Raphe serotonin projections dynamically regulate feeding behavior through targeting inhibitory circuits from rostral zona incerta to paraventricular thalamus

Qiying Ye; Jeremiah Nunez; Xiaobing Zhang

doi:10.1016/j.molmet.2022.101634

Raphe serotonin projections dynamically regulate feeding behavior through targeting inhibitory circuits from rostral zona incerta to paraventricular thalamus

Mol Metab. 2022 Dec:66:101634. doi: 10.1016/j.molmet.2022.101634. Epub 2022 Nov 10.

Authors

Qiying Ye¹, Jeremiah Nunez¹, Xiaobing Zhang²

Affiliations

¹ Department of Psychology, Florida State University, Tallahassee, FL 30304, USA.
² Department of Psychology, Florida State University, Tallahassee, FL 30304, USA. Electronic address: xzhang@psy.fsu.edu.

Abstract

Objective: Rostral zona incerta (ZIR) evokes feeding by sending GABA transmission to paraventricular thalamus (PVT). Although central serotonin (5-HT) signaling is known to play critical roles in the regulation of food intake and eating disorders, it remains unknown whether raphe 5-HT neurons functionally innervate ZIR-PVT neural pathway for feeding control. Here, we sought to reveal how raphe 5-HT signaling regulates both ZIR and PVT for feeding control.

Methods: We used retrograde neural tracers to map 5-HT projections in Sert-Cre mice and slice electrophysiology to examine the mechanism by which 5-HT modulates ZIR GABA neurons. We also used optogenetics to test the effects of raphe-ZIR and raphe-PVT 5-HT projections on feeding motivation and food intake in mice regularly fed, 24 h fasted, and with intermittent high-fat high-sugar (HFHS) diet. In addition, we applied RNAscope in situ hybridization to identify 5-HT receptor subtype mRNA in ZIR.

Results: We show raphe 5-HT neurons sent projections to both ZIR and PVT with partial collateral axons. Photostimulation of 5-HT projections inhibited ZIR but excited PVT neurons to decrease motivated food consumption. However, both acute food deprivation and intermittent HFHS diet downregulated 5-HT inhibition on ZIR GABA neurons, abolishing the inhibitory regulation of raphe-ZIR 5-HT projections on feeding motivation and food intake. Furthermore, we found high-level 5-HT1a and 5-HT2c as well as low-level 5-HT7 mRNA expression in ZIR. Intermittent HFHS diet increased 5-HT7 but not 5-HT1a or 5-HT2c mRNA levels in the ZIR.

Conclusions: Our results reveal that raphe-ZIR 5-HT projections dynamically regulate ZIR GABA neurons for feeding control, supporting that a dynamic fluctuation of ZIR 5-HT inhibition authorizes daily food intake but a sustained change of ZIR 5-HT signaling leads to overeating induced by HFHS diet.

Keywords: Food intake; Paraventricular thalamus; Raphe nuclei; Serotonin; Zona incerta.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Feeding Behavior / physiology
GABAergic Neurons / metabolism
Mice
RNA, Messenger
Serotonin* / metabolism
Thalamus / metabolism
Zona Incerta* / metabolism

Substances

Serotonin
RNA, Messenger

Grants and funding

R01 DK131441/DK/NIDDK NIH HHS/United States