Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.
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This research was funded by the Howard Hughes Medical Institute. Z.F.H.C. was funded by the HHMI Janelia Farm Graduate Scholar program. We thank B. Balleine, M. Schnitzer, N. Ji, A. Lee, Z. Guo for suggestions on experimental design; H. Su for molecular biology; J. Rouchard, S. Lindo, K. Morris, M. McManus for mouse breeding and procedures; M. Copeland for histology; J. Osborne and C. Werner for apparatus design; K. Branson for automated mouse tracking software (Ctrax); J. Dudman, S. Eddy, H. Grill, N. Geary, U. Heberlein for comments on the manuscript.
The authors declare no competing financial interests.
Extended data figures and tables
Extended Data Figure 1 Models for homeostatic regulation of learning food preferences and food-seeking behaviours.
a, The relationship between internal or external cues and Pavlovian approach or instrumental food-seeking actions is strengthened by nutrient ingestion. Nutrients have intrinsically positive valence7 (rewarding), and energy deficit enhances the reward value of outcomes associated with food intake. b, Model of food preference and food-seeking in which learning involves reducing an energy deficit internal state that has negative valence. The relationship between internal or external cues and food preferences or food-seeking actions is strengthened by nutrient ingestion outcomes that reduce energy deficit and associated negative valence (red bar arrows are inhibitory). Conversely, the relationship between internal or external cues and food preference or food-seeking actions is weakened if outcomes do not reduce energy deficit.
Extended Data Figure 2 AGRP neuron activation does not condition taste aversion, and feeding reduction correlates with proportion of AGRP neurons inhibited.
a, Experimental design for conditioned taste aversion experiments. Mice were water restricted and habituated to drink water from a spout during 20 min sessions. Four groups of mice were then allowed to consume a tastant (0.15% saccharin solution) for 20 min (pre-test) and immediately following this session, they were exposed to a conditioning agent (LiCl, saline, 120 min AGRP neuron photostimulation, or AGRPChR2 mice attached to an optical fibre but not phostostimulated; all n = 6 mice). The next day, mice were tested for consumption of the saccharin solution (test 1). For AGRP neuron photostimulated and non-photostimulated groups, conditioning and testing was extended with an additional three conditioning and test sessions. The day following the last testing session for each group, water consumption was also measured (water test). b, c, Consumption of tastant solution for all sessions (b) and comparison for pre-test and test 1 session (c). d, Confocal micrographs of Cre recombinase-expressing AGRP neurons transduced with rAAV-Syn-FLEX-PSAML141F-GlyR-IRES-eGFP. Alexa555-conjugated-Bungarotoxin (Bgt-555) labels PSAML141F-GlyR, which co-localizes with eGFP. Scale bar, 100 µm. e, f, Fos immunofluorescence in the ARC of mice treated with PSEM89S during the first 4 h of the dark period without access to food. AGRPeGFP mice (e) show high levels of Fos in AGRP neurons, and AGRPPSAM-GlyR mice (f) express low levels of Fos in neurons that express PSAM-GlyR (right side); non-transduced neurons (contralateral side) express high levels of Fos. Scale bar, 100 µm. g, Fos immunofluorescence intensity in AGRP neurons from AGRPPSAM-GlyR or AGRPeGFP mice after PSEM89S treatment during the first 4 h of the dark period without access to food (n = 3 mice per condition, n > 50 nuclei per condition). h, Change in food intake for AGRPeGFP mice (n = 12) or AGRPPSAM-GlyR mice (n = 23) treated with PSEM89S during the first 4 h of the dark period relative to saline injected on successive days. i, Diagram of AGRP neuron axon projection fields showing from where transduction efficiency was calculated. i–m, After rAAV-hSyn-FLEX-rev-PSAML141F-GlyR-IRES-eGFP transduction of Agrp-IRES-Cre mice, measurement of eGFP transduction efficiency in AGRP boutons in the PVH (i, k) and PAG (l, m). High transduction efficiency (>50% in AGRP boutons) is shown (i, i) in comparison to low transduction efficiency (<50% in AGRP boutons) (k, m). Scale bar, 20 µm. n, Food intake reduction for mice treated with PSEM89S is correlated with the transduction efficiency of rAAV-hSyn-FLEX-rev-PSAML141F-GlyR-IRES-eGFP in AGRP neurons (eGFP transduced boutons per total AGRP boutons) (n = 35 mice). NS, P > 0.05, ***P < 0.001. Values are means ± s.e.m.
