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Dissociable hindbrain GLP1R circuits for satiety and aversion

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Abstract

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.

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Fig. 1: Hindbrain GLP1R neurons mediate the anorexic and weight-loss effects of GLP1-based obesity drugs.
Fig. 2: In vivo activity dynamics of APGLP1R and NTSGLP1R neurons.
Fig. 3: APGLP1R and NTSGLP1R neurons drive aversion and satiety, respectively.
Fig. 4: Obesity drugs reduce food intake when aversion circuitry (APGLP1R neurons) is blunted.
Fig. 5: APGLP1R and NTSGLP1R neurons form discrete projections to mediate functionally dissociable behaviours.

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Data availability

Source data are provided with this paper. Transcriptomic analyses were generated from publicly-accessible data (NCBI GEO databases: GSE160938, GSE166649, GSE228192). Source data are provided with this paper.

Code availability

Custom codes generated to analyse data from the study are accessible at https://github.com/alhadefflab/2p_imaging_analysis.git.

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Acknowledgements

We thank M. Dietrich and H. Grill for comments on the manuscript; B. Arenkiel and J. Ortiz for providing viral reagents; R. Seeley for providing transgenic mice; P. Bazzino for advice on intraoral catheters; H. Grill for advice on taste-reactivity experiments; C. Ran for advice on two-photon imaging experiments; and Monell Center facilities and administrative staff for animal care and other experimental support. A.L.A. is a New York Stem Cell Foundation Robertson investigator and a Pew biomedical scholar. This work was supported by the National Institutes of Health (R00DK119574 and DP2AT011965 to A.L.A.); the American Heart Association (857082 to A.L.A. and 898990 to K.-P.H.); the New York Stem Cell Foundation (to A.L.A.); the Klingenstein Fund and Simons Foundation (to A.L.A.); the Pew Charitable Trusts (to A.L.A.); the National Science Foundation (2236662 to M.Y.G.); the Penn Institute for Diabetes, Obesity, and Metabolism (to A.L.A.); and the Monell Chemical Senses Center (to K.A.B. and A.L.A.). The confocal microscope used in these studies was purchased with instrumentation grant NIH S10OD030354 (to A.L.A.).

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Author notes

  1. These authors contributed equally: Misgana Y. Ghidewon, Aaron D. McKnight

Authors and Affiliations

  1. Monell Chemical Senses Center, Philadelphia, PA, USA

    Kuei-Pin Huang, Alisha A. Acosta, Misgana Y. Ghidewon, Aaron D. McKnight, Milena S. Almeida, Nathaniel T. Nyema, Nicholas D. Hanchak, Nisha Patel, Yenoukoume S. K. Gbenou, Kevin A. Bolding & Amber L. Alhadeff

  2. Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA

    Misgana Y. Ghidewon, Aaron D. McKnight, Kevin A. Bolding & Amber L. Alhadeff

  3. Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK

    Alice E. Adriaenssens

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Contributions

K.-P.H., M.Y.G., A.D.M. and A.L.A. conceived and designed the experiments. K.-P.H., A.A.A., M.Y.G., A.D.M., M.S.A., N.T.N., N.D.H., N.P., Y.S.K.G., A.E.A., K.A.B. and A.L.A. performed experiments, analysed data and/or interpreted data; A.L.A. wrote the manuscript with comments from K.-P.H. and all authors.

Corresponding author

Correspondence to Amber L. Alhadeff.

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The authors declare that the Monell Chemical Senses Center has filed a patent application related to potential therapeutic compounds.

