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：
10259803
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/10259803
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 Lateral Lead 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 base combat comorbidity dopaminergic neuron dorsal raphe nucleus effective therapy energy balance experimental study feeding gamma-Aminobutyric Acid global health human disease in vivo neural network neurobiological mechanism neurotransmission new therapeutic target novel obese person obesity prevention obesity treatment optogenetics prevent receptor relating to nervous system 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。食物摄入和体重调节可能会导致对抗肥胖和糖尿病的有效策略。中缝背核 (DRN) 中的血清素 (5-HT) 神经元在调节摄食方面发挥重要作用增强的大脑 5-HT 作用可有效抑制食物摄入和体重，但对此我们知之甚少。 Xu 和 Tong 实验室根据初步观察发现了 5-HTDRN 神经元的放电活动是如何受到调节的。提出了一个一般假设，即 5-HTDRN 神经元将多巴胺 (DA) 和 GABA 输入整合到第一个目标是确定腹侧神经元是否释放 DA。被盖区抑制5-HTDRN神经元促进食物摄入将进行体内光遗传学研究。以确定 DAÆDRN 回路的光刺激是否会增加食物摄入量，而光抑制同一回路的 DA 受体（DRD2）将被删除，以测试这是否会发生。缺失会降低小鼠的食物摄入量和体重，并阻断 DAÆDRN 激活的作用。第二个目标是确定下丘脑外侧神经元释放的 GABA 是否抑制将进行类似的光遗传学研究以确定5-HTDRN神经元是否能促进食物摄入。 GABAÆDRN 回路的光刺激会增加食物摄入量，而同一回路的光抑制会增加食物摄入量抑制进食；5-HT 神经元中的 GABA 受体 (?2) 将被删除，以测试这种删除是否会减少第三个目标是抑制小鼠的食物摄入量和体重以及 GABAÆDRN 激活的影响。确定 DA 和 GABA 信号是否汇聚在 5-HTDRN 神经元的相同或不同子集上，以及 DA 和 GABA 来源的回路的刺激是否会产生冗余或协同效应因此，这些实验的完成可能会增进我们对食物摄入量的理解。大脑5-HT系统在调节摄食和能量平衡中的生理作用，我们也可能确定用于人类疾病（例如肥胖症）治疗开发的新靶标（例如 DRD2 和 ş）。