AgRP neurons are a small population of cells in the arcuate nucleus of the hypothalamus that are critical for regulating food intake (Andermann and Lowell, 2017). These cells are progressively activated during food deprivation (Betley et al., 2015; Chen et al., 2015; Hahn et al., 1998; Mandelblat-Cerf et al., 2015), in part due to fluctuations in nutritionally-regulated hormones such as leptin and ghrelin (Beutler et al., 2017; Blouet and Schwartz, 2010; Cowley et al., 2001; Cowley et al., 2003; Dietrich et al., 2013; Nakazato et al., 2001; Pinto et al., 2004; Schneeberger et al., 2013). Optogenetic or chemogenetic stimulation of AgRP neurons promotes intense food seeking and consumption (Aponte et al., 2011; Krashes et al., 2011), whereas silencing of these cells leads to aphagia or starvation (Gropp et al., 2005; Krashes et al., 2011; Luquet et al., 2005). Thus AgRP neurons play a key role in the homeostatic negative feedback loop that links the need for energy to the stimulation of feeding behavior.

Although AgRP neurons are gradually activated during fasting, they are inhibited within seconds when a hungry animal sees or smells food (Betley et al., 2015; Chen et al., 2015; Mandelblat-Cerf et al., 2015). Paradoxically, this rapid inhibition of AgRP neurons often occurs before a single bite of food has been consumed and then persists for the duration of the ensuing meal. These observations raise the question of how AgRP neuron activity is able to drive food consumption, given that these neurons are inhibited during the act of feeding itself (Chen and Knight, 2016).

To reconcile these observations, we hypothesized that AgRP neurons may transmit a long-lasting signal that continues to drive food consumption even after AgRP neurons have been inhibited by food cues (Chen and Knight, 2016). Consistent with this, we showed that brief optogenetic stimulation of AgRP neurons in the absence of food can drive voracious food intake tens of minutes later, long after AgRP neuron stimulation has been terminated (Chen et al., 2016). This indicates that AgRP neurons can generate an unusual ‘sustained hunger drive’ that outlasts their acute firing (Figure 1A). The mechanisms underlying this long-lasting potentiation of feeding behavior are unknown.

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AgRP neurons release three neurotransmitters that can influence feeding: AgRP, NPY and GABA (Andermann and Lowell, 2017; Hahn et al., 1998; Krashes et al., 2013; Tong et al., 2008). We hypothesized that one of these neurotransmitters may play a specific role in the sustained hunger drive generated by AgRP neurons. To test this hypothesis, we blocked signaling through each of these pathways and then tested their role in AgRP neuron driven food intake (Figure 1B). To inactivate GABA signaling, we crossed AgRP-IRES-Cre mice to animals with a floxed allele of the GABA transporter Slc32a1 (Tong et al., 2008) (referred to as GABA-); to block NPY signaling we used NPY knockout mice (Erickson et al., 1996) (NPY-); and for AgRP we used Agouti mice (AgRP-), in which the melanocortin pathway is inactivated by constitutive expression of a melanocortin 4-receptor antagonist (Aponte et al., 2011). We then measured the effect of optogenetic pre-stimulation (Chen et al., 2016) of AgRP neurons in each of these strains, or littermate controls.

We first stimulated AgRP neurons for 15 min in the absence of food, and then shut off the laser and allowed animals to eat for one hour. This pre-stimulation paradigm produced robust food intake in mice lacking GABA or AgRP signaling, and the magnitude of food consumption was similar between mutants and littermate controls (Figure 1C). In striking contrast, pre-stimulation of mice lacking NPY caused no increase in food intake (Figure 1C, bottom row). To measure the quantitative requirement for these neurotransmitters, we repeated this experiment with different durations of pre-stimulation (5, 15, 30 and 60 min; Figure 1D). We found that control mice, as well as mice lacking GABA or AgRP, showed a clear dose-response relationship between pre-stimulation duration and total food intake (Figure 1E,F and Figure 1—figure supplement 1). This increase in food intake was due to an increase in bout size, rather than bout number (Figure 1—figure supplement 2). In contrast NPY- mice showed no dose-dependent increase in food intake following longer durations of AgRP neuron pre-stimulation (Figure 1G). This behavioral defect was not due to a failure to activate AgRP neurons, because we observed robust Fos expression in AgRP neurons after optogenetic stimulation of NPY- mice (Figure 1L). Instead this indicates that NPY is specifically required for the sustained hunger produced by AgRP neuron activation.