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Extended data figures and tables

Extended Data Fig. 1 DVCGLP1R neurons are required for the food intake suppression and weight loss effects of GLP1-based obesity drugs.

a, Representative image and quantification of viral expression (EGFP) in Glp1r-expessing neurons of Glp1r-ires-Cre mice (RNA in situ hybridization). b, Representative images of Glp1r expression (RNA in situ hybridization) in the DVC, ARC, and NG of control mice or mice with GLP1R neuron ablation in each region. c, Quantification of Caspase3- or DTA-mediated neural ablation: relative number (to controls) of GLP1R+ neurons in DVC (left), ARC (middle), and NG (right) of mice with viral injection into DVC, ARC, or NG, respectively (n = 3-5 mice/group, two-sided unpaired t-tests, all ps < 0.01). d, Food intake following IP injection of saline or exendin-4 in fasted control or GLP1R-ablated mice (n = 8-14 mice/group, two-way repeated measures ANOVAs, all ps < 0.01 except DVC where p=ns). e, Body weight at 8 weeks post-surgery in control, DVC, ARC, and NG GLP1R neuron ablation groups (n = 7-8 mice/group, one-way ANOVA, p=ns). f, Percent body weight change during the onset of diet-induced obesity in high-fat diet-fed control (EGFP) or DVCGLP1R neuron-ablated mice receiving semaglutide (n = 11-15 mice/group, two-way repeated measures ANOVA, control versus DVC-Casp3, p < 0.001). g–i, Fat mass (g, n = 11-15 mice/group, two-way ANOVA, Control versus DVC-Casp at 8 and 12 weeks: p < 0.001), lean mass (h, n = 11-15/group, two-way ANOVA, all ps=ns) and cumulative food intake (i, n = 11-13 mice/group, two-sided unpaired t-test, p < 0.05) in high-fat diet-fed control or DVC GLP1R-ablated mice over 12 weeks of biweekly SQ semaglutide. Values are mean ± S.E.M. ¤¤p < 0.01, ¤¤¤p < 0.001 drug x time interaction; *p < 0.05, **p < 0.01, ***p < 0.001 post hoc comparisons. See Supplementary Table 1 for statistical details.

Source Data

Extended Data Fig. 2 DVCGLP1R neuron activation suppresses food intake and energy expenditure.

a, Schematic for continuous food intake and energy expenditure measurements using mouse metabolic chambers. b, Cumulative food intake in high-fat diet-fed control mice or mice with chronic NaChBac-mediated DVCGLP1R neuron activation (n = 7-8 mice/group, two-way repeated measures ANOVA, control versus NaChBac: p < 0.001). Shaded areas represent dark periods. c, Average inter-meal interval of high-fat diet-fed control mice or mice with chronic NaChBac-mediated DVCGLP1R neuron activation (n = 7-8 mice/group, two-sided unpaired t-test, control versus NaChBac: p < 0.01). d, Average meal size in high-fat diet-fed control mice or mice with chronic NaChBac-mediated DVCGLP1R neuron activation (n = 7-8 mice/group, two-sided unpaired t-test, control vs. NaChBac: p=ns). e, Energy expenditure in high-fat diet-fed control mice or mice with chronic NaChBac-mediated DVCGLP1R neuron activation (n = 7-8 mice/group). Shaded area represents dark period. f, Dark period energy expenditure normalized to lean mass by ANCOVA in high-fat diet-fed control mice or mice with chronic NaChBac-mediated DVCGLP1R neuron activation (n = 7-8 mice/group, ANCOVA, p = 0.06). g, Energy expenditure in fasted chow-fed control mice or mice with chemogenetic DVCGLP1R neuron activation (n = 8 mice/group). Shaded area represents dark period. h, Dark period energy expenditure normalized to body mass by ANCOVA in chow-fed control mice or mice with chemogenetic DVCGLP1R neuron activation (n = 8 mice/group, ANCOVA, p < 0.001). Values are mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 3 Imaging APGLP1R and NTSGLP1R neurons.

