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A neural circuit for the suppression of feeding under persistent pain

Abstract

In humans, persistent pain often leads to decreased appetite. However, the neural circuits underlying this behaviour remain unclear. Here, we show that a circuit arising from glutamatergic neurons in the anterior cingulate cortex (GluACC) projects to glutamatergic neurons in the lateral hypothalamic area (GluLHA) to blunt food intake in a mouse model of persistent pain. In turn, these GluLHA neurons project to pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus (POMCArc), a well-known neuronal population involved in decreasing food intake. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that the GluACC → GluLHA → Arc circuit is activated in mouse models of persistent pain and is accompanied by decreased feeding behaviour in both males and females. Inhibition of this circuit using chemogenetics can alleviate the feeding suppression symptoms. Our study indicates that the GluACC → GluLHA → Arc circuit is involved in driving the suppression of feeding under persistent pain through POMC neuronal activity. This previously unrecognized pathway could be explored as a potential target for pain-associated diseases.

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Fig. 1: Food intake is suppressed in CFA mice.
Fig. 2: The GluACC neurons are activated in CFA 10 d mice.
Fig. 3: GluACC neurons project to GluLHA neurons.
Fig. 4: The GluACC → GluLHA pathway mediates CFA-induced suppression of food intake.
Fig. 5: GluLHA neurons project to POMCArc neurons.
Fig. 6: The GluLHA → POMCArc pathway modulates the suppression of food intake induced by persistent pain.
Fig. 7: Characterization of the ACC → LHA → Arc circuit.

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Acknowledgements

We thank Guo-Qiang Bi for providing Vgat-Cre mice. This work was supported by the National Key Research and Development Program of China (2021ZD0203100 to Z.Z.), the National Natural Science Foundation of China (grants 32025017, 32121002 (to Z.Z.) and 32100808 (to X.Z.)), CAS Project for Young Scientists in Basic Research (YSBR-013, to Z.Z.), the China National Postdoctoral Program for Innovative Talents (BX2021286, to X.Z.), the China Postdoctoral Science Foundation (2020M682018, to X.Z.), the Fundamental Research Funds for the Central Universities (WK9100000005, to X.Z.) and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20211902, to Z.Z.).

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Authors and Affiliations

Authors

Contributions

J.L., J.-M.Y., X.Z. and Z.Z. conceptualized the study; H.-D.T., W.-Y.D. and R.H. performed most of the experiments; J.-Y.H. and Z.-H.H. conducted some of the behavioural experiments; H.-D.T., J.L., J.-M.Y., X.Z. and Z.Z. were responsible for writing; W.X. and T.X. were involved in the revision of the final manuscript; and Z.Z. supervised the study.

Corresponding authors

Correspondence to Ji Liu, Jun-Ma Yu, Xia Zhu or Zhi Zhang.

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The authors declare no competing interests.

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Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 The GluACC neurons are activated in CFA mice.

a, Representative images of c-Fos expression. Scale bars, 200 µm. b, Representative images (left) and statistical analysis (right) showing that c-Fos-labeled neurons in the ACC of CFA 10 d mice predominantly colocalized with the glutamate antibody (n = 7 slices from 6 mice). Scale bar, 10 µm. c, Rheobase values recorded from the GluACC neurons (Saline, n = 49 cells from 8 mice; CFA, n = 43 cells from 7 mice). d, Sample traces of voltage responses to a stepwise series of hyperpolarizing currents (0 to −50 pA, −10 pA/step; duration: 500 ms) recorded in GluACC neurons of the saline (upper left) and CFA (lower left) groups and voltage-current plots derived from these traces (right). e,f, RMP (e) and Rin (f) data from each group (Saline, n = 49 cells from 8 mice; CFA, n = 43 cells from 7 mice). g, An example spike sorting result from a single tetrode in the ACC. h, Example recording of spontaneous and light-evoked spikes from a GluACC neuron. i, Overlay of light-evoked (blue) and averaged spontaneous (orange) spike waveforms from the example unit. j, Whole-cell recording showing the effects of CNO on AAV-DIO-mCherry- or AAV-DIO-hM4Di-mCherry-expressing GluACC neurons (n = 3 cells from 3 mice per group). k, Example recording of spontaneous spikes (left) and statistical data (right) showing the firing rates of GluACC neurons in CaMK2-Cre mice injected with AAV-DIO-mCherry or AAV-DIO-hM4Di-mCherry (mCherry, n = 49 cells from 4 mice; hM4Di-mCherry, n = 44 cells from 4 mice). l,m, Spatial location heatmaps (l) and quantitative analysis (m) from free feeding tests of CFA mice with chemogenetic inhibition of GluACC neurons (n = 10 mice per group; left, F3,36 = 17.44, P < 0.0001; right, F3,36 = 59.74, P < 0.0001). Significance was assessed by two-tailed nested t test in (c,e and f), two-way repeated-measures ANOVA with post hoc comparison between groups in (j), two-tailed unpaired Student’s t test in (k), and one-way ANOVA with post hoc comparison between groups in (m). All data are presented as the mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001.

