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

• DOI: 10.1016/j.molmet.2022.101634
• Publication Date: 2022-11-06T16:32:23Z
• Authors: Qiying Ye; Jeremiah Nunez; Xiaobing Zhang
• Keywords: Paraventricular thalamus; 2. Zero hunger; Serotonin; 0303 health sciences; Feeding Behavior; RC31-1245; Zona incerta; Mice; 03 medical and health sciences; Thalamus; Food intake; Animals; Zona Incerta; Original Article; RNA, Messenger; GABAergic Neurons; Raphe nuclei; Internal medicine

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.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.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.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.