Overlapping Brain Circuits for Homeostatic and Hedonic Feeding

Central regulation of food intake is a key mechanism contributing to energy homeostasis. Many neural circuits that are thought to orchestrate feeding behavior overlap with the brain’s reward circuitry both anatomically and functionally. Manipulation of numerous neural pathways can simultaneously influence food intake and reward. Two key systems underlying these processes—those controlling homeostatic and hedonic feeding—are often treated as independent. Homeostatic feeding is necessary for basic metabolic processes and survival, while hedonic feeding is driven by sensory perception or pleasure. Despite this distinction, their functional and anatomical overlap implies considerable interaction that is often overlooked. Here, we argue that the neurocircuits controlling homeostatic feeding and hedonic feeding are not completely dissociable given the current data and urge researchers to assess behaviors extending beyond food intake in investigations of the neural control of feeding. Central regulation of food intake is a key mechanism contributing to energy homeostasis. Many neural circuits that are thought to orchestrate feeding behavior overlap with the brain’s reward circuitry both anatomically and functionally. Manipulation of numerous neural pathways can simultaneously influence food intake and reward. Two key systems underlying these processes—those controlling homeostatic and hedonic feeding—are often treated as independent. Homeostatic feeding is necessary for basic metabolic processes and survival, while hedonic feeding is driven by sensory perception or pleasure. Despite this distinction, their functional and anatomical overlap implies considerable interaction that is often overlooked. Here, we argue that the neurocircuits controlling homeostatic feeding and hedonic feeding are not completely dissociable given the current data and urge researchers to assess behaviors extending beyond food intake in investigations of the neural control of feeding. Tightly regulating energy intake is necessary for survival of all animals. A critical component of energy balance is the ability to obtain and consume food sufficient to meet ongoing metabolic demands. The neurocircuits controlling feeding behavior are thought to be disrupted in pathologies of hypophagia (e.g., resulting in anorexia nervosa) or hyperphagia (e.g., resulting in obesity). In other pathologies, such as substance abuse, the neural circuits traditionally thought to control feeding may be co-opted by drugs of abuse, suggesting overlapping feeding and reward circuitry within the brain. The cells most closely linked to facilitating feeding are intermingled with the cells most closely linked to reward-guided behavior. A comprehensive understanding of these systems will greatly facilitate our understanding of pathologies that rely on feeding and reward circuits. Here, we pose the question of whether such circuits are indeed dissociable and should ultimately be considered separately given the current data and accepted approaches. For more than half a century, scientists have struggled to understand the intermingled neural basis of reward and feeding (Berridge, 1996Berridge K.C. Food reward: brain substrates of wanting and liking.Neurosci. Biobehav. Rev. 1996; 20: 1-25Crossref PubMed Scopus (1183) Google Scholar, Hoebel and Teitelbaum, 1962Hoebel B.G. Teitelbaum P. Hypothalamic control of feeding and self-stimulation.Science. 1962; 135: 375-377Crossref PubMed Google Scholar, Margules and Olds, 1962Margules D.L. Olds J. Identical “feeding” and “rewarding” systems in the lateral hypothalamus of rats.Science. 1962; 135: 374-375Crossref PubMed Google Scholar, Wise, 2004Wise R.A. Dopamine, learning and motivation.Nat. Rev. Neurosci. 2004; 5: 483-494Crossref PubMed Google Scholar). Despite early recognition that feeding and reward are intimately linked, these two topics have frequently been examined in isolation for practical reasons. For example, studies have looked at the contribution of particular brain regions to body weight regulation, energy expenditure, and food intake (for review, see Elmquist et al., 1999Elmquist J.K. Elias C.F. Saper C.B. From lesions to leptin: hypothalamic control of food intake and body weight.Neuron. 1999; 22: 221-232Abstract Full Text Full Text PDF PubMed Google Scholar, Morton et al., 2006Morton G.J. Cummings D.E. Baskin D.G. Barsh G.S. Schwartz M.W. Central nervous system control of food intake and body weight.Nature. 2006; 443: 289-295Crossref PubMed Scopus (1606) Google Scholar), while others focused on the role of neuronal populations in reward-guided behavior (Corbett and Wise, 1980Corbett D. Wise R.A. 