Serotonin Signaling in Zona Incerta and Paraventricular Thalamus Regulate Feeding Behavior

未定带和室旁丘脑中的血清素信号传导调节进食行为

• 批准号: 10344015
• 负责人: Xiaobing Zhang
• 金额: $ 37.07万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10344015
• 关键词: Ablation; Agonist; Animal Behavior; Area; Attenuated; Axon; Behavioral Assay; Brain; Brain Stem; Brain region; Chronic; Complex; Data; Depressed mood; Diet; Dorsal; Eating; Eating Disorders; Electrophysiology (science); FOS gene; Fatty acid glycerol esters; Feeding behaviors; Food; Food Intake Regulation; Food deprivation (experimental); Glutamates; Human; Hyperphagia; Hypothalamic structure; Instinct; Label; Light; Measures; Medial; Mediating; Metabolic; Motivation; Mus; Neural Pathways; Neurons; Obesity; Pathway interactions; Pharmacological Treatment; Pharmacology; Physiological; Play; Regulation; Reporting; Rewards; Role; Satiation; Serotonergic System; Serotonin; Signal Transduction; Slice; System; Testing; Thalamic structure; Tracer; Transgenic Mice; Weight Gain; Work; adeno-associated viral vector; antagonist; base; behavioral study; brain dysfunction; dopaminergic neuron; experimental study; feeding; gamma-Aminobutyric Acid; immunocytochemistry; immunoreactivity; mind control; motivated behavior; nerve supply; neural circuit; neurotransmission; novel; obesity treatment; optogenetics; patch clamp; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; raphe nuclei; relating to nervous system; response; serotonin receptor; sugar; tool; transmission process; zona incerta

PROJECT SUMMARY Increasing evidence indicates that both zona incerta (ZI) and paraventricular thalamus (PVT) play important roles in the regulation of feeding. Our previous study reported that activation of ZI GABA neurons and their projections to PVT rapidly evokes binge-like eating. Food deprivation activates ZI GABA neurons and selective ablation of ZI GABA neurons suppresses daily food intake and body weight gain in mice, supporting the importance of ZI GABA neurons in the physiological feeding control. However, it remains largely unknown how the ZI-PVT pathway is innervated and controlled by other brain areas for the feeding regulation. In this application, we propose to study how central serotonin (5-HT) signaling targeting both ZI and PVT for the feeding control. Although the importance of central 5-HT signaling in the satiety regulation is well-known, little is known what raphe 5-HT projections regulate feeding motivation. Our pilot data show that both ZI and PVT receive dense 5-HT projections from raphe nuclei, including both dorsal and medial raphe. Food deprivation depressed the activity of dorsal raphe neurons that project to ZI and PVT. In addition, 5-HT excited PVT neurons but inhibited ZI neurons as well as ZI-PVT GABA transmission. Based on the significant role of the ZI- PVT neural pathway in feeding control, we hypothesize that: 1) raphe neurons send 5-HT signaling to modulate both ZI and PVT neurons, and inhibit ZI-PVT GABA transmission. 2) raphe 5-HT projections to ZI and PVT regulate feeding motivation and food intake. 3) chronic high-fat high-sugar (HFHS) diet alters 5-HT inhibition on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Aim 1 of the proposal is focused on the study about the functional 5-HT neural projections from raphe to both ZI and PVT, and the modulatory effects of 5- HT signaling on ZI and PVT neurons. Using slice electrophysiology in combination with optogenetics to target specific neurons in brain slices, we will corroborate the differential modulation of 5-HT signaling on ZI and PVT neurons as well as ZI-PVT GABA transmission. In Aim 2, we will examine how raphe 5-HT projections to both ZI and PVT regulate feeding motivation and food intake. In the proposed experiments for the behavioral study, we will use optogenetic tools to manipulate raphe 5-HT neurons and their projections to ZI and PVT. We will also use slice electrophysiology and c-fos immunoreactivity to study how ZI- and PVT-projecting 5-HT neurons respond to the metabolic states, revealing the role of raphe 5-HT projections to ZI and PVT in the physiological feeding regulation. In Aim 3, we will study how chronic HFHS diets alter 5-HT inhibition on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Together, the proposal in this application will elucidate a novel role of 5-HT signaling in the regulation of food intake by targeting both ZI and PVT. Also, the findings from this project will help further understand how dysfunctional brain 5-HT signaling is involved in overeating and obesity.

项目总结