Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation

• Published in: Metabolism, clinical and experimental clinical and experimental, 2024-12, Vol.163, p.156099, Article 156099
• Main Authors: Conde, Kristine M., Wong, HueyZhong, Fang, Shuzheng, Li, Yongxiang, Yu, Meng, Deng, Yue, Liu, Qingzhuo, Fang, Xing, Wang, Mengjie, Shi, Yuhan, Ginnard, Olivia Z., Yang, Yuxue, Tu, Longlong, Liu, Hesong, Liu, Hailan, Yin, Na, Bean, Jonathan C., Han, Junying, Burt, Megan E., Jossy, Sanika V., Yang, Yongjie, Tong, Qingchun, Arenkiel, Benjamin R., Wang, Chunmei, He, Yang, Xu, Yong
• Format: Article
• Language: English
• Subjects: Dopamine; GABA; Meal initiation; Serotonin
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2024.156099

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. [Display omitted] •ARH-projecting 5-HTDRN neurons regulate meal initiation.•5-HTDRN inhibition allows the initiation of a meal.•DRD2 signals in 5-HTDRN neurons are required to fully respond to GABA inhibitory inputs.•5-HT neurons in the DRN are inhibited by synergistic actions of GABA and Dopamine (via DRD2).