a, Coronal images of soma-restricted AAV5-EF1a-DIO-EGFPL10a in the DVC of Glp1r-ires-Cre mice across the rostral-caudal axis. Scale bar, 100 µm. b, Quantification of GLP1R neurons in AP and NTS across the rostral-caudal axis (n = 3 mice/group). c, Coronal images of soma-restricted AAV5-EF1a-DIO-EGFPL10a in the DVC of Glp1r-ires-Cre;Ai9(tdTomato) mice. Images depict the dense GLP1R projection into the NTS but not into the AP. Scale bar, 100 µm. d, Maximum projection two-photon images (transverse plane) of the DVC from Glp1r-ires-Cre;Ai9(tdTomato) mice injected with Cre-dependent GCaMP6s depicting the red halo of GLP1R projections into the NTS, part of the strategy to draw boundaries between AP and NTS (see Methods for additional details). Scale bar, 100 µm. e, Two-photon images of the DVC from Glp1r-ires-Cre;Ai9(tdTomato) mice injected with Cre-dependent GCaMP6s across the z-axis. AP and NTS neurons are visible on all imaging planes because of the angle of the medulla for imaging (see Methods for additional details). f, Top, schematic for simultaneous in vivo two-photon imaging of APGLP1R and NTSGLP1R neurons in mice. Bottom, images of surgical prep and cranial window for in vivo two-photon imaging of calcium dynamics in APGLP1R and NTSGLP1R neurons. g, Proportion of APGLP1R and NTSGLP1R neurons activated by semaglutide (n = 5 mice, two-sided paired t-test, p=ns). h, Heat maps depicting z-scored responses of semaglutide-activated APGLP1R (n = 678 neurons, 5 mice) and NTSGLP1R (n = 388 neurons, 5 mice) neurons sorted by activation time. i, Median time to semaglutide-induced activation in APGLP1R and NTSGLP1R neurons depicted in h (n = 5 mice, two-sided unpaired t-test, p=ns). j, Mean time to semaglutide-induced activation in APGLP1R and NTSGLP1R neurons depicted in h (n = 5 mice, two-sided unpaired t-test, p=ns). Values are mean ± S.E.M. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 4 In vivo responses of APGLP1R and NTSGLP1R neurons to nutritive and aversive stimuli.

a, Heat maps depicting z-scored responses of APGLP1R neurons (n = 375 neurons, 5 mice) and NTSGLP1R neurons (n = 266 neurons, 5 mice) to saline or Ensure. Dashed white lines indicate start of stimulus. b, Average z-scored activity responses in APGLP1R neurons (blue) and NTSGLP1R neurons (green) to saline or Ensure administration (n = 6 mice, two-way ANOVA, AP: saline versus Ensure: p < 0.01, NTS: saline versus Ensure p < 0.001). c, Individual data points comparing APGLP1R (blue) and NTSGLP1R (green) neuron z-scored activity responses to saline and semaglutide. Dotted lines represent threshold for statistically significant neural activation (z = 1.64, see Methods for additional details). d, Individual heat maps for each mouse (n = 7) depicting z-scored responses of APGLP1R and NTSGLP1R neurons to Ensure or cinacalcet. e, Representative two-photon images of GCaMP6s across the z axis with neurons colour-coded based on responses to Ensure (most responsive in blue, index = −10) and cinacalcet (most responsive in red, index=10). AP/NTS boundary indicated in yellow. f, Individual heat maps for each mouse (n = 6) depicting z-scored responses of APGLP1R and NTSGLP1R neurons to Ensure or LiCl. g, Probability calculations for activation of individual cells by Ensure or aversive stimuli (n = 6-7 mice/group, two-sided paired t-tests, p < 0.001). We compare the product of the probabilities of a neuron being activated by either Ensure or aversive stimuli [P(Ensure) x P(cinacalcet) or P(Ensure) x P(LiCl)] to the probability of a neuron being activated by both stimuli [P(Ensure and cinacalcet) or P(Ensure and LiCl)]. That the probability of a cell being activated by both stimuli is generally lower than the product of individual probabilities suggests a level of specialization of individual cells where most are biased toward nutritive or aversive stimuli, with less overlap than would be expected by chance. Values are mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 5 Comparison of motion correction strategies for extracting calcium dynamics.

