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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要越来越多的证据表明未定带 (ZI) 和室旁丘脑 (PVT) 都发挥着重要作用摄食调节中的作用。我们之前的研究报道了 ZI GABA 神经元的激活及其对 PVT 的预测会迅速引发暴饮暴食。食物匮乏激活 ZI GABA 神经元并选择性 ZI GABA 神经元的消融抑制了小鼠的日常食物摄入和体重增加，支持 ZI GABA 神经元在生理摄食控制中的重要性。然而，目前仍不清楚如何 ZI-PVT 通路受其他大脑区域的神经支配和控制，以进行摄食调节。在这个应用中，我们建议研究中枢血清素 (5-HT) 信号如何针对 ZI 和 PVT 喂料控制。尽管中枢 5-HT 信号传导在饱腹感调节中的重要性众所周知，但很少有人知道已知中缝 5-HT 预测调节摄食动机。我们的试点数据显示 ZI 和 PVT 接收来自中缝核的密集 5-HT 投射，包括中缝背侧和中缝。食物匮乏抑制投射到 ZI 和 PVT 的中缝背神经元的活动。此外，5-HT 激发 PVT 神经元，但抑制 ZI 神经元以及 ZI-PVT GABA 传输。基于 ZI 的重要作用 PVT神经通路在摄食控制中的作用，我们假设：1）中缝神经元发送5-HT信号进行调节 ZI 和 PVT 神经元，并抑制 ZI-PVT GABA 传递。 2) 中缝5-HT对ZI和PVT的投影调节进食动机和食物摄入量。 3）长期高脂高糖（HFHS）饮食改变5-HT抑制 PVT 投射 ZI 神经元和 ZI-PVT GABA 传输。该提案的目标 1 侧重于研究关于从中缝到 ZI 和 PVT 的功能性 5-HT 神经投射，以及 5-HT 的调节作用 ZI 和 PVT 神经元上的 HT 信号传导。利用切片电生理学结合光遗传学来靶向脑切片中的特定神经元，我们将证实 5-HT 信号传导对 ZI 和 PVT 的差异调节神经元以及 ZI-PVT GABA 传输。在目标 2 中，我们将研究中缝 5-HT 如何投影到两者 ZI 和 PVT 调节喂养动机和食物摄入量。在拟议的行为研究实验中，我们将使用光遗传学工具来操纵中缝 5-HT 神经元及其对 ZI 和 PVT 的投影。我们将还使用切片电生理学和 c-fos 免疫反应性来研究 ZI 和 PVT 投射 5-HT 神经元对代谢状态做出反应，揭示中缝 5-HT 投射对 ZI 和 PVT 在生理学中的作用饲养调节。在目标 3 中，我们将研究长期 HFHS 饮食如何改变对 PVT 预测 ZI 的 5-HT 抑制神经元和 ZI-PVT GABA 传输。总之，本申请中的提案将阐明新的作用通过靶向 ZI 和 PVT 来调节食物摄入中的 5-HT 信号。另外，本次调查的结果该项目将有助于进一步了解功能失调的大脑 5-HT 信号传导如何与暴饮暴食和肥胖有关。