Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation

Authors: CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); WONG, HUEY ZHONG - 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, QINGZHOU - 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: Obesity is becoming a major health issue worldwide, and there are not many effective oral medications to treat it. Serotonin (5-HT) is a neurotransmitter that could be a good target for developing new weight-loss treatments. However, we still need to understand how 5-HT produced in the dorsal raphe nucleus (DRN) affects the start of eating. In our study, we used an optogenetic technique to explore how the 5-HT neurons from the DRN connect to the arcuate nucleus (ARH) and how this circuit is involved in starting meals. We found that these 5-HT neurons receive inhibitory signals from GABAergic neurons in the DRN, and that the response of these neurons is stronger when an individual is hungry. We also discovered that removing a specific subunit of the GABAA receptor in the 5-HT neurons affected the initiation of meals, but it did not impact the feeling of fullness after eating. Additionally, we looked into how dopamine influences this process and found that dopamine receptor D2 helps enhance the feeding response triggered by GABA. In summary, our findings suggest that the 5-HT neurons in the DRN are inhibited by both GABA and dopamine, which work together to initiate meals. This research helps clarify the role of serotonin in meal initiation and could inform future weight-loss therapies.

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.