To determine whether alternate motion correction strategies improved calcium imaging analyses in our setup, we compared rigid-body motion correction (“Rigid”) with two other strategies (and the two strategies combined). First, we applied the piecewise rigid function (“pw-rigid”) in NoRMCorre to create a grid within each of our images, where each patch of the grid was corrected to better adjust for non-rigid distortions. Second, we applied PyStackReg to realign all frames using an affine transformation. We compared the resulting proportions of activated neurons and individual neuron calcium traces for each method. Although these alternate motion correction strategies did not significantly change our data, we note for readers that some imaging preparations (especially those that have more ROIs around the edges of frames) may require such strategies. a, Comparison of proportions of neurons activated by nutritive (Ensure, blue), aversive (cinacalcet, pink), or both (green) stimuli in APGLP1R and NTSGLP1R neurons across one z-level from each of two example mice chosen at random, after imaging analysis following different motion correction strategies. b, Comparison of individual neuron calcium traces in APGLP1R and NTSGLP1R neurons activated by nutritive (Ensure, blue), aversive (cinacalcet, pink), or both (green) stimuli after imaging analysis following different motion correction strategies. Traces were chosen pseudo-randomly, excluding neurons that were not selected as ROIs in each of the four analyses [these, however, were included in a, where we did not exclude any neurons], and accounting for representation of Ensure-activated, cinacalcet-activated, and both-activated neurons where possible.

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Extended Data Fig. 6 Real-time and conditioned orofacial taste reactivity in mice.

a,b, Schematics of stereotyped hedonic (a) and aversive (b) orofacial responses in mice. Modified from schematics in ref. 22. c,d, Composite score (c, n = 5-10 mice/group, one-way ANOVA, all ps<0.05) and individual behaviours (d, n = 5-10 mice/group, two-way ANOVA, all ps<0.001) for hedonic taste reactivity responses to quinine concentrations (0, 2.4, 4 mM). e,f, Composite score (e, n = 5-10 mice/group, one-way ANOVA, all ps<0.01) and individual behaviours (f, 5-10 mice/group, two-way ANOVA, all ps<0.05) for aversive taste reactivity responses to quinine concentrations (0, 2.4, 4 mM). g,h, Composite scores (g, n = 6 mice/group, two-sided paired t-tests, ps<0.05) and individual behaviours (h, 6 mice/group, two-way ANOVA, RMM: p < 0.05, G: p < 0.001) for real-time hedonic and aversive taste reactivity responses to a flavour paired with cinacalcet (15 µmol/kg, IP). i,j, Composite scores (i, n = 6 mice/group, two-sided paired t-tests, aversive: p < 0.05) and individual behaviours (j, 6 mice/group, two-way ANOVA, G: p < 0.001) for conditioned hedonic and aversive taste reactivity responses to a flavour paired with cinacalcet (15 µmol/kg, IP). k,l, Composite scores (k, n = 5 mice/group, two-sided paired t-tests, ps<0.01) and individual behaviours (l, 6 mice/group, two-way ANOVA, RMM: p < 0.001, PL: p < 0.05, G: p < 0.001, CR: p < 0.001) for real-time hedonic and aversive taste reactivity responses to a flavour paired with LiCl (6 mmol/kg, IP). m,n, Composite scores (m, n = 5 mice/group, two-sided paired t-tests, ps<0.05) and individual behaviours (n = 6 mice/group, two-way ANOVA, RMM: p < 0.05, G: p < 0.001, CR: p < 0.05) for conditioned hedonic and aversive taste reactivity responses to a flavour paired with LiCl (6 mmol/kg, IP). o, Schematic for chemogenetic stimulation of DVCGLP1R neurons. p,q, Individual hedonic taste reactivity behaviours at baseline and after conditioning in control (p, n = 6 mice/group, two-way ANOVA, all ps=ns) and experimental (q, n = 7 mice/group, two-way ANOVA, RMM: p < 0.001, LTP: p < 0.05) mice. r,s, Individual aversive taste reactivity behaviours at baseline and after conditioning in control (r, n = 6 mice/group, two-way ANOVA, all ps=ns) and experimental (s, n = 7 mice/group, two-way ANOVA, G: p < 0.01, CR: p < 0.001) mice. Values are mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 7 Number of APGLP1R, but not NTSGLP1R, neurons expressing chemogenetic receptors correlates with avoidance behaviour.

