Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance

项目摘要： 食物的过度消费和身体活动的减少会导致肥胖，但了解有限 调节这些行为的神经元回路的缺陷阻碍了治疗方法的发展。以来 大脑的外侧下丘脑区（LHA）控制着进食和移动的动机， 已经研究了支持减肥的潜力，但大多数LHA神经元促进摄入， 体重增加.相比之下，在上一个资助期，我们发现LHA神经元表达 抑制摄食和促进能量消耗的神经肽神经降压素（Nts） 重量.奇怪的是，激活LHA Nts神经元也会引起大量的水摄入， 导致体重增加，但一旦饮酒正常化，然后进食抑制和增加能量 支出导致体重减轻。总的来说，这些数据表明， LHA Nts介导的摄食抑制和体力活动的行为和偏倚 可能会提高减肥的程度。根据我们的初步数据， LHA Nts神经元密集地投射到大脑中两个独立的部位，这两个部位与大脑中的神经元的活动有关。 分别控制饮水和进食。这些数据导致了这一中心假设 更新应用：LHA Nts神经元通过以下方式协调摄食抑制和饮水： VTA和LPO分别需要通过神经降压素受体-1进行信号传导 （NtsR1）。为了研究这一点，我们将使用束示踪剂和体内钙成像来确定 特定的LHA细胞和回路，组织进食与饮水，因此精确的神经靶点 介导减肥行为（目的1）。定义Nts投影到VTA的功能 vs.我们将通过光遗传学方法刺激LHA各位点的Nts末端，从而揭示 有足够的专用回路来引导进食与饮水（目标2）。我们将定义 在VTA或LPO中经由NtsR1的Nts信令用于能量平衡的必要性，以及 这些NtsR1神经元介导体重减轻而没有副作用（Aim 3）。综合起来看， 这些研究将确定LHA Nts神经元介导的回路、信号和行为 减肥，建议在哪里以及如何针对未来的药物治疗肥胖。

Project Summary: Overconsumption of food and reduced physical activity cause obesity, but limited understanding of the neuronal circuits regulating these behaviors has hindered development of therapies. Since the lateral hypothalamic area (LHA) of the brain controls the motivation to ingest and move it has been studied for potential to support weight loss, but most LHA neurons promote ingestion and weight gain. In contrast, during the last funding period we identified LHA neurons expressing the neuropeptide neurotensin (Nts) that restrain feeding and promote energy expenditure to decrease weight. Curiously, activating LHA Nts neurons also invokes a burst of water intake that acutely causes weight gain, but once drinking normalizes then feeding suppression and increased energy expenditure lead to weight loss. Taken together, these data suggest that preventing dipsic behavior and biasing specifically for LHA Nts-mediated feeding restraint and physical activity might improve the degree of weight loss. This could be possible, based on our preliminary data that LHA Nts neurons densely project to two separate sites in the brain that are implicated in the control of drinking and feeding, respectively. These data led to the central hypothesis of this renewal application: LHA Nts neurons coordinate feeding suppression and drinking via the VTA and LPO, respectively, which requires signaling via neurotensin receptor-1 (NtsR1). To investigate this we will use tract tracers and in vivo calcium imaging to define the specific LHA cells and circuits that organize feeding vs. drinking, and hence precise neural targets to mediate weight loss behaviors (Aim 1). To define the functions of Nts projections to the VTA vs. the LPO we will optogenetically stimulate LHA Nts terminals in each site, thereby revealing if there are dedicated circuits sufficient to direct feeding vs. drinking (Aim 2). We will then define the necessity of Nts signaling via NtsR1 in the VTA or LPO for energy balance, and the ability of these NtsR1 neurons to mediate weight loss without adverse effects (Aim 3). Taken together, these studies will define the circuits, signals and behaviors by which LHA Nts neurons mediate weight loss, suggesting where and how to target future pharmacological therapies to treat obesity.