Making Sense of the Sensory Regulation of Hunger Neurons

Insights & Perspectives Making sense of the sensory regulation Think again of hunger neurons Yiming Chen and Zachary A. Knight* AgRP and POMC neurons are two key cell types that regulate feeding in such as leptin, and increases the level of response to hormones and nutrients. Recently, it was discovered that these hormones that promote feeding, such as neurons are also rapidly modulated by the mere sight and smell of food. This ghrelin. This hormonal switch activates rapid sensory regulation ‘‘resets’’ the activity of AgRP and POMC neurons AgRP neurons and inhibits POMC neu- before a single bite of food has been consumed. This surprising and rons, creating a “hunger drive” that counterintuitive discovery challenges longstanding assumptions about the motivates animals to find and consume food, and that persists until food intake function and regulation of these cells. Here we review these recent findings and replenishes the body of nutrients. In this discuss their implications for our understanding of feeding behavior. We way, a simple negative feedback loop is propose several alternative hypotheses for how these new observations might thought to explain the remarkable be integrated into a revised model of the feeding circuit, and also highlight some coordination of feeding behavior with of the key questions that remain to be answered. physiologic need. While this homeostatic model is Keywords: widely accepted, one key piece of data has been missing: information about anticipatory; arcuate nucleus; feeding; homeostasis; hunger; hypothalamus; . the activity dynamics of these neurons neural circuit in vivo. In the past year, this gap has Introduction consumption [3–6]. POMC neurons, in been closed, as three groups have contrast, are activated by energy surfeit, reported measurements of AgRP and The body weight of most animals is and their activity promotes fasting and POMC neuron dynamics in awake, remarkably stable over time, suggesting weight loss [3, 7]. These two cell types are behaving mice [12–14]. Contrary to that a homeostatic system balances food often described as the “gas pedal” and expectations, these experiments intake and energy expenditure over the the “brake” for the neural control of revealed that AgRP and POMC neurons long-term [1]. Two neural cell types in the feeding. Together, they have been stud- are rapidly modulated by the mere sight hypothalamus, termed Agouti-related ied in far greater depth than any other and smell of food, in a way that “resets” protein (AgRP) and Proopiomelanocortin neurons in the brain that have a special- their activity before any food is con- (POMC) neurons, are thought to be ized role in energy balance. sumed. This paradoxical discovery has critical components of this homeostatic AgRP and POMC neurons are regu- prompted reassessment of the regula- system (Fig. 1A). AgRP neurons are lated by circulating signals of nutri- tion and function of these long-studied activated by energy deficit [2] and their tional state, which modulate these cells cells [12–15]. In this essay, we summa- activity promotes food seeking and in opposite directions consistent with rize these recent findings and discuss their function. For example, the hor- their implications for our understanding mone leptin, which signals energy of the neural regulation of feeding. DOI 10.1002/bies.201500167 availability, activates POMC neurons and inhibits AgRP neurons [8, 9]. The Department of Physiology, University of California, hormone ghrelin, which signals energy The sensory detection of San Francisco, CA, USA scarcity, has the opposite effect [10, 11] (Fig. 1B). Based on these observations, food rapidly resets AgRP *Corresponding author: Zachary A. Knight an intuitive and widely accepted model and POMC neurons E-mail: [email protected] has emerged for how these two cell types control feeding. According to this AgRP and POMC neurons were first Abbreviations: AgRP, agouti-related protein; GABA, gamma- model, food deprivation decreases the implicated in the control of feeding aminobutyric acid; POMC, proopiomelanocortin. level of hormones that inhibit feeding, almost 20 years ago [2, 16–20], yet their 316 www.bioessays-journal.com Bioessays 38: 316–324, ß 2016 WILEY Periodicals, Inc. .....Insights & Perspectives Y. Chen and Z. A. Knight types. To overcome these obstacles, it was necessary to develop new methods that enable optical [21, 22] or Think again electrophysiological [23] recordings from genetically defined cell types at deep brain sites and in freely behaving animals. Three such methods have now been developed and applied to investigate the dynamics of AgRP and POMC neurons (Fig. 2). The first study used an approach called fiber photometry, which utilizes an optical fiber to record fluorescence signals