Extended Data Figure 3 AGRP neuron activation does not condition appetite or reinforce instrumental responding.
a, Experimental design to test conditioned appetite. After closed-loop place preference and extinction testing (Fig. 2), AGRPChR2 mice showed reduced occupancy in the photostimulation-paired side of the chamber. Avoidance in extinction indicated conditioning to offset of a negative-valence signal from AGRP neurons. An alternative hypothesis is that induction of food-seeking on the photostimulation side in the absence of food led the mouse to seek food. Because photostimulation was stopped when the mouse passed to the other side of the chamber, this might increase occupancy on the non-photostimulated side. However, this is not consistent with the increased avoidance of the previously photostimulated side in extinction (Fig. 2k) unless the contextual cues previously associated with photostimulation conditioned increased appetite. To test whether conditioned avoidance might be associated with conditioned hunger, we measured food intake in ad libitum fed mice after closed-loop place preference and extinction tests in Fig. 2g–k on each side of the apparatus in the absence of photostimulation. b, Mice did not show conditioned food consumption on the previously photostimulated side (paired t-test, n = 8 mice). This indicates that avoidance observed in extinction was not a consequence of food-seeking behaviours being differentially engaged on one side of the apparatus. c, d, Cessation of AGRP neuron photostimulation did not condition instrumental responding. c, Nose pokes by ad libitum fed AGRPChR2 mice (n = 9) during photostimulation, where a nose poke resulted in a 20 s pause in light pulses for each behavioural session. Nose pokes reduced across sessions indicating the absence of instrumental conditioning. Filled circles: active port, empty circles: inactive port. d, For ad libitum fed AGRPChR2 mice previously trained to hit a lever for food, lever presses during photostimulation, where a lever press gives a 20 s pause in light pulses for each behavioural session (repeated measures ANOVA F(7,40) = 1.19, P = 0.330; n = 8 mice). e–h, Optogenetic silencing with Arch (550–600 nm, 8–11 mW per mm2). e, Cell-attached recording of AGRP neuron firing rate in brain slices from Agrp-IRES-Cre;Ai35d (AGRPArch) mice during light illumination. f, Whole cell recording of AGRPArch during optogenetic inhibition. g, Membrane potential change in AGRP neurons expressing Arch during light illumination (n = 6). h, AGRP neuron firing rate during optogenetic inhibition of Arch-expressing AGRP neurons (n = 4). i, Optogenetic silencing of AGRP neurons in food-restricted mice did not condition free operant instrumental responding. Nose pokes by AGRPArch mice resulted in 60 s of 561 nm light delivered to an optical fibre over the ARC. Nose poking reduced over multiple sessions (ANOVA F(3,24) = 7.835, P < 0.001; n = 7 mice), indicating that silencing AGRP neurons did not directly reinforce instrumental responding. NS, P > 0.05 Values are means ± s.e.m.
Extended Data Figure 4 Lever pressing for food is sensitive to AGRP neuron photostimulation duration.
a, Experimental design of progressive ratio 7 lever-press experiment from Fig. 3 for a food-restricted AGRP neuron photostimulated group and an ad libitum fed non-photostimulated group. The two additional groups of mice were trained to lever press in food-restriction on a PR7 reinforcement schedule. For the food-restricted with photostimulation group, mice were maintained on food-restricted and tested with PR7 reinforcement tests over 15 sessions with photostimulation. Each session was 2 h, where levers were available for the first 40 min of the session, and photostimulation was delivered for the length of the session (120 min, grey). Mice were then ad libitum re-fed and tested on a non-photostimulated PR7 session. For the ad libitum fed non-photostimulated group, mice were ad libitum re-fed following lever-press training and tested with PR7 reinforcement tests over 16 sessions, with no photostimulation delivered (beige). b, Lever presses for each PR7 session for food-restricted AGRP neuron photostimulated mice (grey, n = 11) mice and ad libitum fed non-photostimulated mice (beige, n = 8). For comparison, data are shown for food-restricted and 120 min photostimulated groups that are reproduced from Fig. 3b. c, Lever presses on first (1) and last (15) sessions in PR7 test for food-restricted with photostimulation mice (grey) mice and sated no photostimulation mice (beige). Also shown are data for food-restricted and 120 min photostimulated groups that are reproduced from Fig. 3c. d, Experimental design of progressive ratio 7 lever-press experiment from Fig. 3 for a 40 min photostimulation group. One additional group of mice was trained to lever press in food-restriction on a PR7 reinforcement schedule. Mice were then ad libitum re-fed and tested with PR7 reinforcement tests over 15 sessions. Each session was 2 h, where levers were available for the first 40 min of the session, and photostimulation was delivered only while levers were available (grey). A non-photostimulated PR7 session was also performed after the fifteenth test session. e, Lever presses for each PR7 session for 40 min photostimulated (grey, n = 12) mice. Also shown are data for food-restricted and 120 min photostimulated groups that are reproduced from Fig. 3b. f, Lever presses on first (1) and last (15) sessions in PR7 test for 40 min photostimulated mice (grey). Also shown are data for food-restricted and 120 min photostimulated groups that are reproduced from Fig. 3c. NS, P > 0.05, **P < 0.01, ***P < 0.001. Values are means ± s.e.m.