Source data

Extended Data Fig. 2 Mapping outputs of GluACC neurons.

a, Schematic of viral injection. b, Representative confocal image of AAV-DIO-ChR2-mCherry expression in the ACC. Scale bar, 200 µm. c, Representative confocal images of mCherry+ fiber expression in the CPu, BLA, MDL and VM of CaMK2-Cre mice injected AAV-DIO-ChR2-mCherry into the ACC. Scale bars, 50 µm. d, Schematic of viral injection. e,f, Representative confocal image of AAV-DIO-ChR2-mCherry expression in the ACC and in the PVT, Arc, PBN and Sol. Scale bars, 200 µm (e) and 50 µm (f). CPu, caudate putamen. BLA, basolateral amygdaloid nucleus. MDL, mediodorsal thalamic nucleus. VM, ventromedial thalamic nucleus. PVT, paraventricular thalamic nucleus. PBN, parabrachial nucleus. Sol, nucleus of the solitary tract.

Extended Data Fig. 3 Mapping inputs of GluLHA neurons and GABALHA neurons.

a, Schematic of viral injection. b, Representative confocal image of the starter neurons (yellow) within the LHA of VgluT2-Cre mice. Scale bar, 200 µm. The white box depicting the area shown in the box of the LHA. Scale bar, 10 µm. c, Representative confocal images of DsRed+ neurons expression in the MPA, PVN, CeA and DRD of mice injected with helper and RV-EvnA-DsRed into the LHA. Scale bars, 200 µm. d, Schematic of viral injection. e, Representative confocal images of the starter neurons (yellow) within the LHA of Vgat-Cre mice. Scale bar, 200 µm. The white box depicting the area shown in the box of the LHA. Scale bar, 10 µm. f,g, Representative confocal images of RV-DsRed expression in the ACC and in the PVN, CeA, and RtTg. Scale bars, 200 µm. MPA, medial preoptic area. PVN, paraventricular hypothalamic nucleus. CeA, amygdala. DRD, dorsal raphe nucleus. RtTg, reticulotegmental nucleus of the pons.

Extended Data Fig. 4 Enhanced excitability of GluLHA neurons in CFA 10 d mice are reversed by chemogenetic inhibition of GluACC neurons.

a, Representative confocal images (left) and statistical analysis (right) showing c-Fos-positive neurons in the LHA of saline and CFA 10 d mice injected with AAV-DIO-mCherry or AAV-DIO-hM4Di-mCherry into the ACC (n = 8 slices from 6 mice per group; F2,21 = 81.58, P < 0.0001). Scale bars, 200 µm. b, Representative confocal images (left) and statistical analysis (right) showing that c-Fos-labeled neurons in the LHA of CFA 10 d mice predominantly colocalized with the glutamate antibody (n = 7 slices from 6 mice). Scale bar, 10 µm. c, Sample traces of voltage responses to a stepwise series of hyperpolarizing currents (0 to −50 pA, −10 pA/step; duration: 500 ms) recorded in GluLHA neurons of saline::mCherry (top), CFA::mCherry (upper middle), and CFA::hM4Di-mCherry (lower middle) groups and voltage-current plots derived from these traces (bottom). d,e, RMP (d) and Rin (e) data of the three groups (Saline::mCherry, n = 40 cells from 8 mice; CFA::mCherry, n = 47 cells from 8 mice; CFA::hM4Di-mCherry, n = 47 cells from 8 mice; d, F2,21 = 12.57, P < 0.001). Significance was assessed by one-way ANOVA with post hoc comparison between groups in (a), and nested one-way ANOVA with post hoc comparison between groups in (d and e). All data are presented as the mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001.

Source data

Extended Data Fig. 5 The effects of activation of GluLHA neurons on food intake.