To examine the kinetics of AgRP neuron driven hunger, we pre-stimulated AgRP neurons for five minutes and then inserted a delay of varying lengths between the termination of stimulation and the availability of food (15, 30, or 60 min; Figure 1H). We found that all genotypes except for NPY- mice exhibited robust food consumption that gradually declined with increasing delay duration up to 60 min (Figure 1I–K). By pooling data from all control animals, we estimated that this hunger signal has a rise time of approximately four minutes (logarithmic growth; N = 23; R-Square = 0.72; Figure 1M) and a decay-time of approximately 47 min (exponential decay; N = 19; R-Square = 0.87; Figure 1N). This indicates that AgRP neuron activity rapidly generates a durable, NPY-dependent signal that drives feeding behavior.

AgRP neurons promote not only food consumption but also behaviors that lead to food discovery (Krashes et al., 2011). We therefore examined the requirement for each of these neurotransmitters in AgRP driven appetitive behavior. To do this we used a progressive ratio three lever-pressing task, in which delivery of each subsequent pellet of food requires three additional lerel presses (Figure 2A). We observed vigorous lever pressing following pre-stimulation of AgRP neurons in AgRP- and GABA- mice, as well as controls (Figure 2B–F). In contrast pre-stimulation had no effect on operant responding in animals lacking NPY (Figure 2B,C,F). This indicates that NPY is critical for the ability of AgRP neurons to drive food seeking behavior as well as food consumption.

Figure 2

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To investigate with greater temporal resolution the requirement for NPY in AgRP driven feeding behavior, we developed a paradigm that alternates between concurrent and pre-stimulation. In this paradigm, animals are given constant access to food, and then subjected to two minutes of stimulation (20 Hz; Laser ON) followed by two minutes of no stimulation (Laser OFF) in a pattern that repeats for two hours (Figure 3A). In control mice, this protocol stimulated robust food consumption (Figure 3B,C). Importantly, food intake was equally distributed between the Laser ON and OFF epochs (Figure 3C–I), indicating that wild-type animals do not distinguish the boundary between these two-minute intervals, presumbly due to the sustained hunger produced by AgRP neuron stimulation.

Figure 3

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We then repeated this experiment in each of the genotypes described above. Remarkably, loss of NPY caused food intake to become strictly time-locked to the laser stimulus: that is, NPY- animals ate during concurrent stimulation, but then stopped eating within seconds of the laser shutting off (Figure 3C,D,F,I). In contrast, mice lacking GABA or AgRP signaling, as well as their littermate controls, showed no difference in feeding between the Laser ON and OFF periods (Figure 3E–H). These results were robust to variations in the paradigm, such as changing the duration of the stimulation epoch (Figure 3G–I). This indicates that, in the absence of NPY, AgRP neuron driven hunger dissipates within seconds of the offset of AgRP neuron firing.

NPY is expressed in cell types other than AgRP neurons. This raises the possibility that global NPY knockout could cause changes in other circuits that indirectly lead to deficits in AgRP neuron driven feeding. To exclude this possibility, we used a viral approach to rescue NPY expression selectively in AgRP neurons of NPY- mice. We generated two Cre-dependent AAVs, one expressing NPY and the other expressing GFP as a control, and then injected these AAVs into the ARC of NPY- mice (Figure 3J). Mice injected with AAV expressing NPY, but not GFP, showed restoration of NPY expression in the ARC (Figure 3K) and complete rescue of the feeding phenotypes associated with NPY- knockout (Figure 3L–P). For example, NPY re-expression in AgRP neurons caused feeding behavior in NPY- mice to become uncoupled from the onset and offset of laser stimulation, in a way that was indistinguishable from wild-type animals (Figure 3N–P). This indicates that the phenotypes observed in NPY- mice are due to loss of NPY expression in AgRP neurons, rather than effects of this mutation on other circuits or development.

