Genetically Dissecting Chorinergic Signaling in Body Weight Control

摘要/项目摘要 与肥胖相关的疾病，如糖尿病和心血管疾病， 美国的死因。大约有三分之一的美国人口肥胖，据估计， 近一半的人口将在未来二十年内肥胖。迄今为止，研究神经系统的研究 对体重控制的贡献主要集中在下丘脑中的神经肽能信号， 与进食行为有关的关键脑区然而，来自下丘脑外脑区的信号 还涉及调节营养代谢、食欲和饱腹感。我们最近发现了一个 一种新的机制，通过这种机制，基底前脑中的多巴胺能信号强烈影响摄食和身体 体重控制这一发现提供了有趣的证据，表明在大脑中的特定的多巴胺能信号通路， 大脑严格地调节进食行为和体重动态平衡。为了阐明 前脑神经元能信号影响体重管理、摄食行为和代谢，我们 将检验这一假设，即多巴胺能基底前脑回路调节代谢和食欲程序 来调节体重使用条件遗传靶向、光遗传学操作、 电生理学和行为分析，我们将着手确定基底前脑多巴胺能神经元的作用， 在体重控制和肥胖症中的信号传导。

Abstract/Project Summary Obesity-associated diseases such as diabetes and cardiovascular disease together account for the leading cause of death in the United States. Roughly one-third of the U.S. population is obese, and it is estimated that nearly half of the population will be obese within the next two decades. To date, studies investigating the neural contribution to body weight control have focused largely on neuropeptidergic signaling in the hypothalamus, a key brain region involved in feeding behavior. However, signaling from extra-hypothalamic brain regions has also been implicated in regulating nutrient metabolism, appetite, and satiety. We have recently uncovered a novel mechanism by which glutamatergic signaling in the basal forebrain strongly influences feeding and body weight control. This discovery provides intriguing evidence that specific glutamatergic signaling pathways in the brain critically regulate feeding behavior and body weight homeostasis. To elucidate the mechanisms by which forebrain glutamatergic signaling influences body weight management, feeding behaviors, and metabolism, we will test the hypothesis that glutamatergic basal forebrain circuits modulate metabolic and appetitive programs to regulate body weight. Using a combination conditional genetic targeting, optogenetic manipulations, electrophysiology, and behavioral analysis, we will set out to determine the role for basal forebrain glutamatergic signaling in body weight control and obesity.