemic conditions [289], suggesting that they may be the primary glucose sensors in the LHA, whereas the others are indirectly regulated. Leptin blunts the activation of OX neurons in response to low glucose via GABA and Nts-mediated signaling, presumably from upstream LHA Nts-LepRb neurons [133]. Furthermore, it is highly probable that the glucose-sensitive OX neurons link the LHA with DA-mediated motivated feeding behavior, as decreased glucose elevates LHA OX neuron-mediated excitatory input onto the VTA DA neurons [133]. Additionally, some GABAergic LHA neurons are directly inhibited by elevated glucose levels [149], though their contributions to energy balance have yet to be determined. By contrast, glucose depolarizes MCH neurons [287] via a KATP channel mechanism, which may contribute to modulating glucose homeostasis [290].

2.5.4 Dehydration The brain receives information about the hydration status of the body through two direct mechanisms: 1) via circulating hormones, such as vasopressin, angiotensin II and aldosterone and 2) via specialized circumventricular regions within the LT that directly sense serum osmolality [5]. The LHA is a dehydration-sensitive brain region, as thirst increases neuronal activation within a subset of LHA neurons [291]. However, the LHA is not one of the circumventricular organs or part of the LT, and it is positioned far from the blood-brain barrier or ventricles via which hydration-status hormones might be rapidly conveyed. Thus, rather than directly detecting hydration status, it is more likely that the LHA receives indirect feedback on fluid status from LT neurons or hormone-responsive neurons throughout the brain. It remains to be determined what precise circuits convey the dehydration “message” to the LHA, but it increases the expression of corticotropin-releasing hormone (CRH) [96, 98] and Nts expression within the LHA of rodents [96] that correlates with the intensity of dehydration-induced anorexia (a phenomenon in which water-deprived rodents cease eating, and only after sating their thirst will they ingest food) [96]. Most of the dehydration-responsive LHA CRH neurons co-express Nts, whereas

Anatomy and Connectivity of the LHA  37

comparatively few contain OX and/or MCH [97], suggesting that LHA Nts neurons may be a specialized population for detecting aberrant fluid homeostasis. However, once animals are rehydrated, OX neurons are selectively activated, suggesting their involvement in relieving the anorexic effect of dehydration [97]. Given that LHA Nts neurons project to and inhibit OX neurons, there is rationale to support Nts neurons as the indirect “dehydration sensors” of the LHA that inhibit OX neurons and perhaps OX-mediated food seeking until water is restored, though this remains to be systematically tested. • • • •

39

chapter 3

Roles of LHA Neurons in Regulating Feeding 3.1

Overview of the LHA in Control of Feeding

Of the many behaviors and physiologic functions regulated by the LHA, feeding is perhaps the most well-studied. Indeed, even though feeding and drinking were equally blunted by LHA lesions, the field has primarily focused on the role of the LHA in feeding rather than water intake, which promoted its initial moniker as a “feeding center.” Since then, the field has come to recognize that the LHA coordinates a vast array of physiologic processes, and cannot be considered a center for any one behavior. However, feeding remains the single most studied behavior controlled via the LHA, in part because of its potential relevance for understanding the pathogenesis and possible treatment of obesity and eating disorders. Here we will review the current understanding of how LHA neurons modify feeding, focusing on populations defined by their neurotransmitter or neuropeptide content (summarized in Figure 11).

Figure 11: Specific Roles of LHA Neurons in Feeding.

40  Lateral Hypothalamic Control of Energy Balance

3.2

Melanin-Concentrating Hormone (MCH) Neurons in Control of Feeding

The neuropeptide melanin-concentrating hormone (MCH) is specifically derived from LHA neurons, and increases food intake and weight gain [95, 274, 292–294]. MCH indiscriminately increases the amount of food or palatable substances consumed in a given meal or feeding bout, be it homeostatic or palatable food/liquids [295, 296], suggesting that it is a non-specific orexigen. Endogenous MCH expression is elevated in hungry rodents, or in models of genetic obesity in which animals are overweight but chronically hyperphagic [274, 293]. By contrast, mice genetically lacking MCH consume less food and sucrose, and are lean compared with intact controls; these weight effects are long-lasting, as these mice are even protected from normal agingrelated weight gain [297–299]. Pharmacologic inhibition of MCH signaling, via antagonists of MCHR-1, also suppresses meal size and overall food intake that produces weight loss in normal weight and obese rodents, implicating MCH as the key orexigenic factor released from MCH neurons [300–302]. Most studies of MCH action have been conducted in rodents, which only express MCHR-1. MCH action via MCHR-2, however, may exert opposing actions to MCHR-1; indeed, introduction of MCHR-2 into rodents who normally lack it caused them to consume less high fat diet compared with controls with only MCHR-1, and protected mice from weight gain [119]. Because both MCHR-1 and MCHR-2 are expressed in the human brain, further study into the respective roles of MCH action via these receptors is needed to understand how MCH regulates human energy balance. Intriguingly, MCH neurons may also be involved in the noted sex differences in feeding behavior [303], which could have clinical rel­ evance to development of eating disorders that are predominantly observed in females. Given that MCH is required for some of the effects of olanzapine, an atypical antipsychotic with some efficacy for treating individuals with the restricting-type of anorexia nervosa, overlap of the MCH and disordered feeding circuits bears examination in eating disorders [304]. MCH neurons modify feeding, at least in part, via the mesolimbic DA system. For example, MCH increases rodents’ willingness to work for palatable foods via operant conditioning, which is considered the gold standard test to assess DA-mediated motivated behavior. However, administration of an MCHR-1 antagonist blunts operant responding for palatable food, highlighting a key role for MCH-MCHR1 action in motivated feeding [305]. MCH may modulate the DA system via distinct connections. For example, MCH boutons have been noted within the VTA, and experimental modulation of MCH neurons modifies the rewarding value of caloric vs. non-caloric sweet substances via a taste-independent mechanism [297]; these data suggest a role for MCH in post-ingestive calorie-sensing, perhaps to couple need

Roles of LHA Neurons in Regulating Feeding  41

for energy with intake of calorie-providing substances. MCH neurons also project directly to the NA, and the MCH → NA circuit is thought to remove a GABAergic brake on feeding and potentiate feeding responses [235, 306, 307]. Additionally, MCH signaling is necessary for hippocampal learning and memory that influences motivated feeding behavior, suggesting that pharmacologic interruption of MCH-MCHR1 signaling might be useful to suppress nonhomeostatic food seeking that contributes to overeating and weight gain [308, 309].