Extended Data Figure 5 AGRP neuron-associated body weight increase does not suppress AGRP neuron-evoked food-seeking.
a, Weight gain for the 120 min AGRP neuron photostimulated (n = 11) group in the PR7 experiment (from Fig. 3) after 15 sessions. Weight gain is due to eating after the test session when the mouse is returned to the homecage and is associated with long-lasting effects from release of AGRP44. Previous experiments have shown that AGRP is not responsible for the acute feeding behaviour investigated in this study4,5,45. However, metabolic changes associated with weight gain could be an alternative cause of reduced instrumental food-seeking shown in Fig. 3. To test the effect of weight gain in mice trained to lever press for food on a PR7 reinforcement schedule, we induced weight gain without the negative reinforcement extinction protocol from Fig. 3. b, Experimental design of progressive ratio 7 lever-press experiment with AGRP neuron photostimulation-induced weight gain but lacking disruption of negative reinforcement during food-seeking. AGRPChR2 mice were trained under food deprivation to lever press under a PR7 schedule for food pellets. After training, both groups were ad libitum re-fed, and the mice were divided into two groups: (1) control mice with no induction of weight gain (blue) and (2) the induced weight gain group (red). Both groups were then tested on a PR7 reinforcement schedule under AGRP neuron photostimulation conditions (PR7 test 1). Following this session, a photostimulation-induced weight gain protocol was initiated for the second group. Mice received one 2 h experimental session per day, where they were photostimulated for the whole experimental session and body weight was monitored daily. During these sessions, levers were not available, but free food was provided during these sessions (the amount of food was matched in quantity to the average amount of food acquired by the 120 min photostimulation group under the PR7 experiment from Fig. 3 for the corresponding session). The photostimulation-induced weight grain protocol was conducted for 22 consecutive days, which was required for body weight gain to be comparable to levels acquired by the 120 min AGRP neuron photostimulation group in the PR7 experiment (∼28%) from Fig. 3. Control mice were tethered to a fibre but did not receive photostimulation, otherwise they received the same experimental manipulation as induced weight gain mice (access to the same amount of food), and their body weight was also monitored. After the induced weight gain group achieved a 28% weight gain, a second PR7 test was conducted for both groups in the same manner as the first one. c, Per cent body weight change for control (blue, n = 6) and induced weight gain (red, n = 6) mice. Grey dotted line: per cent body weight change for photostimulated mice in PR7 experiment from Fig. 3. d, Lever presses for control (blue) and AGRP neuron photostimulation-induced weight gain (red) mice on first (1) and second (2) PR7 test, prior and after weight gain induction protocol, respectively. There was no significant reduction in lever pressing between PR7 sessions within either group. NS, P > 0.05, ***P < 0.001. Values are means ± s.e.m.
Extended Data Figure 6 Free food consumption is not reduced with repeated daily AGRP neuron photostimulation sessions.
a, Experimental design of free feeding experiment over repeated sessions. Three groups of AGRPChR2 mice were tested on a 15 session free feeding protocol (no lever pressing required) either under food restriction (black), ad libitum fed AGRP neuron photostimulated (cyan), or ad libitum fed without AGRP neuron photostimulation (grey) conditions. On each day, mice received one 2 h session where food was freely available for the first 40 min of the session. AGRP neuron photostimulated group received photostimulation for the entire 2 h session (cyan). b, Food intake for each session of the free feeding experiment for food restricted (black, n = 6), AGRP neuron 120 min photostimulated (cyan, n = 6), and no photostimulation (grey, n = 6) groups. NS, P > 0.05. Values are means ± s.e.m.