a, Representative image of hM3Dq expression in the DVC (AP and NTS). b, Correlation between the number of hM3Dq-expressing neurons (x-axis) and behaviour [y-axis; avoidance (CS+ intake in CFA assay) or anorexia (food intake) elicited by DVCGLP1R neuron stimulation] in the AP (left graphs) or NTS (right graphs) (n = 9 mice, Pearson correlation, p < 0.05 for AP/avoidance, other ps=ns). Red colour indicates statistical significance. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 8 APGLP1R and NTSGLP1R neurons are largely unique populations of hindbrain neurons with dissociable behavioural effects.

a,b, Schematic and representative images of viral (AAV2.2-FLEX-tdTomato) separation of AP (a) and NTS (b) using 20 nl intracranial injections. c, Quantification of tdTomato-expressing GLP1R neurons in AP and NTS after viral injection into AP (n = 3 mice). d, Quantification of tdTomato-expressing GLP1R neurons in AP and NTS after viral injection into NTS (n = 3 mice). e, Strategy for viral injections to directly compare behavioural results of activation of DVCGLP1R, APGLP1R, and NTSGLP1R neurons: we used the same viral serotype and injection protocol to activate neurons in each of these regions. f, 12-h food intake in mice following activation of DVCGLP1R, APGLP1R, and NTSGLP1R neurons (n = 7-11 mice/group, two-way ANOVA, all ps<0.001). g, Meal size in fasted mice following chemogenetic activation of APGLP1R or NTSGLP1R neurons (n = 10-11 mice/group, two-way ANOVA, APGLP1R-hM3Dq vehicle versus CNO: p < 0.001, NTSGLP1R-hM3Dq vehicle versus CNO: p=ns). h,i, Energy expenditure in fasted mice with chemogenetic APGLP1R (h) or NTSGLP1R (i) neuron activation (n = 11 mice/group). Shaded area represents dark period. j, Dark period energy expenditure normalized to body mass by ANCOVA in mice with chemogenetic APGLP1R (blue) or NTSGLP1R (green) neuron activation (n = 11 mice/group, ANCOVA, p=ns). k, Schematic describing protocol for taste reactivity experiments. l,m, Individual hedonic taste reactivity behaviours at baseline and after conditioning with chemogenetic APGLP1R (l, n = 8 mice, two-way ANOVA, RMM baseline versus conditioned p < 0.001) or NTSGLP1R (m, n = 5 mice, two-way ANOVA, all ps=ns) neuron activation. n,o, Individual aversive taste reactivity behaviours at baseline and after conditioning with chemogenetic APGLP1R (n, n = 8 mice, two-way ANOVA, CR baseline versus conditioned: p < 0.001) or NTSGLP1R (o, n = 5 mice, two-way ANOVA, all ps=ns) neuron activation. p, Uniform manifold approximation and projection (UMAP) plot showing AP and NTS neuron subtypes. Analysis was made after combining data sets from ref. 13, ref. 16, and ref. 17, which all contained cells from both the AP and NTS. q, Dot plots indicating normalized expression of genes in Glp1r+ cells of the AP and NTS. Values are mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 9 Deletion of GLP1R in DVC attenuates anorexia and aversion by obesity drugs.