3.3

Orexin (OX) Neurons in Control of Feeding

The first reports of OX identified it as a feeding-inducing (orexigenic) peptide, prompting one of the two discovering groups to dub it “Orexin” [93, 124]. Central treatment with OX acutely induces feeding when given to rodents during the light cycle (when they normally are sleeping), but not during their normal arousal period when they do the bulk of their feeding [310, 311]. These data suggested that OX is not purely an orexigen, but perhaps, more accurately facilitates arousal necessary for feeding to occur. Indeed, OX neurons and OX itself were subsequently demonstrated to promote alertness and arousal [312, 313], and in this context, it is reasonable that awake animals may spend some of their alert time feeding, accounting for the orexigenic features of this neuropeptide. This may account for why experimental activation of OX neurons promotes arousal, locomotor activity and feeding together; awake animals will naturally move and ingest [127]. Physiologic activation of OX neurons may thus serve to coordinate metabolic status and arousal as necessary to modify feeding and maintain energy homeostasis. Consistent with this idea, OX neurons are activated by physiologic cues signaling energy deficit, including fasting, ghrelin, low glucose or circulating amino acids, that may occur during muscle catabolism [272, 282, 284, 303, 314–317], and thus act to promote food intake and arousal necessary to obtain food when peripheral energy stores are low. By contrast, peripheral cues of energy excess, such as leptin or elevated glucose levels, inhibit the activity of OX neurons and hence OX-mediated feeding [133, 141, 288, 318–320]. Based on these independent lines of data, OX neurons are generally viewed as a permissive switch for arousal-induced food intake, but not as necessary for feeding per se. It may thus seem counterintuitive that animals and humans lacking OX are prone to becoming obese and developing obesity-linked diabetes, as loss of permissive OX feeding drive might have been expected to suppress feeding and cause leanness. However, the lack of OX signaling results in narcolepsy, leading to insufficient arousal and waking-mediated energy expenditure despite maintenance of relatively normal feeding that potentiates weight gain [321–324]. In an intact system, the activation of OX is dynamically regulated by metabolic status to

42  Lateral Hypothalamic Control of Energy Balance

appropriately coordinate arousal and feeding. For example, fasting increases the formation of excitatory synapses onto OX neurons, but re-feeding or leptin administration reverses this effect and accordingly decreases the OX-mediated arousal and feeding that are not priorities in the sated, energy-replete state [273]. Additionally, LHA LepRb neurons project to and inhibit OX neurons, including those that co-express Nts or Gal, thus leptin also indirectly facilitates inhibitory tone onto OX neurons to decrease their activity [271, 139, 141, 140]. Together, these data have led to the view that activation of OX neurons supports feeding via OX actions. However, recent work has challenged this concept, and instead suggests that the immediate activation of OX neurons supports non-eating behaviors such as locomotor activity that prevent feeding—in short, animals that are busy moving will find it difficult to eat. These data offer an alternate explanation for the obesity that results from genetically lacking OX or after depletion of OX neurons: there is no longer any OX-mediated physical activity that would normally distract animals from feeding, hence they engage in unchecked overconsumption that promotes weight gain [325]. Going forward it will be important to define whether OX neurons directly dictate feeding, or if their activation and locomotor behavior lead to a secondary induction of feeding necessary to replace calories used to support movement. OX also influences the motivation, or “wanting” of non-homeostatic palatable foods and other reinforcing substances, including drugs of abuse, that may potentiate their intake. This aspect of OX action appears to be regulated by projections to the VTA that increase the activation of DA neurons [129]. OX-mediated regulation of VTA DA neurons modifies seeking and intake of motivationally salient stimuli such as cocaine and palatable food [326–328]. Reinforcers such as cocaine may act, in part, via increasing excitatory signaling onto OX neurons to strengthen induction of a motivated-drive circuit and presumably release of OX [329]. Similarly, natural rewards, such as calorically dense, palatable foods may increase the activation of OX neurons, along with subsequent OX-dependent activation of VA DA neurons [330]. OX signaling directly via VTA DA neurons contributes to seeking of natural (food) and pharmacologic rewards [331], which is diminished via treatment with OX-1 receptor antagonists [327, 332–334, 335]. These data imply direct roles for OX in motivated intake, but OX neurons also release glutamate and dynorphin to the VTA, which may exert biased action on distinct subpopulations of VTA DA neurons to differentially modify DA-dependent behaviors [130]. Taken together, these data suggest that there may be independent OX mechanisms to modify homeostatic vs. non-homeostatic food intake. OX neurons may also coordinate sensory stimuli and learning behaviors with arousal necessary to facilitate feeding. For example, OX neurons were selectively activated by an auditory cue that was previously associated with sucrose, promoting arousal and necessary muscle tone to support intake behavior [336].

Roles of LHA Neurons in Regulating Feeding  43

3.4

Neurotensin (Nts) Neurons in Control of Feeding

Pharmacologic Nts has been implicated in suppressing feeding and promoting weight loss, but also in regulating locomotor activity, social behavior, sleep, body temperature, blood pressure, nociception and response to addictive drugs [106, 337–341]. There are many populations of Nts neurons through the brain, yet it remained unclear which Nts neurons mediated the disparate physiologic actions of Nts, including the anorectic effect. The development of NtsCre mice has begun to enable systematic testing of anatomically distinct Nts populations, including those in the LHA [139], to define their physiologic importance. Activation of all LHA Nts neurons suppresses food intake via an NTSR-1–dependent mechanism, including limiting fastinginduced refeeding and motivated sucrose responding [342]. Simultaneously, activation of LHA Nts neurons increases locomotor activity, hence the increased energy expenditure and modest anorexia is sufficient to cause weight loss [99, 342]. At least some LHA Nts neurons project to and release Nts to the VTA, which promotes activation of VTA DA neurons and DA release into the NA via an NTSR-1–dependent mechanism [99]. Given that NTSR-1 is directly expressed on VTA DA neurons, and pharmacologic Nts treatment within the VTA activates DA neurons and DA release to the NA that suppresses feeding, it is likely that LHA Nts → VTA neurons may directly mediate DA-dependent anorexia and locomotor activity [343–347]. LHA Nts neurons can be differentiated via their projection targets and, to some extent, their molecular phenotypes. Some LHA Nts neurons project locally and inhibit neighboring OX neurons [141], whereas others project to the VTA where pharmacologic Nts administration produces anorexia and locomotor activity [342]. A subset of LHA Nts neurons, which expresses LepRb, is activated by leptin, and co-expresses markers of GABA synthesis [105, 139, 142]. Developmental loss of LepRb specifically from LHA Nts neurons results in reduced striatal DA action, increased adiposity, and disrupted feeding response to leptin [105, 139]. Thus, LHA Nts neurons may be useful to promote weight loss behaviors including via suppression of food intake, whereas disruption of Nts-mediated DA signaling might contribute to the development of obesity. Consistent with this view, genetically obese mice and rats exhibit reduced Nts mRNA and protein in the hypothalamus, but there is insufficient data to evaluate whether Nts is selectively decreased in the LHA, and whether this is a cause or effect of long-term hyperphagia [348–350]. Some LHA Nts → VTA projections have been reported to induce reward seeking via a glutamatergic mechanism, suggesting that some LHA Nts neurons express gluta­ mate [351]. However, close examination of the distribution of these LHA Nts neurons suggests that they may be a more rostral population compared with the LHA Nts neurons implicated in