a, Projection of confocal images of AGRP neurons from brain slices after mice expressed GCaMP6s for 10 months after viral injection. A total of >99.5% neurons show nuclear exclusion of GCaMP6s, indicating good cell health. Red arrow, rare example of filled nucleus. Scale bar, 15 µm. b, Characterization of the relationship between action potential firing rate (cell attached recordings) and change of GCaMP6f fluorescence activity in brain slices by puffing AMPA for activation (top, middle) or muscimol for inhibition (bottom). c, Epifluorescence images of AGRPGCaMP6f neurons (left) from ad libitum mice after ghrelin injection by deep-brain calcium imaging and their ROI spatial filters (right) for image analysis. Scale bar, 15 µm. d, For freely moving ad libitum fed mice during in vivo imaging, fluorescence traces of individual AGRPGCaMP6f neurons in c before and after ghrelin injection (fluorescence responses separated in time by 4 min, during which time ghrelin was injected). e, Changes in mean Ca2+ activity before and 4 min after ghrelin/saline injections (90 neurons, 4 ad libitum fed mice). f, Time course of changes in mean Ca2+ activity after ghrelin (blue) or saline (red) injection (90 neurons, 4 mice). Green dashed line, exponential fit. g, Distribution of individual time constants for decline of ghrelin-mediated fluorescence increase for individual neurons showing goodness of fit >0.85 (67/90 neurons, 4 mice). h, Baseline GCaMP6f fluorescence at the start of each trial before 1 min exposure to food/wood in each trial. i, GCaMP6f fluorescence comparing initial baseline activity, exposure to an inaccessible but visible food outside the cage, and subsequent consumption of food (60 neurons, 2 mice). NS, P > 0.05, ***P < 0.001. Multiple comparisons with Holm’s correction. Values are means ± s.e.m.
a, Schematic of injection targeting of hM3Dq-mCherry to SFO neurons. b, Epifluorescence image of mCherry fluorescence in a coronal section containing the SFO (box) targeted stereotaxically by co-injection of rAAV-hSyn-Cre and rAAV-Ef1a-DIO-hM3Dq-mCherry. Scale bar, 1 mm. c, Confocal micrograph of SFO neurons co-transduced with rAAV-hSyn-Cre and rAAV-Ef1a-DIO-hM3Dq-mCherry. Scale bar, 100 µm. d, Number of licks for a representative SFOhM3Dq mouse during evoked water consumption following activation of SFO neurons by CNO injection. e, Number of licks for SFOhM3Dq mice following saline or CNO injection (n = 5 mice). f, Cumulative lever pressing for a SFOhM3Dq mouse following injection of CNO (red) or saline (black). g, h, For SFOhM3Dq mice, lever presses (red/black: active lever, grey: inactive lever) (g) and breakpoint reinforcement ratio (h) on a PR-3 water reinforcement schedule following either saline or CNO injection (n = 5 mice). i, Top, experimental design to test if activation of SFO neurons can elicit food consumption in the absence of water. SFOhM3D mice were presented with access to food but not water for one hour (pre), which was followed by CNO injection, and food intake was measured for an additional hour. Bottom, food intake by SFOhM3D mice that lack access to water before (pre) and after the application of CNO (paired t-test, n = 3). j, Top, experimental design to test if activation or offset of SFO neurons elevate food consumption behaviour. SFONOS1-ChR2 mice had access to food and water, and both were measured before (1 h, pre), during (20 Hz, 1 h), and after photostimulation (1 h, post). Bottom, food consumed by SFONOS1-ChR2 mice before (pre), during (20 Hz), or after (post) photostimulation (paired t-test, n = 5). NS, P > 0.05. Values are means ± s.e.m.
Left, baseline Ca2+ activity in AL-fed mouse before ghrelin injection; right, 4 min after ghrelin injection. Video is 3× speed. (MOV 9953 kb)
Food rapidly reduced Ca2+ activity of AGRP neurons during food consumption of a mouse chow pellet. Video is 3× speed. (MOV 7870 kb)
GCaMP6f fluorescence in AGRP neurons was rapidly reduced by presenting inaccessible food pellets. Subsequent consumption of food also reduced AGRP neuron activity. Video is 3× speed. (MOV 6959 kb)
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Betley, J., Xu, S., Cao, Z. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015). https://doi.org/10.1038/nature14416
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