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，共同占主导地位 在美国的死因。大约三分之一的美国人口肥胖，据估计 在接下来的20年里，近一半的人口将会肥胖。到目前为止，研究神经的研究 对体重控制的贡献主要集中在下丘脑的神经肽能信号，一个 大脑中与摄食行为有关的关键区域。然而，来自下丘脑以外区域的信号 也与调节营养新陈代谢、食欲和饱腹感有关。我们最近发现了一种 基底前脑谷氨酸能信号强烈影响摄食和身体的新机制 体重控制。这一发现提供了有趣的证据，表明特定的谷氨酸能信号通路在 大脑对进食行为和体重动态平衡起着至关重要的调节作用。为了阐明通过什么机制 前脑谷氨酸能信号影响体重管理、摄食行为和新陈代谢 将检验谷氨酸能基底前脑回路调节新陈代谢和食欲程序的假说 来调节体重。使用条件遗传靶向，光遗传操作， 电生理学和行为分析，我们将着手确定谷氨酸能在基底前脑中的作用 控制体重和肥胖的信号。

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.