We have focused here on the behavioral effects of AgRP neuron pre-stimulation (Chen et al., 2016). While this paradigm cannot replicate the precise details of asynchronous natural activity, it does mimic the broad features of the natural regulation of these cells (i.e. that AgRP neurons are more active before food discovery than during food consumption). In contrast, many earlier studies used a protocol in which AgRP neurons are stimulated concurrently with food consumption (Aponte et al., 2011; Atasoy et al., 2012; Betley et al., 2013; Betley et al., 2015). This protocol induces an activity pattern that is the opposite of what occurs naturally (i.e. greater AgRP neuron activity during feeding than before). To place our results in the context of this earlier work, we concurrently stimulated AgRP neurons using either chemogenetics (Figure 4A–C) or optogenetics (Figure 4E–H) and then measured food intake in NPY+ and NPY- mice. We found that concurrent chemogenetic stimulation increased food consumption in mice lacking NPY (Figure 4C,D and Figure 4—figure supplement 1), consistent with a previous report (Krashes et al., 2013). In contrast, during concurrent optogenetic stimulation NPY- mice consumed only a small fraction of the food consumed by NPY+ controls (Figure 4E,F). We could partially rescue food intake in NPY- mice by using a higher intensity optogenetic stimulation protocol (Figure 4F), whereas NPY+ controls showed no difference in food consumption between high and moderate intensity stimulation (high intensity refers to continuous 20 Hz stimulation, whereas moderate intensity refers to 20 Hz stimulation in a 2 s ON, 3 s OFF pattern; Figure 4G). This indicates that intense concurrent optogenetic stimulation of AgRP neurons can partially overcome the requirement for NPY, likely through increased release of GABA (Atasoy et al., 2012; Krashes et al., 2013; Tong et al., 2008). It remains unclear why concurrent chemogenetic stimulation of AgRP neurons does not also require NPY to induce feeding (Figure 4C,D and Krashes et al., 2013). In contrast to these variable responses to concurrent stimulation, we found that increased stimulation intensity could not compensate to any degree for loss of NPY in a pre-stimulation paradigm (Figure 4H). This is presumably because endogenous GABA and AgRP are unable to drive food intake effectively on the timescale of sustained hunger (tens of minutes immediately after the offset of stimulation).

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NPY was implicated in the regulation of feeding decades ago, but its precise contribution has been difficult to establish (Loh et al., 2015). Early studies showed that infusion of picomoles of NPY into the PVH can elicit voracious food intake (Clark et al., 1985; Stanley and Leibowitz, 1984), identifying NPY as an unusually potent orexigen. Consistent with this, NPY is highly expressed in hunger-promoting AgRP neurons (Hahn et al., 1998), and its expression in these cells is increased by energy deficit (Sahu et al., 1988; White and Kershaw, 1990). However genetic deletion of NPY, alone (Erickson et al., 1996) or in combination with AgRP (Qian et al., 2002), had little effect on food intake or body weight. Similarly deletion of NPY receptors, alone (Kushi et al., 1998; Marsh et al., 1998; Pedrazzini et al., 1998) or in combination (Nguyen et al., 2012), failed to produce the expected lean phenotype. More recently, the advent of cell-type-specific tools for neural manipulation made it possible to acutely stimulate AgRP neurons and then measure the effect of blocking NPY signaling. One study found that food intake following chemogenetic stimulation of AgRP neurons requires either NPY or GABA signaling, but not both (Krashes et al., 2013). Another study showed that antagonists of NPY or GABA receptors in PVH could partially block feeding induced by optogenetic stimulation of AgRP neurons (Atasoy et al., 2012). Taken together, these observations have led to a general view that NPY and GABA have partially redundant functions in mediating food intake by AgRP neurons.