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The need to feed: homeostatic and hedonic control of eating.Neuron. 2002; 36: 199-211Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar) (Table 1). Despite much progress toward understanding how certain parts of the brain contribute to either feeding or reward, questions of motivated behavior continue to be framed in terms of homeostatic feeding—food intake that is necessary to maintain typical body weight and metabolic function—or hedonic feeding—food intake driven by sensory perception or pleasure. These distinctions can be helpful to guide first-pass efforts to define basic functional elements of integrated neural circuits; however, homeostatic and hedonic feeding systems are likely both activated during all feeding situations. 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Note that manipulations are grouped by whether they putatively increase (↑) or decrease (↓) neuronal output, but different manipulations that have similar net effects on cellular activity are not necessarily equivalent to each other.+, increase; –, decrease; /, no effect; +/–, increase or decrease depending on experimental conditions; ?, effect unknown.Arc, arcuate nucleus of the hypothalamus; AgRP, agouti-related peptide; CeA, central nucleus of the hypothalamus; CGRP, calcitonin gene-related peptide; ChIEF, fast-closing mutated channelrhodopsin hybrid; ChR2, channelrhodopsin-2; Crf, corticotrophin releasing factor; D1R, d1-like dopamine receptor; D2R, d2-like dopamine receptor; eArch3.0, archaerhodopsin-3.0; eNpHR3.0, halorhodopsin-3.0; Gq, hM3Dq (Gq-coupled designer receptor exclusively activated by designer drug); Gi, hM4Dq (Gi-coupled designer receptor exclusively activated by designer drug); Htr2a, serotonin receptor 2a; Gs, Gs-coupled designer receptor exclusively activated by designer drug; LHA, lateral hypothalamic area; MC4R, melanocortin 4 receptor; NAc, nucleus accumbens; Oxtr, oxytocin receptor; PACAP, pituitary adenylate cyclase-activating polypeptide; PBN, parabrachial nucleus; PFC, prefrontal cortex; PKCδ, protein kinase C delta type; POMC, proopiomelanocortin; PVN, paraventricular nucleus of the hypothalamus; Sim1, single-minded 1; Sst, somatostatin; Tac2, tachykinin 2; TRH, thyrotropin-releasing hormone; TRPV1, transient receptor potential cation channel subfamily V member 1; Vgat, vesicular GABA transporter; Vglut2, vesicular glutamate transporter 2; VTA, ventral tegmental area. Open table in a new tab Appetitive behavior was limited to place preference and self-stimulation behavior. Note that manipulations are grouped by whether they putatively increase (↑) or decrease (↓) neuronal output, but different manipulations that have similar net effects on cellular activity are not necessarily equivalent to each other. +, increase; –, decrease; /, no effect; +/–, increase or decrease depending on experimental conditions; ?, effect unknown. Arc, arcuate nucleus of the hypothalamus; AgRP, agouti-related peptide; CeA, central nucleus of the hypothalamus; CGRP, calcitonin gene-related peptide; ChIEF, fast-closing mutated channelrhodopsin hybrid; ChR2, channelrhodopsin-2; Crf, corticotrophin releasing factor; D1R, d1-like dopamine receptor; D2R, d2-like dopamine receptor; eArch3.0, archaerhodopsin-3.0; eNpHR3.0, halorhodopsin-3.0; Gq, hM3Dq (Gq-coupled designer receptor exclusively activated by designer drug); Gi, hM4Dq (Gi-coupled designer receptor exclusively activated by designer drug); Htr2a, serotonin receptor 2a; Gs, Gs-coupled designer receptor exclusively activated by designer drug; LHA, lateral hypothalamic area; MC4R, melanocortin 4 receptor; NAc, nucleus accumbens; Oxtr, oxytocin receptor; PACAP, pituitary adenylate cyclase-activating polypeptide; PBN, parabrachial nucleus; PFC, prefrontal cortex; PKCδ, protein kinase C delta type; POMC, proopiomelanocortin; PVN, paraventricular nucleus of the hypothalamus; Sim1, single-minded 1; Sst, somatostatin; Tac2, tachykinin 2; TRH, thyrotropin-releasing hormone; TRPV1, transient receptor potential cation channel subfamily V member 1; Vgat, vesicular GABA transporter; Vglut2, vesicular glutamate transporter 2; VTA, ventral tegmental area. The anatomical interconnectedness, as well as the functional consequences of perturbation, of classical homeostatic and hedonic neurocircuits suggests that they contribute to a more complex motivational system. With a few notable exceptions discussed below, optogenetic or chemogenetic activation of appetite-stimulating cells often produces rewarding phenotypes (a preference or willingness to work for stimulation), whereas activating appetite-inhibiting cells tends to be aversive (avoidance of stimulation) (Jennings et al., 2013aJennings J.H. Rizzi G. Stamatakis A.M. Ung R.L. Stuber G.D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding.Science. 