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A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia

Abstract

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

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Acknowledgements

This work was supported by grants from the NIH (K99DK107008 to PX; R01DK111436, R01ES027544, R21CA215591 to ZS), USDA/CRIS (6250-51000-059-04S to YX), American Diabetes Association (1-17-PDF-138 to YH), American Heart Association awards (17GRNT32960003 to YX, 16GRNT30970064 to ZS, and 16POST27260254 to CW), National Natural Science Foundation of China (81400886 to NQ), Hubei Province health and family planning scientific research project (WJ2015Q033 to NQ) and Population and Family Planning Commission of Wuhan (WX14B34 to NQ). We also appreciated support by award and fellowships from Wuhan Young & Middle-Aged Talents, Health and Family Planning Commission of Wuhan Municipality and China Scholarship Council (File No. 201608420019 to NQ).

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NQ, YH, and CW were involved in experimental design and most of procedures, data acquisition and analyses, and writing the manuscript. PX, YY, XC, HL, KY, ZP, and IH assisted in production of study mice, surgical procedures, and blinded evaluation of mouse behaviors. ZS, MF, YL, and QL were involved in study design and writing the manuscript. YX is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Yong Xu.

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Qu, N., He, Y., Wang, C. et al. A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia. Mol Psychiatry 25, 1006–1021 (2020). https://doi.org/10.1038/s41380-019-0506-1

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