a, Schematic for deletion of GLP1R in DVC neurons using Glp1rfl/fl mice and injection of AAV2.2-Cre. b, Quantification of efficacy of GLP1R deletion: relative number of Glp1r+ neurons in the DVC in WT and Glp1rfl/fl mice after DVC injection of AAV2.2-Cre (n = 3 mice/group, two-sided unpaired t-test, p < 0.001). c, Mice underwent a conditioned flavour avoidance assay to semaglutide. d, Intake of flavour paired with semaglutide (CS+) in control (WT) or DVC GLP1R-deleted (Glp1rfl/fl) mice before (baseline) and after conditioning (n = 6-8 mice/group, two-way ANOVA, WT baseline versus conditioned: p < 0.001, Glp1rfl/fl baseline vs. conditioned: p=ns). e, Food intake (4 h) was measured in response to exendin-4 or semaglutide. For exendin-4 studies, food was returned immediately after injection. For semaglutide studies, food was returned 4 h post-injection. f, Food intake in response to exendin-4 in WT and Glp1rfl/fl mice (e, n = 6-7 mice/group, two-way ANOVA, WT: p < 0.01, Glp1rfl/fl: p=ns). g, Food intake in response to semaglutide in WT and Glp1rfl/fl mice (e, n = 7-8 mice/group, two-way ANOVA, WT: p < 0.05, Glp1rfl/fl: p=ns). Values are mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for statistical details.

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Extended Data Fig. 10 Representative images and injection verifications for neural tracing experiments.

a, Representative image of viral expression of AAV5-DIO-ChR2-EYFP at the injection site (DVC: AP and NTS) of Glp1r-ires-Cre mice (n = 3 mice). cc, central canal; DMV, dorsal motor nucleus of the vagus. b–f, Representative images of DVCGLP1R axons in brain regions involved in feeding behaviour: lPBN (b), PVH (c), ARC (d), BNST (e), CeA (f). Boxes indicate zoomed in regions. 3 V, third ventricle; ac, anterior commissure; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; LV, lateral ventricle; Scp, superior cerebellar peduncle. g, Left, Cre-dependent H129-ΔTK-TT was injected into the DVC of Glp1r-ires-Cre mice (n = 3). Right, representative image of starter cells for anterograde H129-ΔTK-TT-mediated tracing from DVCGLP1R neurons. h, Schematic of mechanism for fluorophore expression using PRV-263. i, Glp1r-ires-Cre mice (n = 3 mice/group) were injected in the lPBN or PVH with PRV-263 and DVC brain sections were imaged for retrogradely-transported Cre-positive (GLP1R+, mCerulean/EYFP, green) and Cre-negative (GLP1R−, tdTomato, red) neurons in the AP and NTS. j, Representative image of lPBN injection site. Scale bar, 200 µm. k, Representative image of PVH injection site. Scale bar, 100 µm. l, Representative images of PRV-263 in Cre-positive (GLP1R+, mCerulean/EYFP, green) and Cre-negative (GLP1R-, tdTomato, red) neurons of the AP and NTS after viral injection in the lPBN (left) or PVH (right). Distances indicate mm from bregma. Scale bar, 50 µm. m, Representative image of injection site in AP after injection of Cre-dependent AAV2.2-DIO-ChR2-EYFP in APGLP1R neurons in Glp1r-ires-Cre mice (n = 3 mice). Scale bar, 50 µm. n, Representative image of PVH in mouse with EYFP injection in APGLP1R neurons. Scale bar, 50 µm. o, Representative images of PBN projections across the rostral-caudal axis, distances indicate mm from bregma. p, Representative image of injection site in NTS after injection of Cre-dependent AAV2.2-DIO-ChR2-EYFP in NTSGLP1R neurons in Glp1r-ires-Cre mice (n = 3 mice). Scale bar, 50 µm. q, Representative image of lPBN in mouse with EYFP injection in NTSGLP1R neurons. Scale bar, 50 µm. r, Representative images of PVH projections across the rostral-caudal axis, distances indicate mm from bregma. Scale bar, 100 µm.

