Cholinergic Basal Forebrain Signaling in Body Weight Homeostasis

描述(申请人提供)：与肥胖相关的疾病，如心血管疾病和糖尿病，是美国主要的死亡原因。此外，进食障碍，如厌食症和神经性暴食症，影响着全球数百万人。进食行为在很大程度上是由大脑调节的，大脑整合了来自全身的不同信号，以调节身体对进食的反应。调节这一过程的大脑回路的扰动导致了进食和代谢紊乱的发病。因此，充分了解大脑在调节食物摄入中的作用，对于开发有效的治疗这些疾病的方法是至关重要的。为了达到这一目标，我们最近发现，基底前脑胆碱能神经元的丢失会导致成年小鼠摄食量增加和严重肥胖。此外，我们已经证明，这些神经元投射到下丘脑，并接受下丘脑的输入，下丘脑是摄食行为的主要控制中心。利用遗传学、生理学和行为测试的创新技术，我们建议确定胆碱能基底前脑信号在体重动态平衡中的作用。具体地说，我们建议(1)确定胆碱能基底前脑信号受损或增强对摄食、能量消耗和摄食相关肽信号的影响，以及(2)映射、表征和机械地确定参与胆碱能介导的摄食行为和体重动态平衡影响的神经元大脑回路。

DESCRIPTION (provided by applicant): Obesity-associated diseases such as cardiovascular disease and diabetes account for the leading causes of death in the United States. In addition, eating disorders such as anorexia and bulimia nervosa affect millions of people worldwide. Feeding behavior is largely regulated in the brain, which integrates diverse signals from throughout the body in order to modulate the body's response to eat. Perturbations to the brain circuits that regulate this process contribute to the pathogenesis of eating and metabolic disorders. Therefore, fully understanding the brain's role in regulating food intake is essential fr developing effective therapies to treat these disorders. Towards this goal, we have recently discovered that loss of cholinergic neurons from the basal forebrain leads to increased food intake and severe obesity in adult mice. Furthermore, we have shown that these neurons project to, and receive input from, the hypothalamus, a major control center of feeding behavior. Using innovative techniques in genetics, physiology, and behavioral testing, we propose to determine the role of cholinergic basal forebrain signaling on body weight homeostasis. Specifically, we propose to (1) determine the effect of impaired or enhanced cholinergic basal forebrain signaling on food intake, energy expenditure, and feeding- associated peptide signaling, and (2) map, characterize, and mechanistically determine the neuronal brain circuits involved in cholinergic-mediated effects on feeding behavior and body weight homeostasis.