44  Lateral Hypothalamic Control of Energy Balance

suppressing feeding, which are located more caudally within the perifornical LHA [105, 139, 342]. Additionally, in rats, Nts is highly expressed within LHA CRH neurons [97], which are known to regulate stress responses [352, 353] and feeding [354]. Moreover, the LHA Nts neurons are responsive to inflammation-induced stress induced by lipopolysaccharide (LPS) injections and cFos mapping [103]. However, there is much yet unknown about how LHA Nts circuits mechanistically act to link stress and feeding. Understanding how Nts engages the DA system to modify motivated behaviors, including the specific role of LHA Nts neurons, will be important for discerning the therapeutic potential for Nts in regulating energy balance. Peripheral injection of  Nts analogs or NtsR-1 agonists are sufficient to suppress food intake and either induce weight loss or prevent weight gain in lean rodents [355, 356]. Interestingly, these compounds also restrain feeding and reduce body weight in genetically obese rodents, indicating that Nts may have translational potential as an anti-obesity agent [355, 356]. In both of these studies, however, the obese animal models were genetically deficient in leptin signaling; given the overlap between leptin and Nts action, inducing Nts signaling might have simply rescued their disrupted leptin-induced Nts signaling to potentiate weight loss. The anorectic potential of Nts in diet-induced obesity, which is the common cause of human obesity, has yet to be examined. Peripheral Nts or intra-VTA Nts does reduce operant responding for sucrose [357, 358], suggesting that Nts may indeed be capable of suppressing intake of palatable, obesogenic foods. Furthermore, mice genetically lacking NTSR-1 display increased sucrose preference and susceptibility to weight gain on palatable diet but not chow, implicating the requirement of NtsR-1 for restraint of hedonic intake [142, 359]. In 2016, Nts received considerable attention in the context of obesity when it was shown that Nts knockout mice were protected from obesity on a high fat diet. This report focused on peripheral Nts, suggesting that Nts produced within the gastrointestinal tract is essential to facilitate intestinal fat absorption. As a result, loss of Nts-mediated fat absorption led to protection from diet-induced obesity. The authors also showed that circulating Nts levels were increased in the blood of obese individuals, and that elevated Nts in lean individuals predicted future weight gain [360]. Although this study implicates an important role for peripheral Nts in energy accumulation, it also underscores the importance for site-specific investigation of Nts action to discern its contributions to physiology. The potentially differing roles of Nts in the brain (to suppress feeding) compared with the gut (to promote fat absorption) must also be taken into account in the development of future pharmaceuticals that target the Nts system. Given the very short half-life of circulating Nts, and the unlikelihood of the neuropeptide to traverse the blood-brain barrier to access the LHA, the LHA and VTA effects of Nts are unlikely to be mediated by peripherally generated Nts.

Roles of LHA Neurons in Regulating Feeding  45

3.5

Galanin (Gal) Neurons in Control of Feeding

Galanin (Gal) is an orexigenic neuropeptide, yet intriguingly a subset of LHA neurons express Gal as well as LepRb that contributes to leptin-mediated suppression of feeding [147]. At face value, this co-expression of an orexigenic and anorexigenic system seems counterintuitive, yet may be similar to the expression of LepRb on orexigenic AgRP/NPY neurons in the ARC. Indeed, leptin acts in part via LepRb expressing LHA Gal neurons to suppress feeding, though it remains unclear how Gal signaling contributes to this effect [140]. Deletion of LepRb from the LHA GalLepRb neurons modifies nutrient choice, such that mice prefer sucrose over fat, and this is mediated via projections onto OX neurons. Because OX neurons express Gal receptors they may be directly inhibited via Gal-induced signaling. Thus, loss of leptin-mediated activation of LHA GalLepRb neurons could lead to dis-inhibition of OX neurons, and thereby account for the increased activation of LHA OX neurons observed in mice lacking LepRb in LHA GalLepRb neurons [140]. LHA GalLepRb neurons also project to the locus coeruleus, which is enriched in noradrenergic neurons, suggesting yet to be examined roles for these neurons in modifying arousal physiology [140]. At least some LHA Gal neurons also express Nts, but the nature of these co-neuropeptide cells and their function remains to be determined. Initially it was suggested that there may be a single population of Gal-Nts-LepRb neurons in the LHA [147]. However, mice lacking LepRb from LHA Gal neurons vs LHA Nts neurons have strikingly different phenotypes, indicating that LHA GalLepRb and NtsLepRb neurons are distinct populations that act via separate projection targets to differentially modify feeding vs. movement behaviors to modify energy balance [105, 140]. Additionally, not all LHA Gal neurons (or LHA Nts neurons) express LepRb, suggesting that perhaps the overlapping Gal-Nts neurons might share leptin-independent actions. However, chemogenetic activation of LHA Gal neurons promotes motivated feeding, whereas activation of LHA Nts neurons suppresses it, suggesting that the majority of LHA Gal and Nts neurons are functionally, and likely anatomically, distinct [148, 342].

3.6

Corticotropin Releasing Hormone (CRH) Neurons in Control of Feeding

Corticotropin releasing hormone (CRH) is implicated in promoting stress or anxiety behaviors that often present with diminished feeding, suggesting CRH as a link for affective and homeostatic control [361]. Pharmacologic CRH suppresses feeding in both lean and obese mice [362]

46  Lateral Hypothalamic Control of Energy Balance

and endogenous CRH contributes to the feeding suppression observed in dehydration-induced anorexia, a physiologic “stress” state in which water deprivation causes rodents to cease food intake until they regain fluid access and re-establish serum osmolality [363]. CRH is expressed widely within the brain, including within a subset of LHA neurons that are activated by dehydration anorexia [97, 352]. Additionally, dehydration increases CRH expression in the LHA, and correlates with the severity of the fluid and subsequent energy deficit [96]. In rats the LHA neurons expressing CRH overlap with Nts, and both of these neuropeptides are upregulated during dehydration-anorexia. Unfortunately, the LHA CRH neurons remain understudied, and their specific contributions to feeding behavior have yet to be established.

3.7

GABA Neurons in Control of Feeding

LHA GABAergic neurons are broadly defined as being “orexigenic.” This effect is specific to the independent population of GABA neurons, and is not due to extensive overlap with, or effects mediated by the orexigenic MCH and OX neuropeptides. Although a small subset of MCH neurons co-express proteins necessary for the synthesis of GABA, they lack the vGAT (vesicular GABA transporter) required for transmitter release, suggesting that they may not be functionally GABAergic [227]. Thus, LHA GABA neurons are molecularly and functionally distinct from OX and MCH neurons [149, 150, 227, 364, 365]. Optogenetic activation of all LHA GABAergic neurons enhances food seeking [150] and consumption (including of food pellets, caloric liquid diets or water) [150, 366], but also promotes gnawing and consumption of biologically irrelevant materials such as wood [366], as well as social interaction and other moti­ vated behaviors [224]. This broad range of observed behaviors could be because of the simulta­ neous activation of all LHA GABAergic neurons, which may include distinct subpopulations that have yet to be neurochemically and functionally differentiated. Indeed, in vivo calcium imaging studies have identified subsets of GABA neurons whose activity differs according to food expectation or ingestion, signifying that there are at least two separate LHA GABA populations involved in consummatory vs. appetitive behaviors that contribute to feeding [150]. Some LHA GABA populations might be defined by co-expression of  MC4R [56], LepRb [104], Gal [148], or Nts [139], or in LHA neurons that are selectively glucose sensitive [149], as all of these neural types have been linked with GABA signaling. It is possible, however, that precise molecular phenotyping of these supposed GABAergic subsets will show that they express the proteins necessary to synthesize GABA but not to release it (as is the case for MCH and OX neurons), hence they could be functionally GABA “silent.” However, neurons can co-express and co-release

