Cholinergic Basal Forebrain Signaling in Body Weight Homeostasis

描述（由申请人提供）：肥胖相关疾病，如心血管疾病和糖尿病是美国主要的死亡原因。此外，厌食症和神经性贪食症等饮食失调影响着全世界数百万人。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各种信号，以调节身体对进食的反应。对调节这一过程的大脑回路的干扰有助于饮食和代谢紊乱的发病机制。因此，充分了解大脑在调节食物摄入方面的作用对于开发治疗这些疾病的有效疗法至关重要。为了实现这一目标，我们最近发现，基底前脑胆碱能神经元的损失导致成年小鼠的食物摄入量增加和严重肥胖。此外，我们已经表明，这些神经元的项目，并接受输入，下丘脑，一个主要的控制中心的进食行为。利用遗传学、生理学和行为测试的创新技术，我们提出确定胆碱能基底前脑信号对体重稳态的作用。具体而言，我们建议（1）确定受损或增强的胆碱能基底前脑信号传导对食物摄入、能量消耗和摄食相关肽信号传导的影响，以及（2）绘制、表征和机械确定参与胆碱能介导的对摄食行为和体重稳态的影响的神经元脑回路。

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.