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， 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 神经对体重控制的贡献主要集中在神经肽能信号传导上， 下丘脑，一个与进食行为有关的关键大脑区域。然而，来自下丘脑外的信号 大脑区域也与调节营养代谢、食欲和饱腹感有关。我们最近 揭示了一种新的机制，通过这种机制，基底前脑中的胆碱能信号强烈影响身体 体重控制这一发现提供了有趣的证据，表明特定的胆碱能信号通路， 大脑严格地调节进食行为和体重动态平衡。为了阐明 前脑胆碱能信号影响体重管理、摄食行为和代谢，我们 将测试胆碱能信号调节代谢和食欲程序的假设， 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胆碱能信号在体内的作用， 体重控制和肥胖。

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.