Roles of LHA Neurons in Regulating Feeding  47

neuropeptides and classical transmitters, so it is possible that there are functional GABA and coexpressing neuropeptide populations within the LHA. Documenting such populations will be important, because release of the classical transmitter and neuropeptide may occur in response to different signals and may exert distinct effects on target neurons, as is now appreciated for OXglutamate neurons [130, 131, 234]. Differential release could enable neurons to respond to distinct physiologic cues and might explain why different stimulation frequencies of LHA GABA → VTA projections produced different types of feeding behaviors. Low frequency stimulation of LHA GABA → VTA projections induced food consumption behavior, and this stimulation is sufficient for classical transmitter release but perhaps not for that of dense-core granule containing neuropeptides [229]. By contrast, high frequency stimulation may promote release of GABA and any co-expressed neuropeptides from the neurons, and may underlie the observed rewarding value of circuit stimulation itself, independent of any food stimulus [229]. Going forward, it will be important to discriminate the separate GABAergic subpopulations in the LHA and how they are physiologically regulated to modify feeding. Projection specified LHA GABA neurons may exert unique control of feeding via specific brain targets, though these have yet to be carefully mapped. For example, optogenetic activation of the LHA GABA → PVH circuit and release of GABA into the PVH increases feeding, which is diminished by elimination of GABAA receptors from the PVH [94]. By contrast, optogenetic stimulation of LHA GABA → VTA projections causes inhibition of VTA GABA neurons that normally inhibit neighboring DA neurons; thus, activation of this circuit lifts the inhibition of VTA DA neurons to increase their activity and promotes release of DA into the NA [224]. Thus, both LHA GABA input to the PVH and VTA induce feeding, but via very distinct mechanisms. Furthermore, PVH-regulated feeding is presumably more homeostatic than DA-mediated motivated feeding, and so these LHA GABA circuits may be activated in response to different cues. These data further speak to the need to define the molecular and projection signatures of the broad population of LHA GABA neurons to understand their physiologic contributions to feeding. There are, at present, at least two potentially molecularand projection-specified populations of LHA GABA neurons: those that co-express Gal and project within the LHA (LHA GABAGal neurons) vs. those expressing Nts that can project within the LHA and to the VTA (LHA GABANts neurons). Indeed, chemogenetic activation of Nts-expressing LHA neurons increases Nts release into the VTA and NTSR-1–dependent DA release into the NA, but it is unclear if GABA is also co-released from these neurons [99]. Chemogenetic activation of LHA Gal neurons, a subset of which contain GABA, act via local OX neurons to induce food seeking behavior without the compulsive-like locomotor effects evident from activating all LHA GABA neurons [148]. Together, these data support the view

48  Lateral Hypothalamic Control of Energy Balance

that there are molecularly and functionally distinct LHA GABA neurons, and that systematic definition and testing of these populations is warranted to understand how they modify feeding and other behaviors that contribute to energy balance.

3.8

Glutamate Neurons in Control of Feeding

The population of LHA glutamate neurons is comparatively modest compared with the numerous LHA GABAergic neurons. OX neurons all co-express glutamate and are functionally glutamatergic [227]. Additionally, there are other LHA glutamate neurons that do not overlap with OX or any other detailed neuropeptide or receptor-defined LHA population. Optogenetic stimulation of LHA glutamate neurons suppresses feeding, which seems counterintuitive if this manipulation also activates the OX-containing glutamate neurons implicated in promoting arousal and food intake [152]. In contrast, inhibition of LHA glutamate neurons promotes feeding, whereas genetic ablation of this population selectively increases intake of palatable, calorie-dense food (but not of standard chow) to induce weight gain [151]. The LHA glutamate neurons have yet to be fully anatomically mapped, but projections have been described to the VTA and the LHb. Stimulation of the LHA Glutamate → VTA pathway leads to place avoidance, decreased social interaction and decreases in DA levels in the NA without significant effects on feeding [224]. Stimulation of the LHA glutamate → LHb pathway suppresses intake of palatable food but not of regular chow [151]. Given the anatomical and functional differences observed between LHA glutamate neurons, it is likely that there may be molecularly distinct subpopulations of these neurons to mediate distinct facets of feeding and other behaviors relevant to energy balance. • • • •

49

chapter 4

Role of the LHA in Drinking Behavior 4.1

Overview of the LHA in Control of Drinking

Water intake is crucial for maintaining cellular osmolality and survival; thus, thirst is an essential drive to maintain health. Inappropriate body water due to insufficient intake (dehydration) or excessive intake prompted after extreme exercise, ecstasy-use or in psychogenic polydipsia promotes severe neurological consequences that can lead to death. Despite the exigency of water for survival, we still know very little about the physiologic mechanisms by which the brain coordinates the need for water with the behavior to get it. LHA lesion and stimulation studies (reviewed in Chapter 1) identified an essential role for the LHA in modifying water intake, yet surprisingly, little investigation has followed into how the LHA modifies water seeking and intake behavior. Defining the fundamental neural mechanisms underlying drinking behavior, including the contributions of the LHA in this process, is paramount for developing therapies to treat water intake disorders that threaten survival. Below we examine the modest literature concerning how specific neuropeptide and neurotransmitter-defined LHA populations contribute to LHA-dependent drinking behavior (summarized in Figure 12).

Figure 12: Specific Roles of LHA Neurons in Drinking.

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4.2

Melanin-concentrating hormone (MCH) Neurons in Control of Drinking

Central MCH increases water intake independent of food availability, but also increases intake of other rewarding liquids including sucrose and ethanol [95, 295, 296]. Thus, MCH likely serves as a general promoter of intake (be it liquid or food) rather than a signal coordinating specific intake [95]. By contrast, treatment with an MCHR-1 receptor antagonist blunts ethanol intake and its perceived rewarding value [367–369], consistent with a role for MCHMCHR-1 signaling in inducing intake of palatable or rewarding substances. Alcohol intake and reward is also altered in mice genetically lacking MCHR-1 [369–370]. The connectivity of MCH neurons implies that they function more in modulating intake of rewarding substances rather than coordinating physiologic need-based drinking behavior. Indeed, MCH neurons access the DA system that modulates motivated behavior, but do not appear to receive input from osmosensing LT regions necessary to communicate physiologic thirst [256]. This may explain why optogenetic activation of the LHA MCH neurons increases consumption of a palatable sucrose solution, but not of water alone [297]. It is possible that MCH neurons intercept neuroendocrine signals to regulate fluid balance, and indeed they are activated by vasopressin (AVP) and express AVP receptor-1 [371]. Thus, the current evidence suggests that MCH exerts a permissive, but non-essential role in intake of non-aversive liquids.