a, Schematic of viral injection and chemogenetic activation design. b, Representative confocal image of AAV-DIO-hM3Dq-mCherry expression in the LHA of VgluT2-Cre mice. Scale bar, 200 µm. c, Whole-cell recording showing the effects of CNO on AAV-DIO-mCherry- or AAV-DIO-hM3Dq-mCherry-expressing GluLHA neurons (mCherry, n = 3 cells from 3 mice; hM3Dq-mCherry, n = 4 cells from 4 mice). d, Example recording of spontaneous spikes (left) and statistical data (right) showing the GluLHA firing rates in VgluT2-Cre mice injected with AAV-DIO-mCherry or AAV-DIO-hM3Dq-mCherry (mCherry, n = 53 cells from 5 mice; hM3Dq-mCherry, n = 55 cells from 5 mice). e, Effects of chemogenetic activation of GluLHA neurons on food intake in mice deprived of food for 24-hour (mCherry, n = 12 mice; hM3Dq-mCherry, n = 11 mice; F1,21 = 14.67, P = 0.001). f, Spatial location heatmaps from free feeding tests of mice deprived of food for 24-hour and chemogenetic activation of GluLHA neurons. g, Quantitative analysis of time in the food zone (%) (left) and food intake (right) for mice as indicated in (f) (n = 11 mice per group; left, t20 = 6.175, P < 0.0001; right, t20 = 3.607, P = 0.002). h, Effects of chemogenetic activation of GluLHA neurons on pain threshold in CFA 10 d mice (mCherry, n = 12 mice; hM3Dq-mCherry, n = 11 mice). Significance was assessed by two-way repeated-measures ANOVA with post hoc comparison between groups in (c and e), and two-tailed unpaired Student’s t test in (d,g and h). All data are presented as the mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001.

Source data

Extended Data Fig. 6 Mapping outputs of GluLHA neurons and inputs of POMCArc neurons.

a, Schematic of viral injection. b, mCherry+ fiber expressions at different bregma sites in the Arc of mice injected AAV-DIO-ChR2-mCherry into the LHA. Scale bars, 100 μm. c, Schematic of viral injection. d, Representative confocal image of AAV-DIO-ChR2-mCherry expression in the LHA. Scale bar, 200 µm. e, Representative confocal images of mCherry+ fiber expression in the LHb, PF, SNR and PAG of mice injected AAV-DIO-ChR2-mCherry into the LHA. Scale bars, 50 µm. f, Schematic of viral injection. g, Representative confocal images of RV-DsRed expression in the PVT, opt, PVN and VMH, but not the ACC from mice injected with helper and RV-EvnA-DsRed into the Arc. Scale bars, 50 µm. LHb, lateral habenular nucleus. PF, parafascicular thalamic nucleus. SNR, substantia nigra, reticular part. PAG, periaqueductal gray. opt, olivary pretectal nucleus. PVN, paraventricular hypothalamic nucleus. VMH, ventromedial hypothalamic nucleus.

Extended Data Fig. 7 Enhanced excitability of POMCArc neurons in CFA 10 d mice are reversed by chemogenetic inhibition of GluLHA neurons.

a, Representative confocal images (left) and statistical data (right) showing c-Fos-positive neurons in the Arc of saline and CFA mice injected with AAV-DIO-mCherry or AAV-DIO-hM4Di-mCherry into the LHA (n = 8 slices from 6 mice per group; F2,21 = 43.91, P < 0.0001). Scale bars, 50 µm. b, Representative confocal images (left) and statistical data (right) showing that c-Fos-labeled neurons in the Arc of CFA 10 d mice predominantly colocalized with the POMC antibody (n = 7 slices from 6 mice). Scale bar, 10 µm. c, Sample traces of voltage responses to a stepwise series of hyperpolarizing currents (0 to −50 pA, −10 pA/step; duration: 500 ms) recorded in POMCArc neurons of saline::mCherry (top), CFA::mCherry (upper middle), and CFA::hM4Di-mCherry (lower middle) groups and voltage-current plots derived from these traces (bottom). d,e, RMP (d) and Rin (e) data of the three groups (Saline::mCherry, n = 47 cells from 8 mice; CFA::mCherry, n = 50 cells from 9 mice; CFA::hM4Di-mCherry, n = 52 cells from 9 mice). Significance was assessed by one-way ANOVA with post hoc comparison between groups in (a), and nested one-way ANOVA with post hoc comparison between groups in (d and e). All data are presented as the mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001.

Source data

Extended Data Fig. 8 The effects of chemogenetic activation or inhibition of POMCArc neurons on food intake.

a, Schematic of viral injection. b, Spatial location heatmaps from free feeding tests of CFA mice with chemogenetic inhibition of POMCArc neurons. c, Quantitative analysis of time spent in the food zone (%) (left) and food intake (right) for mice as indicated in (b) (mCherry, n = 13 mice; hM4Di-mCherry, n = 10 mice; left, t21 = 9.924, P < 0.0001; right, t21 = 11.80, P < 0.0001). d, Effects of chemogenetic inhibition of POMCArc neurons on pain threshold in CFA 10 d mice (mCherry, n = 13 mice; hM4Di-mCherry, n = 10 mice). e, Schematic of viral injection. f, Representative confocal image of AAV-DIO-hM3Dq-mCherry expression in the Arc of POMC-Cre mice. Scale bar, 100 µm. g, Effects of chemogenetic activation of POMCArc on food intake in mice deprived of food for 24-hour (n = 10 mice per group). h, Effects of chemogenetic activation of POMCArc neurons on the pain threshold in POMC-Cre mice (n = 10 mice per group). Significance was assessed by two-tailed unpaired Student’s t test in (c,d and h), and two-way repeated-measures ANOVA with post hoc comparison between groups in (g). All data are presented as the mean ± SEM. ** P < 0.01, *** P < 0.001.

