Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation

Authors: CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); WONG, HUEYZHONG - Children'S Nutrition Research Center (CNRC); FANG, SHUZHENG - Children'S Nutrition Research Center (CNRC); LI, YONGXIANG - Children'S Nutrition Research Center (CNRC); YU, MENG - Children'S Nutrition Research Center (CNRC); DENG, YUE - Children'S Nutrition Research Center (CNRC); LIU, QINGZHUO - Children'S Nutrition Research Center (CNRC); FANG, XING - Children'S Nutrition Research Center (CNRC); WANG, MENGJIE - Children'S Nutrition Research Center (CNRC); SHI, YUHAN - Children'S Nutrition Research Center (CNRC); GINNARD, OLIVIA - Children'S Nutrition Research Center (CNRC); YANG, YUXUE - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIU, HAILAN - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); BEAN, JONATHAN - Children'S Nutrition Research Center (CNRC); HAN, JUNYING - Children'S Nutrition Research Center (CNRC); BURT, MEGAN - Children'S Nutrition Research Center (CNRC); JOSSY, SANIKA - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); TONG, QINGCHUN - University Of Texas Health Science Center; ARENKIEL, BENJAMIN - Baylor College Of Medicine; WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); HE, YANG - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2024
Publication Date: 12/10/2024
Citation: Conde, K.M., Wong, H., Fang, S., Li, Y., Yu, M., Deng, Y., Liu, Q., Fang, X., Wang, M., Shi, Y., Ginnard, O.Z., Yang, Y., Tu, L., Liu, H., Liu, H., Yin, N., Bean, J.C., Han, J., Burt, M.E., Jossy, S.V., Yang, Y., Tong, Q., Arenkiel, B.R., Wang, C., He, Y., Xu, Y. 2024. Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation. Metabolism. 163. Article 156099. https://doi.org/10.1016/j.metabol.2024.156099.
DOI: https://doi.org/10.1016/j.metabol.2024.156099

Interpretive Summary: Reward linked signaling molecules in the brain play a significant role in food choice and eating habits. When such reward pathways are disrupted, eating habits can be detrimental to human health. In this study we identified a brain circuit that directly controls eating behaviors, with a specific role in meal initiation with respect to hunger state. This relates to USDA/ARS priorities in that these findings provide needed information on the brain circuits and signaling molecules that control eating habits. In particular, these pathways are often indirectly affected by patients that are being pharmacologically treated for neuropsychiatric or mood disorders.

Technical Abstract: Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HTDRN'arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.