Neural pathways for obesity development by AgRP neurons

项目摘要 由于不良副作用，治疗肥胖症的治疗药物的开发一直没有成功 疗效有限。我的长期研究目标是描绘出影响体重的神经通路 动态平衡，并为有效和特定的治疗肥胖症提供了框架。在美国的研究 在过去的几十年中，已经发现下丘脑中表达刺鼠相关蛋白(AgRP)的弓状神经元是一种 饲料中的关键节点。最近，我们和其他人证明了AgRP神经元或成人的慢性激活 这些神经元中瘦素受体的缺失导致饮食中与瘦素相当的大规模肥胖 缺乏症。已知的AgRP神经元释放GABA、NPY和AgRP，并独立和平行地发送 投射到几个关键的大脑部位。重要的是，瘦素受体的表达被认为是 更突出的是那些投射到下丘脑外区域的AgRP神经元。然而，如何 神经递质和个体AgRP神经元投射介导慢性肥胖 AgRP神经元的激活尚不清楚。此外，单个AgRP神经元投射如何调节 瘦素对肥胖的作用也是未知的。 为了解决这些知识差距，我们的目标是研究AgRP单个神经递质的作用(目标1)， AgRP神经元的投射特异性亚群(Aim 2)及其Lepr的表达(Aim 3) 慢性AgRP神经元激活导致肥胖的发生。高级病毒跟踪和 将利用小鼠的交叉遗传学来实现AgRP神经元中的投影特异性操作 实现强有力的调查。这项建议是基于我们之前建立的巨大肥胖小鼠 慢性AgRP神经元激活或Lepr缺失的模型，并利用 诱导性缺失和示踪以验证单个传递体和投射的相对重要性 肥胖的发展。这一结果将填补AgRP神经元潜在神经回路机制的空白。 关于肥胖的发展，并将设立阶段，以确定关键的下游介质和神经元的调节 瘦素和AgRP神经元在肥胖发生中的作用，代表了理解大脑的重要一步 体重调节的机制。

Project Summary The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects and limited efficacy. My long-term research goal is to delineate neural pathways responsible for body weight homeostasis, and provide a framework for effective and specific therapeutics against obesity. Research in the last decades has identified arcuate neurons in the hypothalamus expressing agouti-related protein (AgRP) as a key node in feeding. Recently, we and others demonstrate that chronic activation of AgRP neurons or adult deletion of leptin receptors in these neurons leads to massive obesity on chow diet that is comparable to leptin deficiency. AgRP neurons are known to release GABA, NPY and AgRP and send independent and parallel projections to several key brain sites. Importantly, the expression of leptin receptor has been suggested to be more prominent in those AgRP neurons that project to extra-hypothalamic areas. However, how the neurotransmitters and the individual AgRP neuron projections mediate the obesity produced by chronic activation of AgRP neurons are unknown. Additionally, how the individual AgRP neuron projections mediates leptin action on obesity is also unknown To address these knowledge gaps, we aim to examine the role of AgRP individual neurotransmitters (Aim 1), projection-specific subpopulations of AgRP neurons (Aim 2) and their LepR expression (Aim 3) in mediating the obesity development produced by chronic AgRP neuron activation. Advanced viral tracing and intersectional mouse genetics will be used to achieve projection-specific manipulations in AgRP neurons to achieve robust investigation. This proposal is based on our previously established massive obese mouse models with chronic AgRP neuron activation or LepR deletion in AgRP neurons, and utilizes a combination of inducible deletion and tracing to ex-amine the relative importance of individual transmitters and projections in obesity development. The results will fill the gap in the underlying neurocircuit mechanism for AgRP neurons on obesity development and will set up stages to identify key downstream mediators and neurons mediating leptin and AgRP neurons in obesity development, representing a significant step in understanding brain mechanisms in body weight regulation.