Serotonin Neurons Integrate GABA and Dopamine Inputs To Regulate Meal Initiation

Authors

Kristine M Conde
HueyZhong Wong
Shuzheng Fang
Yongxiang Li
Meng Yu
Yue Deng
Qingzhuo Liu
Xing Fang
Mengjie Wang
Yuhan Shi
Olivia Z Ginnard
Yuxue Yang
Longlong Tu
Hesong Liu
Hailan Liu
Na Yin
Jonathan C Bean
Junying Han
Megan E Burt
Sanika V Jossy
Yongjie Yang
Qingchun Tong
Benjamin R Arenkiel
Chunmei Wang
Yang He
Yong Xu

Publication Date

2-1-2025

Journal

Metabolism

DOI

10.1016/j.metabol.2024.156099

PMID

39667432

PMCID

PMC11924950

PubMedCentral® Posted Date

3-20-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, gamma-Aminobutyric Acid, Dopamine, Mice, Serotonergic Neurons, Serotonin, Male, Feeding Behavior, GABAergic Neurons, Dorsal Raphe Nucleus, Optogenetics, Mice, Inbred C57BL, Receptors, Dopamine D2, Meal initiation, Serotonin, GABA, Dopamine

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.