5-HT NEURONS INTEGRATE NEURAL INPUTS TO REGULATE FOOD INTAKE

肥胖是II型糖尿病和代谢综合征的主要危险因素。加深了对 食物摄入量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5-羟色胺(5-HT)神经元在调节摄食中起重要作用 行为。增强的大脑5-羟色胺作用强烈地抑制食物摄入量和体重，但对此知之甚少 5-HTDRN神经元的放电活动是如何调节的。根据飞行员的观察，徐和童的实验室提出了 提出了一个普遍的假设，即5-HTDRN神经元整合了多巴胺(DA)和GABA的传入 增加食物摄入量。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神经元以促进食物摄取。将进行体内光遗传学研究 确定在光抑制的同时，DA？DRN回路的光刺激是否增加了食物的摄入量 5-羟色胺神经元中的DA受体(DRD2)将被删除，以测试这是否 缺失减少了小鼠的摄食量和体重，并阻断了DA？DRN激活的影响。这个 第二个目标是确定下丘脑外侧区神经元释放的GABA是否抑制 5-HTDRN神经元促进食物摄取。将进行类似的光遗传学研究，以确定 GABA？DRN回路的光刺激增加了食物的摄入量，而同一回路的光抑制 抑制进食；5-羟色胺神经元中的GABA受体(Ȗ2)将被删除，以测试这种缺失是否会减少 小鼠摄食量、体重和GABA？DRN激活的阻断效应。第三个目标是 确定DA和GABA信号是否会聚在相同或不同的5-HTDRN神经元子集上 刺激DA和GABA来源的回路是否会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 大脑5-羟色胺系统在调节摄食和能量平衡中的生理作用，我们也可能 为肥胖等人类疾病的治疗发展确定新的靶点(例如DRD2和Ȗ)。

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.