权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

5-HT NEURONS INTEGRATE NEURAL INPUTS TO REGULATE FOOD INTAKE

5-HT 神经元整合神经输入来调节食物摄入量

基本信息

批准号：
10654765
负责人：
Qingchun Tong
金额：
$ 43.1万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10654765
关键词：
American Animals Body Weight Brain DRD2 gene Diabetes Mellitus Dopamine Dopamine Receptor Eating Energy Intake Energy Metabolism Equilibrium Feeding behaviors Fenfluramine Food Intake Regulation GABA-A Receptor Goals Homeostasis Hunger Hyperphagia Hypothalamic structure Intake Laboratory Finding Lateral Mediating Metabolic syndrome Modeling Mus Neural Pathways Neurons Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Overweight Pharmaceutical Preparations Physiological Play Population Prevalence Regimen Regulation Research Risk Risk Factors Role Satiation Serotonergic System Serotonin Signal Transduction Testing Therapeutic Ventral Tegmental Area Work combat comorbidity dopaminergic neuron dorsal raphe nucleus effective therapy energy balance experimental study feeding gamma-Aminobutyric Acid global health human disease in vivo neural neural network neurobiological mechanism neurotransmission new therapeutic target novel obese person obesity prevention obesity treatment optogenetics prevent receptor side effect therapeutic development

项目摘要

Obesity is a major risk factor for type II diabetes and metabolic syndromes. Increased understanding of food intake and body weight regulation may lead to effective strategies to combat obesity and diabetes. Serotonin (5-HT) neurons in the dorsal Raphe nucleus (DRN) play an essential role in regulating feeding behavior. Enhanced brain 5-HT actions robustly inhibit food intake and body weight but little is known about how firing activity of 5-HTDRN neurons is regulated. Based on pilot observations, the Xu and Tong labs put forward a general hypothesis that 5-HTDRN neurons integrate dopamine (DA) and GABA inputs to promote food intake. The first objective is to determine whether DA released by neurons in the ventral tegmental area inhibits 5-HTDRN neurons to promote food intake. In vivo optogenetic studies will be carried out to determine whether photostimulation of the DAÆDRN circuit increases food intake while photoinhibition of the same circuit inhibits eating; a DA receptor (DRD2) will be deleted in 5-HT neurons to test whether this deletion decreases food intake and body weight and block effects of DAÆDRN activation in mice. The second objective is to determine whether GABA released by neurons in the lateral hypothalamus inhibits 5-HTDRN neurons to promote food intake. Similar optogenetic studies will be carried out to determine whether photostimulation of the GABAÆDRN circuit increases food intake while photoinhibition of the same circuit inhibits eating; a GABA receptor (Ȗ2) will be deleted in 5-HT neurons to test whether this deletion decreases food intake and body weight and block effects of GABAÆDRN activation in mice. The third objective is to determine whether DA and GABA signals converge on the same or distinct subsets of 5-HTDRN neurons and whether stimulation of both DA and GABA-originated circuits produce redundant or synergistic effects on food intake. Thus, accomplishment of these experiments may advance our understanding about the physiological roles of brain 5-HT system in the regulation of feeding and energy balance, we may also identify novel targets (e.g. DRD2 and Ȗ) for therapeutic development of human diseases, e.g. obesity.

肥胖是II型糖尿病和代谢综合征的主要危险因素。更加了解食物摄入和体重调节可能会导致有效的战略，以打击肥胖症和糖尿病。中缝背核（DRN）内5-羟色胺（5-HT）神经元在摄食调节中起重要作用行为增强的大脑5-HT作用强烈地抑制食物摄入和体重，但对 5-HTDRN神经元的放电活动是如何调节的。根据试点观察，徐和童实验室提出了提出了一个普遍的假设，即5-HTDRN神经元整合多巴胺（DA）和GABA输入，促进食物摄入。第一个目的是确定腹侧神经元是否释放DA，被盖区抑制5-HTDRN神经元促进食物摄取。将进行体内光遗传学研究以确定DANORT-DRN回路的光刺激是否会增加食物摄入量，而光抑制是否会增加食物摄入量。在5-HT神经元中，多巴胺受体（DRD 2）将被删除，以测试这是否会影响饮食。在小鼠中，缺失降低食物摄入和体重，并阻断DAVID DRN活化的作用。的第二个目的是确定下丘脑外侧区神经元释放的GABA是否抑制 5-HTDRN神经元促进食物摄入。将进行类似的光遗传学研究，以确定是否 GABA能DRN回路的光刺激增加食物摄入，而相同回路的光抑制抑制进食;将在5-HT神经元中删除GABA受体（GABA 2），以测试这种删除是否会减少食物摄入量和体重以及GABA 1 DRN激活的阻断作用。第三个目标是确定DA和GABA信号是否会聚在5-HTDRN神经元的相同或不同子集上，刺激DA和GABA起源的回路是否产生冗余或协同效应，食物摄入量因此，这些实验的完成可能会促进我们对脑5-HT系统在摄食和能量平衡调节中的生理作用，鉴定用于人类疾病（例如肥胖症）的治疗开发的新靶点（例如DRD 2和DRD 3）。