from a genetically encoded calcium reporter (e.g. GCaMP6s) targeted to a specific cell type [22]. This approach measures population-level calcium dynamics but does not resolve single cells (Fig. 2). In the key experi- ment in this study, mice were fasted overnight and then presented with a Figure 1. AgRP and POMC neurons regulate feeding in response to nutritional signals. piece of food, and during this time the A: AgRP and POMC neurons are intermingled in the arcuate nucleus of the hypothalamus. B: The anorexigenic hormone leptin and the orexigenic hormone ghrelin regulate AgRP/ calcium dynamics of AgRP and POMC POMC neurons in opposite directions. neurons were optically recorded [12]. Contrary to the predictions of homeostatic models, it was found that food in vivo dynamics were only described in the arcuate nucleus (ARC) of the presentation alone rapidly inhibited the past year [12–14]. This long delay hypothalamus, which is located at the AgRP neurons and activated POMC was due to technical challenges associ- base of the forebrain and contains a neurons. This response began the ated with recording neural activity from diversity of intermingled neural cell moment that food was presented and was complete within seconds, often before a single bite of food could be consumed. Thus sensory cues associ- ated with food, rather than the post-ingestive effects of feeding, are primarily responsible for resetting the activity of these cells [12]. This finding was counterintuitive in part because it revealed that AgRP neurons, which promote food intake, are actually less active when a mouse is eating, and conversely that POMC neurons, which inhibit food intake, are more active during feeding. This paradoxical activity pattern creates a puzzle for explain- ing how these neurons are able to perform their presumed functions. Further characterization of the rapid sensory modulation of these neurons revealed five important prop- erties [12]. (i) The response depends on Figure 2. Techniques for cell-type-specific recording of deep brain neural activity. (Left) nutritional state, since neurons from Microendoscopic calcium imaging utilizes a head-mounted, miniaturized microscope to record fasted mice respond more strongly to fluorescence signals from a genetically encoded calcium indicator targeted to a specific cell food cues than neurons from fed mice. type. This method can be used to probe deep brain structures by coupling the microscope to a (ii) It depends on food palatability, gradient refractive index (GRIN) lens of appropriate length. (Middle) Optrode recordings utilize an since energy dense foods such as electrode array paired with an optical fiber to perform extracellular recordings. The optical fiber peanut butter induce a stronger enables cells expressing channelrhodopsin to be identified by their short latency responses to light stimulation. (Right) Fiber photometry uses a single optical fiber to both excite and record response than energy poor foods such fluorescence from a population of neurons expressing a calcium reporter. The publications that as chow. (iii) It depends on food used each of these approaches to investigate AgRP/POMC neurons are listed below. accessibility, since food that is hidden Bioessays 38: 316–324, ß 2016 WILEY Periodicals, Inc. 317 Y. Chen and Z. A. Knight Insights & Perspectives..... or inaccessible induces a weaker and electrode recordings based on their light that predicts food availability [28]. The less durable response. (iv) It is contin- sensitivity [23] and, unlike calcium anticipatory response in this case is gent on eventual food consumption, imaging, provide reliable measurement the secretion of saliva containing diges- since removal of food before it can be of single action potentials (Fig. 2). In tive enzymes, which functions to pre- consumed causes reversion of neural this study ChR2 was targeted to AgRP pare the oral cavity for food ingestion activity back to its prior state. (vi) It is neurons, so that AgRP neurons could be just moments before the food arrives. By integrative, because these factors identified as light-activated units and contrast, the function of the anticipa- interact with each other to determine putative POMC neurons could be iden- tory regulation of AgRP and POMC the magnitude of the response. As an tified as light-inhibited units. Using this neurons is less clear. We consider below example of this last property, presen- approach AgRP neuron firing rates were five alternatives. Think again tation of a palatable food such as found to gradually increase throughout peanut butter was shown to modulate the course of the light phase, consistent these neurons even in fed mice, which with the slow development of energy Hypothesis #1: Sensory were otherwise insensitive

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