5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding

Authors: HE, YANLIN - Pennington Biomedical Research Center; CAI, XING - Chinese Academy Of Sciences; LIU, HAILAN - Children'S Nutrition Research Center (CNRC); CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - University Of Illinois; LI, YONGXIANG - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); YU, MENG - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIANG, CHEN - Children'S Nutrition Research Center (CNRC); YANG, TINGTING - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); YU, KAIFAN - Children'S Nutrition Research Center (CNRC); WANG, JULIA - Children'S Nutrition Research Center (CNRC); ZHENG, RONG - Children'S Nutrition Research Center (CNRC); LIU, FENG - University Of Texas Health Science Center; SUN, ZHENG - Baylor College Of Medicine; HEISLER, LORA - University Of Aberdeen; WU, QI - Children'S Nutrition Research Center (CNRC); TONG, QINGCHUN - University Of Texas Health Science Center; ZHU, CANJUN - South China Agricultural Univerisity; SHU, GANG - South China Agricultural Univerisity; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular Psychiatry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/29/2021
Publication Date: 7/21/2021
Citation: He, Y., Cai, X., Liu, H., Conde, K., Xu, P., Li, Y., Wang, C., Yu, M., He, Y., Liu, H., Liang, C., Yang, T., Yang, Y., Yu, K., Wang, J., Zheng, R., Liu, F., Sun, Z., Heisler, L., Wu, Q., Tong, Q., Zhu, C., Shu, G., Xu, Y. 2021. 5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding. Molecular Psychiatry. 26:7211-7224. https://doi.org/10.1038/s41380-021-01220-z.
DOI: https://doi.org/10.1038/s41380-021-01220-z

Interpretive Summary: Obesity is a serious health issue primarily caused by consumption of too much food. For some people, hunger primarily drives overeating, while others overeat without the presence of hunger. Here, we used a mouse model to test how specific brain circuits inhibit food intake. We found parallel circuits, which modulate feeding behavior either in response to hunger or to hunger-independent cues. These circuits provide potential targets for medication to suppress overeating.

Technical Abstract: Obesity is primarily a consequence of consuming calories beyond energetic requirements, but underpinning drivers have not been fully defined. 5-Hydroxytryptamine (5-HT) neurons in the dorsal Raphe nucleus (5-HT^DRN) regulate different types of feeding behavior, such as eating to cope with hunger or for pleasure. Here, we observed that activation of 5-HT^DRN to hypothalamic arcuate nucleus (5-HT^DRN->ARH) projections inhibits food intake driven by hunger via actions at ARH 5-HT2C and 5-HT1B receptors, whereas activation of 5-HT^DRN to ventral tegmental area (5-HT^DRN -> VTA) projections inhibits non-hunger-driven feeding via actions at 5-HT2C receptors. Further, hunger-driven feeding gradually activates ARH-projecting 5-HT^DRN neurons via inhibiting their responsiveness to inhibitory GABAergic inputs; non-hunger-driven feeding activates VTA-projecting 5-HT^DRN neurons through reducing a potassium outward current. Thus, our results support a model whereby parallel circuits modulate feeding behavior either in response to hunger or to hunger-independent cues.