Source data

Extended Data Fig. 9 Identification of the GluACC → GluLHA → POMCArc circuit.

a, Schematic of a triple tracing strategy. b, Representative confocal images of DsRed+ neurons expression in the BNST, PVN, CeA and PBN of mice. Scale bars, 50 µm. c, Schematic of viral injection. d,e, Typical images of FG (blue) signals from the Arc were frequently detected to traced EGFP+ neurons (green) from the ACC (d) and colocalized with the glutamate antibody in the LHA (e). Scale bars, 200 µm (d) and 20 µm (e). f, Schematic of viral injection. g, Representative images of c-Fos expression. Scale bars, 200 µm. h, Representative confocal images (left) and quantitative analysis (right) showing that c-Fos-labeled neurons in the LHA of CFA 10 d mice predominantly colocalized with the glutamate antibody (n = 7 slices from 6 mice). Scale bar, 20 µm. i, Representative confocal images (top) and quantitative analysis (bottom) showing that c-Fos-labeled neurons in the Arc of CFA 10 d mice predominantly colocalized with mCherry expressed by POMC neurons (n = 6 slices from 6 mice). Scale bar, 20 µm. j, Schematic of viral injection and cannula implantation. k,l, Representative confocal images (k) and quantitative analysis (l) showing c-Fos-positive neurons in the LHA and Arc of CFA mice as indicated in (j). Scale bars, 200 µm (n = 8 slices from 6 mice per group; LHA, t14 = 6.585, P < 0.0001; Arc, t14 = 7.748, P < 0.0001). m, Schematic of viral injection and cannula implantation. n,o, Representative confocal images (n) and quantitative analysis (o) showing c-Fos-positive neurons in the LHA and Arc of CFA mice as indicated in (m) (n = 8 slices from 6 mice per group; LHA, t14 = 0.949, P = 0.359; Arc, t14 = 8.210, P < 0.0001). Scale bars, 200 µm. Significance was assessed by two-tailed unpaired Student’s t test in (l and o). All data are presented as the mean ± SEM. *** P < 0.001.

Source data

Extended Data Fig. 10 Activation of LHA-projecting ACC neurons is sufficient for suppression of food intake.

a, Schematic chemogenetic activation design. b, Representative confocal image of AAV-DIO-hM3Dq expression in the ACC of B6 (C57) mice. Scale bar, 200 µm. c, Example recording of spontaneous spikes (left) and statistical data (right) showing the GluACC firing rates in B6 (C57) mice injected with AAV-DIO-mCherry or AAV-DIO-hM3Dq-mCherry (mCherry, n = 57 cells from 6 mice; hM3Dq-mCherry, n = 57 cells from 6 mice). d, Representative confocal images (left) and statistical analysis (right) showing c-Fos-positive neurons in the Arc of mice injected with AAV-DIO-mCherry or AAV-DIO-hM3Dq-mCherry into the ACC (n = 6 slices from 6 mice per group; t10 = 11.09, P < 0.0001). Scale bars, 200 µm. e, Representative confocal images (left) and statistical analysis (right) showing that c-Fos-labeled neurons in the Arc predominantly colocalized with the POMC antibody (n = 6 slices from 6 mice). Scale bar, 20 µm. f, Chemogenetic activation of the LHA-projecting ACC neurons significantly decreased food intake (mCherry, n = 12 mice; hM3Dq-mCherry, n = 11 mice; t21 = 5.707, P < 0.0001). Significance was assessed by two-tailed nested t-test in (c), and two-tailed unpaired Student’s t test in (d and f). All data are presented as the mean ± SEM. * P < 0.05, *** P < 0.001.

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Supplementary information

Supplementary Information

Supplementary Methods and Figs. 1–9

Reporting Summary

Supplementary Video 1

In vivo two-photon calcium imaging of GluACC neurons in saline (left) and CFA (right) CaMK2-Cre mice with ACC infusion of AAV-DIO-GCaMP6f. Scale bar, 50 µm.

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Statistical analyses related to Figs. 1–7, Extended Data Figs. 1–10 and Supplementary Figs. 1–9.

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Tang, HD., Dong, WY., Hu, R. et al. A neural circuit for the suppression of feeding under persistent pain. Nat Metab 4, 1746–1755 (2022). https://doi.org/10.1038/s42255-022-00688-5

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