2013; 341: 1517-1521Crossref PubMed Scopus (206) Google Scholar, Jennings et al., 2015Jennings J.H. Ung R.L. Resendez S.L. Stamatakis A.M. Taylor J.G. Huang J. Veleta K. Kantak P.A. Aita M. Shilling-Scrivo K. et al.Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.Cell. 2015; 160: 516-527Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). Here, we will discuss anatomical and functional evidence to support the claim that homeostatic and hedonic feeding circuits are not presently dissociable from one another. We have divided the relevant brain regions into three broad categories: ventricular, intermediate, and monoaminergic. Ventricular neurons are those cells that are positioned adjacent to the third ventricle, regulate food intake, densely express receptors for a variety of circulating hormones, and project to downstream “intermediate” targets. Intermediate neurons are those cells implicated in feeding that are positioned downstream of ventricular cells. Intermediate cell groups can provide synaptic feedback onto ventricular neurons and interact heavily with one another. Determining anatomical and physiological links between ventricular neurons and postsynaptic, molecularly defined intermediate neurons is still an active area of research, but we have included discussion of the evidence where available. Monoaminergic neurons are found downstream and positioned to receive input from intermediate neurons, but direct input from ventricular neurons is sparse (Figure 1). The functions of given cell groups appear to be relatively specific at the level of ventricular neurons; manipulations of these cells produce pronounced effects on energy homeostasis. Intermediate neurons have more general functions, contributing to reward and aversion as well as food intake and body weight regulation. At the most general level, monoaminergic neurons (i.e., mesolimbic dopamine neurons) are involved in arousal, movement, motivation, and many other adaptive functions. We consider each of these levels and how they contribute to feeding behavior in turn. The arrangement of neurons discussed here is one of many possible schemes that could be used when discussing complex neural systems. This simplified framework permits distillation of a rich literature, reaching back nearly a century, into a set of concepts that can be contained within a single manuscript. It is partially conceptual and does not imply that other connections do not exist between these brain regions. Although circulating hormones can directly affect cells throughout the brain, we have chosen hypothalamic ventricular cells as a starting point because they tend to express receptors for circulating feeding molecules such as insulin, leptin, and ghrelin more densely than do intermediate or monoaminergic structures (Hill et al., 1986Hill J.M. Lesniak M.A. Pert C.B. Roth J. 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In addition to signaling from peripheral hormones, ventricular neurons also receive synaptic input, originating primarily from intra-hypothalamic sources (Wang et al., 2015Wang D. He X. Zhao Z. Feng Q. Lin R. Sun Y. Ding T. Xu F. Luo M. Zhan C. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons.Front. Neuroanat. 2015; 9: 40Crossref PubMed Scopus (84) Google Scholar). However, whether the synaptic input reflects feedback mechanisms or whether it can independently drive activity is unclear. Moreover, the neuronal organization described in this review is a framework for understanding a common theme: neurons most closely related to homeostatic feeding directly and indirectly interface with circuits that influence reward and aversion. Finally, the cell types and projections discussed below represent only a subset of the cells that are known to exist within these regions. Other classes of cells may have unique molecular signatures, connectivity, and functions. The present discussion is limited to neurons that are known to be involved in feeding or reward processing, and functionally unrelated cell types and connections have been omitted for clarity. Molecularly defined cell types in the arcuate nucleus of the hypothalamus (Arc) are often targeted as an “entry point” to homeostatic feeding circuits because they are strongly influenced by peripheral signals and perturbation robustly influences food intake. These neurons are located in the hypothalamus along the third ventricle and express receptors for many circulating molecules associated with homeostatic feeding, including leptin, ghrelin, and insulin (Cone, 2005Cone R.D. Anatomy and regulation of the central melanocortin system.Nat. Neurosci. 2005; 8: 571-578Crossref PubMed Scopus (1015) Google Scholar, Hill et al., 1986Hill J.M. Lesniak M.A. Pert C.B. Roth J. Autora