Extended Data Fig. 11 Neural activation in the lPBN and PVH with DVCGLP1R neuron stimulation.

a, Schematic for RNA in situ hybridization for Fos and CGRP (Calca) in lPBN or Fos and Mc4r in PVH after chemogenetic stimulation of DVCGLP1R neurons. b, Representative images (left) and quantification (right) of colocalization of Fos and Calca in the lPBN after control (vehicle) or chemogenetic (CNO) stimulation (n = 3 mice/group, two-sided unpaired t-test, p < 0.05). elPBN, external lateral PBN; clPBN, central lateral PBN. c, Representative images (left) and quantification of colocalization (right) of Fos and Mc4r in the PVH after control (vehicle) or chemogenetic (CNO) stimulation (n = 3 mice/group, two-sided unpaired t-test, p < 0.01). Values are mean ± S.E.M. *p < 0.05, **p < 0.01.

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Extended Data Fig. 12 Behavioural effects of APGLP1R→lPBN and NTSGLP1R→PVH neuron optogenetic activation.

a,b, Food intake (1 h) in control mice expressing EYFP in APGLP1R→lPBN (a, n = 6 mice, paired t-test, p=ns) and NTSGLP1R→PVH (b, n = 5 mice, two-sided paired t-test, p=ns) neurons. (Grey bars (−), no stimulation; coloured bars (+), stimulation). c,d, Time spent in stimulation zone during real-time place avoidance assay in ad libitum-fed control mice expressing EYFP in APGLP1R→lPBN (c, n = 5-6 mice/group, two-way ANOVA, all ps=ns) or NTSGLP1R→PVH (d, n = 5 mice, two-way ANOVA, all ps=ns) neurons. e,f, Time spent in stimulation zone during real-time place avoidance assay in fasted control mice expressing EYFP in APGLP1R→lPBN (e, n = 5-6 mice/group, two-way ANOVA, all ps=ns) or NTSGLP1R→PVH (f, n = 5-6 mice/group, two-way ANOVA, all ps=ns). g,h, Time spent in stimulation zone during real-time place avoidance assay in ad libitum-fed mice expressing ChR2 in APGLP1R→lPBN (g, n = 10-11 mice/group, two-way ANOVA, Trials 2&3 no stim versus stim: ps<0.05) or NTSGLP1R→PVH (h, n = 7 mice, two-way ANOVA, all ps=ns). i,j, Time spent in stimulation zone during real-time place avoidance assay in fasted mice expressing ChR2 in APGLP1R→lPBN (i, n = 11 mice, two-way ANOVA, all ps=ns) or NTSGLP1R→PVH (j, n = 7 mice, two-way ANOVA, all ps=ns) neurons. k,l, Individual hedonic taste reactivity behaviours at baseline (pre-stimulation) and during optogenetic stimulation of APGLP1R→lPBN (k, n = 6 mice, two-way ANOVA, RMM and LTP no stim versus stim: ps<0.05) or NTSGLP1R→PVH (l, n = 6 mice, two-way ANOVA, all ps=ns) neurons. m,n, Individual aversive taste reactivity behaviours at baseline (pre-stimulation) and during optogenetic stimulation of APGLP1R→lPBN (m, n = 6 mice, two-way ANOVA, CR no stim versus stim: p < 0.001) or NTSGLP1R→PVH (n, n = 6 mice, two-way ANOVA, all ps=ns) neurons. Grey bars, no stimulation; coloured bars, optogenetic stimulation. Values are mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for statistical details.

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Supplementary information

Supplementary Table 1

Sample sizes and statistical details for all figures and Extended Data figures.

Reporting Summary

Supplementary Video 1

3D reconstruction of DVCGLP1R neurons following injection of Glp1r-ires-Cre mouse with a Cre-dependent AAV expressing a soma-restricted fluorophore.

Supplementary Video 2

Raw, motion-corrected video (left) and dF/F video (right) of in vivo two-photon calcium imaging of DVCGLP1R neurons.

Supplementary Video 3

Examples of hedonic and aversive orofacial taste reactivity responses.

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Huang, KP., Acosta, A.A., Ghidewon, M.Y. et al. Dissociable hindbrain GLP1R circuits for satiety and aversion. Nature (2024). https://doi.org/10.1038/s41586-024-07685-6

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