4.3

Orexin (OX) Neurons in Control of Drinking

Central administration of OX promotes water intake in rats similar to the effects of treating with the known dipsogen, angiotensin II [372]. Experimental activation of OX neurons promotes drinking, but simultaneously increases arousal and arousal-dependent behaviors, including feeding, and locomotor activity [127]. Thus, animals with activated OX neurons may take in more water (and food) simply because they are awake more, and have more opportunity to ingest. Consistent with this view, OX-R antagonists and mice lacking OX also drink less water, which may be because of their diminished arousal and time to enact goal-directed drinking behavior [310, 321, 373]. However, there are links between the osmolality-sensing and OX systems, which hint that OX neurons may assist in coordinating physiologic drinking behavior. Indeed, the activity of some, but not all, OX neurons is regulated by osmolality status, suggesting that there may be an as-yet uncharacterized OX population capable of coordinating thirst detection and drinking behavior. Moreover, dehydration specifically increases OX mRNA expression [372],

Role of the LHA in Drinking Behavior  51

but OX neurons are inhibited during this state. However, just after restoration of water OX neural activity increases, suggesting that relief of a “brake” on OX neurons might enable OX release and induce drinking behavior [97]. OX neurons project to the SFO, hence could activate these LT neurons that are important regulators of drinking behavior [201, 202, 372]. Going forward, it will be important to gain a more precise temporal understanding of OX neuronal activity and drinking behavior, which is now possible using optogenetic strategies; these type of investigations can resolve whether increased activity of OX neurons drives physiologic drinking behavior or is simply a result of it. OX neurons modulate the DA system, via which OX neurons modify intake of reinforcing substances, including perhaps of rewarding liquids like sucrose and ethanol. Indeed, inhibition of OX signaling reduces alcohol consumption in rodents [333, 374–377], and OX-signaling via the NA shell and medial PFC (two important sites of DA action) modulates willingness to work for alcohol rewards (a DA-dependent behavior) [378]. However, in some circumstances water itself may be considered reinforcing, such as for individuals with psychogenic polydipsia, who voluntarily drink up to 10 liters of water per day and well beyond their physiologic need [379]. Polymorphisms in OXR-1 have been linked to psychogenic polydipsia, and might contribute to dysregulation of DA-mediated pathways that promote excessive water intake [380–382].

4.4

Neurotensin (Nts) Neurons in Control of Drinking

Experimental activation of LHA Nts neurons increases water intake but suppresses feeding [342]. Thus, unlike the other LHA populations that non-specifically promote food and water consumption, LHA Nts neurons preferentially induce water intake over feeding, suggesting that at least some of these neurons may coordinate drinking behavior necessary for fluid homeostasis. Consistent with this possibility, dehydration increases expression of Nts mRNA in the LHA [98], suggesting that osmolality status regulates LHA Nts neuronal function. Because experimental activation of LHA Nts neurons promotes Nts release, and exogenous Nts promotes drinking, then dehydration-induced upregulation of Nts could serve as a physiologic signal to drive water seeking and intake once water becomes available [99, 383]. Intriguingly, LHA Nts-induced polydipsia is not blunted by NTSR-1 antagonists or in mice lacking NTSR-1 [342]. Alternately, Nts-mediated drinking could be mediated via NTSR-2 or via an Nts-independent mechanism, but these possibilities have yet to be tested. Furthermore, LHA Nts-mediated drinking likely occurs via a leptin-independent population of LHA Nts neurons, as mice lacking LepRb in

52  Lateral Hypothalamic Control of Energy Balance

LHA NtsLepRb neurons do not exhibit any disruptions in drinking or bodily fluid content [105]. This raises the possibility that LHA NtsLepRb neurons might mediate the anorectic actions of LHA Nts neurons, whereas a separate Nts-containing population modifies drinking via a leptin-independent mechanism. In any case, these data offer a first potential hint for a specific mechanism by which the LHA could modulate motivated water intake. Going forward it will be important to determine if LHA Nts neurons specifically coordinate physiologic water need and drinking behavior necessary for fluid homeostasis.

4.5

CRH Neurons in Control of Drinking

Physiologic thirst due to hypertonic saline or dehydration increases the expression of CRH within the LHA, and activates LHA CRH neurons [97, 157]. Taken together these data implicate LHA CRH neurons in detecting physiologic cues of osmolality status, hence they could play roles in coordinating the need for water with drinking behavior needed to restore fluid balance. Dehydration-modulated LHA CRH neurons project to the PB [157], an important region for control of fluid homeostasis (refer to Chapter 2), and perhaps this target modifies the drinking behavior itself. Furthermore, because CRH-expression in the rat LHA is largely colocalized with Nts it is possible that a population of CRH-Nts co-expressing neurons modifies drinking behavior, though this has yet to be fully tested.

4.6

GABA and Glutamate Neurons in Control of Drinking

Optogenetic activation of all LHA GABA neurons increases the overall consumption of food and liquids, as well as gnawing directed toward non-caloric objects (the cage floor, empty space, wood) [150, 225, 366]. Thus, in these experiments LHA GABA neurons cannot be considered to induce any specific intake behavior (feeding or drinking), but generally promote appetitive and consumption behavior. However, because there is evidence for distinct subpopulations of GABA neurons [150], it is possible that there are specific LHA GABA populations that direct intake of water vs. food, and that would have been obscured during bulk activation experiments. Interestingly, in some of the LHA GABA activation studies the “food” or “reward” was actually a fluid, either a sucrose solution, ethanol or a calorie-dense meal replacement drink that is both high in sugar and fat (Ensure) [150, 366]. In this case, an observed “feeding” or “reward”

Role of the LHA in Drinking Behavior  53

response might actually be a motivated response to consume water that is only available via the liquid “food/reward.” Going forward it will be important to design experiments to tease apart the selective roles of LHA GABA neurons and whether they promote general consumption, or induce feeding and drinking behaviors via separate mechanisms. The role of LHA glutamate neurons in water intake has not been directly reported. However, inhibition of LHA glutamate neurons increases intake of liquid, palatable food (Ensure) [151]. It is possible that this could reflect an effort to obtain water via the solution rather than food-calories per se. • • • •

55

chapter 5

Role of the LHA in Arousal, Physical Activity, and Energy Expenditure 5.1

Overview of the LHA in Control of Basal and Volitional Energy Expenditure

Energy is expended via the combination of basal metabolic rate (e.g., energy consuming processes necessary to support life) and volitional physical activity. Because individuals must be awake to engage in movement, arousal /sleep status has direct bearing on the amount of volitional physical activity and energy expenditure. We will therefore discuss the current understanding of how LHA neurons modify these aspects of energy expenditure (summarized in Figure 13.)

Figure 13: Specific Roles of LHA Neurons in Arousal, Physical Activity, and Energy Expenditure.

