Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance

项目总结： 过度食用食物和减少体力活动会导致肥胖，但人们对此的认识有限 调节这些行为的神经回路的缺失阻碍了治疗的发展。自.以来 大脑的下丘脑外侧区(LHA)控制着摄取和移动它的动机 已经研究过支持减肥的可能性，但大多数LHA神经元促进摄取和 体重增加。相反，在上一次资助期间，我们发现LHA神经元表达 抑制摄食、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神经元也会引起剧烈的水摄入量 会导致体重增加，但一旦饮酒正常，进食就会受到抑制，能量会增加 支出会导致体重减轻。总而言之，这些数据表明，预防糖尿病 LHA-NTS介导的摄食抑制和体力活动的行为和偏向 可能会改善减肥的程度。根据我们的初步数据，这是可能的 LHA NTS神经元密集投射到大脑中两个独立的位置，这两个位置与 分别控制饮水和喂食。这些数据导致了这一中心假设 更新应用：下丘脑NTS神经元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传递信号 (NtsR1)。为了研究这一点，我们将使用示踪剂和体内钙成像来定义 特定的LHA细胞和回路组织摄食和饮水，因此是精确的神经靶点 调节减肥行为(目标1)。确定NTS投射到VTA的功能 与LPO相比，我们将在每个位置光遗传刺激LHA NTS终末，从而揭示如果 有足够的专用电路来直接喂食和饮酒(目标2)。然后我们将定义 在VTA或LPO中通过NtsR1发送NTS信号以实现能量平衡的必要性，以及 这些NtsR1神经元能够在没有不良反应的情况下调节体重减轻(目标3)。加在一起， 这些研究将定义LHA NTS神经元的电路、信号和行为 减肥，建议在哪里以及如何针对未来的药物疗法来治疗肥胖症。

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.