5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation
Conde, K.; Wong, H.; Fang, S.; Li, Y.; Yu, M.; Deng, Y.; Liu, Q.; Fang, X.; Wang, M.; Shi, Y.; Ginnard, O. G.; 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.; Wang, C.; He, Y.; Xu, Y.
Show abstract
Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN{lozenge}arcuate nucleus (ARH) circuit plays an important role in regulating 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 to GABAergic inputs 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 instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons 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, which allows for the initiation of a meal.
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