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5.2

Melanin-concentrating hormone (MCH) Neurons in Control of Energy Expenditure

MCH is now recognized to play a permissive role in coordinating sleep, and thus may diminish wakefulness and physical activity that contributes to energy balance. Physiologic cues known to support waking, such as histamine and TRH, act in part via inhibiting MCH neurons, which will prevent their ability to induce sleep states and support arousal [384, 385]. Activation of MCH neurons specifically increases rapid eye movement (REM) sleep, and accordingly loss of MCH neurons disrupts the normal diurnal rhythm of REM sleep and wake, but not their amounts [386, 387]. By contrast, optogenetic or chemogenetic activation of MCH neurons promotes transitions from non-REM to REM sleep and can hasten sleep onset [388, 389]. However, although activation of MCH neurons is sufficient to trigger sleep state transitions, it is not necessary for sleep to occur, indicating that MCH exerts permissive but non-essential sleep tone [389]. Consistent with this idea, it has recently been demonstrated that sleep-inducing MCH and arousal-inducing OX neurons are interconnected, and these two populations intercept distinct physiologic cues and synaptically regulate each other. Such reciprocal regulation between the two populations likely enables context-appropriate switching between arousal and sleep states, but may not be required for the occurrence of the state per se [121, 390]. MCH neurons can also influence body weight via modifying physical activity levels and metabolic rate. Mice genetically lacking MCH exhibit elevated energy expenditure and locomotor activity compared with controls with intact MCH, and their net “energy output” protects them from developing diet-induced obesity [294]. By contrast, experimental activation of MCH neurons impairs locomotor activity [123]. Because MCH neurons are activated by insulin and elevated glucose, physiologic cues that the body has sufficient energy resources, they may serve to discontinue physical activity necessary for food seeking and ingestion and to modify peripheral glucose homeostasis [122, 123]. Such behaviors would be unwelcome, however, during prolonged hyperglycemia or energy surfeit, where enhancement of locomotor activity may be useful to promote weight loss. However, mice lacking insulin receptor on MCH neurons are not inhibited during hyperglycemia/hyperlipidemic states, and so have improved locomotor activity and insulin sensitivity compared with controls [123]. MCH neurons also, via polysynaptic regulation of brown adipose tissue, inhibit thermogenesis, whereas loss of action via MCHR-1 antagonists increases thermogenesis and hyperactivity [391–393]. Yet another mechanism by which MCH neurons might influence metabolism is through their impact on stress responses that in turn modify physical activity. MCH treatment increases corticosterone levels and anxiety-like locomotor behaviors, but treatment with an MCHR-1

Role of  the LHA in Arousal, Physical Activity, and Energy Expenditure  57

antagonist blunts these effects, similar to antidepressants [300, 394, 395]. The amount of MCH signaling may convey anxiety status in humans, as suggested by findings that MCH levels are lowest during social interactions associated with low stress. These data suggest that measures to suppress MCH action may be useful for treating anxiety disorders and depression [396], and indeed some anti-psychotic drugs reduce anxiety and hyperlocomotor behaviors via engaging the MCH signaling system [300].

5.3

Orexin (OX) Neurons in Control of Energy Expenditure

Although early studies on OX focused on its roles in promoting feeding, it was subsequently found to have a more profound role in regulating arousal. Loss of OX expression and/or degeneration of OX neurons causes narcolepsy in humans, and loss of OX is now considered patho­ gnomonic confirmation for this disease [397–399]. Experimental depletion of OX or ablation of OX neurons in animal models produces similar features to human narcolepsy, namely, increased sleepiness during normal waking periods, cataplexy and abrupt waking to sleep transitions [312, 321, 400–402]. OX itself directly mediates sleep-wake transition, thus restoration or enhancement of OX signaling can improve arousal regulation, such that OX-R agonists are considered viable pharmacological targets for individuals with narcolepsy [403–405]. Loss of OX-mediated arousal negatively impacts energy balance, as demonstrated by the increased incidence of overweight and type-2 diabetes in individuals with narcolepsy, due in part to their reduced wakingactivity levels [397–399]. Any loss of OX expression or OX activation, however, might disrupt arousal and waking activity levels, as is thought to underlie sickness-induced lethargy [103]. Furthermore, disruption of OX coordinated arousal and activity may lead to inappropriate waking and /or periods of food intake that can potentiate weight gain, or may disable appropriate food seeking behavior in response to fasting [272, 406, 407]. Indeed, rodents lacking OX engage in less volitional physical activity (wheel running), and have diminished energy expenditure that promotes weight gain [321, 322]. By contrast, activation of OX neurons increases locomotor activity, some of which may be due to food and water seeking behavior [127]. OX signaling is also implicated in stress, anxiety and panic-responses that modify volitional locomotor activity and energy expenditure [408]. Optogenetic activation of OX neurons or injection of OX into the hypothalamus increases corticosterone secretion, cardiorespiratory rate, blood pressure and arousal, which are hallmarks of the panic/stress phenotype [102]. Polymorphisms in the OX-Rs have been suggested to alter OX signaling and contribute to

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development of panic disorder [409]. Inhibition of OX signaling, including via OXR-1, may be useful to diminish anxiety responses observed in panic disorder and other psychiatric disorders [410–412]. Intriguingly, leptin can also diminish OX-mediated stress, presumably in part via the LHA LepRb → OX projections demonstrated to inhibit OX neurons [102, 141]. Therefore, LHA OX neurons might be the link to the disrupted/altered feeding behavior observed under chronic stress conditions, and simultaneous impairments in arousal and movement may underlie changes in body weight observed in anxiety disorders. OX neurons also contribute to thermoregulation, both via promoting BAT activity [413] and the differentiation of the BAT tissue [414]. Genetic loss of OX leads to suppression of stress-induced elevation of body temperature [415], characterized by reduced BAT differentiation and BAT hypoactivity [414] whereas central OX administration leads to hyperthermia and increased sympathetic nerve activity in BAT [416]. Moreover, increased OX expression enhances OXR-1 signaling to induce thermogenesis in established BAT, as well as browning of WAT that may further enhance metabolic rate [174].

5.4

Neurotensin (Nts) Neurons in Control of Energy Expenditure

Chemogenetic activation of LHA Nts neurons increases locomotor activity, at least in part by increasing mesolimbic DA signaling [99, 342]. LHA Nts neurons project to the VTA, and so can directly engage a subpopulation of VTA DA neurons that co-express NTSR-1. Activation of the LHA Nts → VTA NTSR-1 circuit induces DA into the NA that directly modifies locomotor activity and potentiates energy expenditure and weight loss [99, 343]. However, ablation of the VTA NTSR-1-DA neurons results in profoundly elevated physical activity and energy expenditure that disrupts energy balance, and leads to low adiposity and body weight [343]. The locomotor-inducing effects of Nts via the VTA are unique, as Nts administered into the ventral pallidum has no effect on locomotor activity, whereas infusion into the striatum inhibits the locomotor response to psychostimulants [417–419]. Because LHA Nts neurons directly provide Nts to the VTA, they are endogenous modulators of DA-mediated locomotor behavior. Thus, the LHA Nts → VTA circuit regulates locomotor activity and increases energy expenditure, which along with Nts-anorectic effects, supports weight loss. LHA Nts neurons may also modify locomotor activity via their local inhibitory regulation of OX neurons, and intact LHA Nts → OX regulation is necessary for adaptive locomotor responses to leptin and ghrelin that are mediated via LHA Nts and OX neurons, respectively [105, 139, 141].

