R01 Application:Genetically Dissecting Cholinergic 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，调查 神经对体重控制的贡献主要集中在神经肽能信号转导。 下丘脑是大脑中参与摄食行为的关键区域。然而，来自下丘脑外的信号 大脑区域也与调节营养新陈代谢、食欲和饱腹感有关。我们最近 发现基底前脑胆碱能信号强烈影响身体的新机制 体重控制。这一发现提供了耐人寻味的证据，表明特定的胆碱能信号通路在 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 前脑胆碱能信号影响体重管理、摄食行为和新陈代谢 将检验胆碱能信号调节新陈代谢和食欲调节程序的假说 体重。使用条件基因打靶、光遗传操作、电生理学、 和行为分析，我们将着手确定基底前脑胆碱能信号在体内的作用 控制体重和肥胖。

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 recently uncovered a novel mechanism by which cholinergic signaling in the basal forebrain strongly influences body weight control. This discovery provides intriguing evidence that specific cholinergic signaling pathways in the brain critically regulate feeding behavior and body weight homeostasis. To elucidate the mechanisms by which forebrain cholinergic signaling influences body weight management, feeding behaviors, and metabolism, we will test the hypothesis that cholinergic signaling modulates 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 cholinergic signaling in body weight control and obesity.