The discovery that AgRP neurons are rapidly silenced by the sensory detection of food (Betley et al., 2015; Chen et al., 2015; Mandelblat-Cerf et al., 2015), and consequently can drive feeding via a long-lasting hunger signal (Chen et al., 2016), led us to wonder whether a specific neurotransmitter might mediate this unusual mechanism for controlling behavior. We therefore reinvestigated the role of these neurotransmitters using an optogenetic pre-stimulation paradigm that mimics the broad features of the natural regulation of AgRP neurons. This revealed a remarkably specific role for NPY in extending the duration of AgRP neurons’ behavioral effects for tens of minutes beyond the window of their immediate firing. This in turn provides a molecular correlate for the long-lasting hunger signal that bridges AgRP neuron dynamics with feeding behavior.

While our findings have emphasized the role of NPY in sustained hunger, previous work has shown that the neuropeptide AgRP can also drive food intake over long timescales. For example, infusion of AgRP into the brain (Hagan et al., 2000) or stimulation of AgRP release (Krashes et al., 2013; Nakajima et al., 2016) can cause modulation of feeding behavior that persists for days. However, this long-lasting potentiation of feeding behavior requires several hours to emerge when endogenous AgRP release is stimulated (Krashes et al., 2013). Consistent with this, we find no evidence that the AgRP peptide is required for the intense food consumption that occurs immediately following AgRP neuron pre-stimulation (Figure 1). Thus our data suggest that NPY and AgRP play complementary roles in the regulation of feeding, with NPY sustaining hunger selectively on the timescale of a meal (tens of minutes after food discovery), whereas AgRP modulates the tone of the feeding circuit over longer timescales. This role for AgRP is consistent with an extensive literature that has implicated the melanocortin system in the long-term regulation of energy balance (Krashes et al., 2016).

A number of questions remain unanswered about how NPY mediates the sustained hunger response described here. Slice recordings have shown that NPY can have persistent effects on membrane excitability and neurotransmitter release in vitro (Dubois et al., 2012; Fu et al., 2004; Roseberry et al., 2004), indicating that NPY may act directly on post-synaptic targets of AgRP neurons to cause durable changes in their activity. We have shown that pre-stimulation of AgRP neuron axon terminals in PVH, BNST, and LH is sufficient to drive sustained feeding (Chen et al., 2016), suggesting that these are the downstream sites where NPY has its long-lasting effects on hunger. However it remains unknown which NPY receptors are involved, in which cell types these receptors are expressed, which molecular mechanisms they utilize, and how this sustained modulation is represented in the dynamics of the next circuit node. Likewise, while we have focused on NPY’s role in appetitive and consummatory aspects of feeding, it remains unknown whether NPY has similar long-lasting effects on metabolism or other adaptive responses to energy state (Dietrich et al., 2017; Padilla et al., 2017; Padilla et al., 2016; Steculorum et al., 2016).

A central challenge of neuroscience is to explain how the neurochemical organization of the brain gives rise to behavior (Bargmann and Marder, 2013). Neural circuits contain an extraordinary diversity of neuropeptides, yet in most cases we have little understanding of how those peptides relate to the function of the underlying cells. We have shown here how a neuropeptide that drives feeding can function on a timescale that is inaccessible to classical neurotransmitters. This in turn allows a neuron that controls hunger to direct ongoing behavior while simultaneously anticipating and responding to impending physiologic changes. It will be important to investigate to what extent other neuropeptides influence behavior in this way.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Yiming Chen

   1. Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
   2. Neuroscience Graduate Program, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Rachel A Essner

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9569-1929

2. Rachel A Essner

   Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   Data curation, Investigation, Methodology

   Contributed equally with

   Yiming Chen

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2240-3911

3. Seher Kosar

   Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Oliver H Miller

   Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Yen-Chu Lin

   Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Sheyda Mesgarzadeh

   Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. Zachary A Knight

   1. Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
   2. Neuroscience Graduate Program, University of California, San Francisco, San Francisco, United States
   3. Department of Physiology, University of California, San Francisco, San Francisco, United States
   4. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   zachary.knight@ucsf.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7621-1478

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