Role of  the LHA in Arousal, Physical Activity, and Energy Expenditure  59

5.5

Galanin (Gal) Neurons in Control of Energy Expenditure

Activation of LHA Gal neurons promotes locomotor activity and energy expenditure. Interestingly, although ~50% of LHA Gal neurons co-express GABA, and activation of either LHA Gal or GABA neurons invokes hyperactivity, there is a markedly different nature of induced activity via these populations. Indeed, activation of LHA Gal neurons causes hyperactivity, but does not result in the compulsive-like locomotor behaviors seen in response to activating LHA GABA neurons, such as digging in bedding and gnawing on food and non-food objects in the cage such as wood, cardboard, or the cage floor [148, 225]. These data suggest that LHA Gal neurons represent a specific subset of all LHA GABA neurons that are involved in food-seeking locomotor behaviors rather than consumption behavior. LHA Gal neurons may regulate locomotor activity via their projections to local OX neurons or projections to the noradrenergic locus coeruleus, both of which play roles in modifying arousal and goal-directed behavior. It remains to be determined if LHA Gal neurons simultaneously project to OX neurons implicated in controlling food reward/selection and to the locus coeruleus, or whether these originate from distinct subpopulations of LHA Gal neurons [140]. It is clear, however, that the subset of leptinresponsive LHA Gal neurons do not contribute to locomotor behavior, as mice lacking LepRb in these neurons have normal levels of basal locomotor activity and energy expenditure [140].

5.6

GABA and Glutamate Neurons in Control of Energy Expenditure

Activation of LHA GABA neurons induces hyperactivity, which can permit food seeking and consumption [150, 366], but also non-goal directed motor behaviors such as digging and gnawing that may be compulsive in nature [366]. This constellation of motor behaviors may result from the simultaneous experimental activation of multiple subgroups of LHA GABA neurons that mediate distinct behaviors, but which are not likely to be physiologically activated at the same time. Such “bulk” activation could result in conflicting direction of locomotor responses without any clear goal, and account for the compulsive-like features observed with activation of all LHA GABA neurons vs. presumed subsets of them (e.g., LHA Gal-GABA neurons). In­ deed, recent data supports the existence of at least two functionally distinct populations of LHA GABA neurons with roles in appetitive vs. consumption behavior, and which may presumably be activated via different cues, inputs, and in a different temporal manner [150]. Although

60  Lateral Hypothalamic Control of Energy Balance

molecular markers of these appetitive vs. consummatory LHA GABA populations have yet to be defined, it is possible they may be differentiated (at least in part) by co-expression of either Gal or Nts. Indeed, the finding that LHA Gal neurons (~50% of which are GABAergic) specifically increases appetitive goal directed activity, without the other compulsive-like behaviors induced by activation of all LHA GABA neurons, confirms that there are subpopulations of LHA GABA neurons that coordinate specific aspects of locomotor behavior. Going forward it will be crucial to define these GABAergic subsets, and to understand how and when they are physiologically activated to understand the repertoire of coordinated energy balance behaviors in service of adaptive energy balance. This is being studied in part via probing the roles of projection-specified LHA GABA neurons. For example, LHA GABA neurons project to and inhibit GABAergic neurons of the thalamic reticular nucleus (TRN) to modify arousal and potential for locomotor activity; thus, activation of this LHA GABA → TRN circuit promotes arousal from NREM sleep, but silencing the circuit increases the duration of NREM sleep [229, 366, 420]. By contrast, LHA GABA → VTA projections are not implicated in arousal per se, but are necessary for reward seeking and intake. This circuit appears to directly engage VTA GABA neurons, such that released LHA GABA suppresses VTA GABA neurons, thereby releasing inhibition of VTA DA neurons to permit goal directed movement and intake behavior [225, 229]. Roles for LHA glutamate neurons are also beginning to be assessed, and activation of LHA Glut → LHb neurons modulates place preference and goal-directed motor locomotor necessary for reward feeding. However, given increasing evidence that the GABA and glutamatedefined groups encompass multiple subsets of molecularly and projection-specified neurons suggests that fully understanding their contributions to behavior will require techniques to differentiate and selectively modulate these subsets. • • • •

61

chapter 6

Role of the LHA in Human Physiology 6.1

What Have 60 Years of LHA Studies in Animals Taught Us About Human Energy Balance?

In the six decades following the seminal reports of rodents with LHA lesions, much has been learned about how this diverse brain region controls ingestive behavior and energy balance. Yet, for as much as we have learned and has been summarized in this volume, there are still many unanswered questions about how the LHA coordinates specific behaviors, and how modulation of this brain region contributes to the pathogenesis of human disease. Of chief concern is how modulation of the LHA contributes to energy balance disorders, such as obesity and eating disorders, and whether manipulation of LHA circuits may be useful in their treatment. The majority of our present understanding of LHA anatomy, cell populations, connectivity and function comes from studies in rodents; this is largely because of the development of genetic tools that can be used in mice and rats to allow for visualization and manipulation of specific LHA populations necessary to determine their function. These rodent models have been instrumental in revealing the roles of specific LHA neuronal populations, as well as their complex interplay, that together permit coordination of energy sensing and behavior to maintain homeostasis. Such anatomically specified circuit dissection studies are simply not possible in humans. However, we must consider the interpretations from animal studies with the ultimate goal of understanding and modifying human disease, and hence at some point need to reconcile how these findings “square” with the human nervous system. There has been very limited study of the LHA in humans, and what data there are lacks the cellular and circuit resolution obtained via rodent studies. Recent advances in the power and resolution of non-invasive imaging promises to improve studies of the human brain, and to identify differences between healthy vs. diseased individuals in terms of their neural activity and connectivity. For instance, functional magnetic resonance imaging (fMRI) has revealed differences in hypothalamic glucose consumption between lean and obese individuals [421], and a recent MRI study demonstrated

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a correlation between hypothalamic signaling and BMI [422]. These human studies largely support findings from the pre-clinical rodent studies describing the mechanistic roles of the hypothalamus in energy balance. We will therefore review the human literature relevant to understanding the role of the LHA in disease, and highlight similarities and discrepancies compared with animal models.

6.2

Role of Melanin-concentrating hormone (MCH) in Human Energy Balance and Disease

Genetic variants in MCHR-1 were recently identified from studies of early-onset obesity patients and obese adolescents and children, suggesting that genetic impairment of MCH action might be a genetic risk factor predisposing individuals to weight gain [423, 424]. Although these polymorphisms have been reported, however, it remains unclear if or how they impact feeding and /or energy balance behaviors. Human serum MCH levels correlate with feeding status and body fat [425, 426], along with fasting-induced elevations in MCH [425] that are consistent with the energy-deficit upregulation of MCH described in rodents. It is unclear how serum MCH levels reflect central MCH content or signaling in humans or animal models, but this information may provide insight into whether assessing MCH levels could be useful for diagnosing energy balance disorders and directing individual-specified treatments.

6.3

Role of Orexin (OX) in Human Energy Balance and Disease

The discovery of OX in rodents led the way to understanding the mechanism underlying human narcolepsy, which results from loss of OX signaling. Indeed, narcolepsy directly tracks with CSF levels of OX, which are diminished or in some cases undetectable in persons with narcolepsy compared with healthy individuals [398, 399]. Post-mortem immunolabeling indicates a loss of ~90% of OX neurons in narcolepsy patients compared with healthy individuals (Fig­ure 14), whereas they have comparable numbers of MCH neurons [397]. These data are consistent with data from rodents, supporting a necessary and sufficient role for OX in the development of narcolepsy, but not of MCH neurons. The underlying mechanism leading to loss of OX protein or neurons in narcolepsy has yet to be understood, but at least in some cases may occur because of genetic mutations that disrupt the expression or processing of the OX peptide. For example,

Role of the LHA in Human Physiology  63

Figure 14: Orexin and narcolepsy in humans. OX immunolabelling of postmortem tissue from the LHA of normal and narcoleptic patients, modified from Thannickal et al. 2000 figure 2.10 Number of OX neurons are reduced in narcolepsy patients compared to healthy individuals.

a mutation in the OX signal peptide explains the total absence of OX immunoreactivity observed from the postmortem brain tissue of some individuals with narcolepsy [399]. Narcolepsy resulting from loss of OX may be treated by agonists of OXR-1 and/or -2 and have prompted work into the design and pre-clinical testing of such brain-permeable agonists [427, 428]. Here again the rodent work is leading the way, but may provide insights into which drugs may have therapeutic rationale for treatment of human narcolepsy. Preclinical work to understand the function of the OX and OX-R signaling system led to the discovery of OX-R antagonists, and the first-in-class dual OXR-1 and OXR-2 antagonist, suvorexant (trade name Belsomara®) 10

 Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000). Used with permission of Elsevier.

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has been approved by the U.S. Food and Drug Administration for treatment of insomnia [128]. Disruptions of OX have also been noted in human psychiatric disorders, such as increased CSF OX levels in individuals with panic anxiety disorder compared with healthy controls [408]. This raises speculation of whether measuring OX levels might have rationale for diagnosing and choosing optimal treatments for psychiatric disorders. For example, the severity of panic disorder may correlate to OX content and might suggest benefit from suvorexant treatment.

6.4

Role of Neurotensin (Nts) in Human Energy Balance and Disease

Whole-exome sequencing recently identified damaging mutations in the NTS and NTSR-1 genes as the most commonly affected biological pathway in patients with anorexia nervosa (5/39 individuals) [429]. Moreover, one individual with a frameshift mutation in exon 1 of NTSR-1 also has a daughter and granddaughter with AN who both inherited the same NTSR1 mutation. This is significant because it indicates that genetic disruption of NTS-NTSR-1 signaling is a novel risk factor that may predispose individuals to develop anorexia nervosa, and may suggest avenues for treatment. Although not all persons with anorexia nervosa harbor mutations in these genes, disruptions upstream of NTS-NTSR-1 could also diminish NTSR-1– dependent behavior and energy balance. Thus, loss of NTSR-1 function may contribute broadly to the development of the disorder. Peripheral changes in Nts content have also been implicated in human disease. For example, elevations in plasma Nts have been reported in children with Prader-Willi syndrome, noted for producing profound hyperphagia and obesity [430]. Similarly, circulating pro-Nts levels correlate with BMI, such that individuals with higher plasma Nts have increased risk of developing obesity [360]. Indeed, peripheral Nts may be important for fat absorption, hence decreasing Nts levels might reduce fat accumulation that prevents further weight gain and might support weight loss. This explanation, however, appears inconsistent with the noted increases of Nts-producing enteroendocrine cells and circulating Nts that occur after bariatric surgery, suggesting that there may be a functional role for peripheral Nts in the process of weight loss [431–433]. Furthermore, although some circulating Nts can gain access to the brain, the effects of central vs. peripherally produced Nts may be differentially regulated, and may mediate distinct aspects of energy balance [434, 435]. Going forward, it will be important to define the sites of action of peripheral and central Nts, including whether measuring circulating Nts might be a useful predictive marker of individuals at risk for developing energy balance disorders.

Role of the LHA in Human Physiology  65

6.5

Role of GABA and Glutamate in Human Energy Balance and Disease

Genetic variant studies conducted for GABA pathway genes in 1000 obese and healthy human subjects found an association between hyperphagia and variants of the GABA synthesis gene GAD2, causing enhanced activity of its promoter [436]. A GAD2 variant has also been associated with hunger and emotional disinhibition susceptibility, elevated levels of carbohydrate and fat intake, and higher weight gain in women over a 6-year period [437]. Given that activation of LHA GABA neuron in rodents promotes voracious feeding [152, 225, 229, 366], it is possible that enhanced GABA synthesis could potentially increase feeding in humans. Thus, human data agrees with the studies of the LHA GABA system in rodents. However, given the extensive distribution of GABA throughout the nervous system and its essential control of many aspects of physiology, significant gain or loss of function mutations would likely be lethal and so may not account for a large proportion of energy balance disorders or observed human disease. • • • •

67

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Author Biographies Gizem Kurt is a Ph.D. candidate in Physiology at Michigan State University under the mentorship of Dr. Gina M. Leinninger. She received her B.S. in Molecular Biology and Genetics from Middle East Technical University, Turkey, in 2011 and her M.S. in Biology from Middle East Technical University, Turkey, in 2014. Her current Ph.D. research focuses on regulation of ingestive behaviors by lateral hypothalamic area neurotensinexpressing neurons.

Dr. Hillary Woodworth is a student in the M.D./Ph.D. program at Michigan State University. After earning a B.S. in Nutritional Science from Michigan State, she went on to join the M.D./Ph.D. program under the mentorship of Dr. Gina Leinninger where her dissertation examined how the neuropeptide, neurotensin, regulates energy balance via mesolimbic dopamine circuits. Her project was funded by an F30 pre-doctoral fellowship from the NIDDK, and she has received travel awards to attend national meetings of the Endocrine Society and the Society for Neuroscience. Upon completion of her medical training, she plans to pursue a career that combines clinical medicine with basic science to improve treatment of neuropsychiatric disease. Dr. Gina M. Leinninger is an Assistant Professor in the Department of Physiology at Michigan State University (MSU) in East Lansing, Michigan. She earned a B.S. in Chemistry at the University of Michigan–Flint, followed by a Ph.D. in Neuroscience from the University of  Michigan–Ann Arbor. After completing her postdoctoral work in the laboratory of Dr. Martin Myers Jr. at the University of Michigan, she joined the MSU faculty in 2012. Dr. Leinninger’s laboratory studies show that neuronal circuits in the brain modify feeding, physical activity, and other behaviors to regulate body

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weight, particularly focusing on the role of the lateral hypothalamic area in these processes. The long-term goal of her work is to understand how communication between the brain and body is disrupted to promote the development of energy balance disorders, such as obesity or anorexia, and potential circuits amenable for treatment of these diseases. She combines cutting edge molecular and viral tools to define the mechanisms by which specific types of neurons modulate ingestive and locomotor behaviors that impact body weight. Her research program is funded by the National Institutes of Health (NIH), and she has authored over 30 peer-reviewed publications. • • • •