Role of VTA Neurotensin Receptor-1 Expressing Neurons in Energy Balance

项目摘要 腹侧被盖区(VTA)中的多巴胺(DA)神经元调节摄食和身体活动，但 这些行为的中断促进了全球肥胖症的流行。而VTA DA的子集 神经元促进或抑制摄食，缺乏分子标记来区分这些群体 阻止了支持减肥行为的靶向治疗的发展。这项提议的目标是 确定一个新的分子定义的VTA DA神经元亚群是否表达神经降压素受体-1 (NtsR1)可能有助于减肥；我将其称为“VTA NtsR1神经元”。有趣的是，配体 当神经降压素注射到VTA时，只支持双重减肥行为，尽管NtsR1神经元 分布在整个大脑中。此外，NtsR1基因缺失的小鼠扰乱了DA信号，过度消费 可口的食物和变得超重，这表明一些NtsR1神经元是调节 体重。因此，我假设含有DA的VTA NtsR1神经元专门刺激体重减轻 行为通过依赖于NtsR1的机制。为了检查这一点，我将使用DREADD技术 实验激活VTA NtsR1神经元，并确定它们是否足以促进减肥 行为。我还将使用新的NtsR1flx小鼠选择性地从VTA中删除NtsR1，从而确定其 控制体重的必要性。这些数据将揭示VTA NtsR1神经元如何改变体重，以及 可以指导使用新的激动剂，选择性地针对这一人群治疗肥胖症。同时，我 我将学习连接神经科学和药理学的尖端技能，这对我的发展是必要的 成为研究疾病发病机制和治疗的独立学术教员。

Project Summary Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate feeding and physical activity, but disruption of these behaviors has promoted the worldwide obesity epidemic. While subsets of VTA DA neurons promote or suppress feeding, the lack of molecular markers to distinguish these populations has prevented development of targeted therapies to support weight loss behaviors. The goal of this proposal is to determine whether a new molecularly-defined subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) may be useful to support weight loss; I refer to these as “VTA NtsR1 neurons”. Intriguingly, the ligand neurotensin only supports dual weight loss behaviors when injected into the VTA, although NtsR1 neurons are distributed throughout the brain. Furthermore, NtsR1 null mice have disrupted DA signaling, overconsume palatable foods and become overweight, indicating that some NtsR1 neurons are necessary for regulating body weight. I thus hypothesize that the DA-containing VTA NtsR1 neurons specifically incite weight loss behaviors via an NtsR1-dependent mechanism. To examine this, I will use DREADD technology to experimentally activate VTA NtsR1 neurons and to determine if they are sufficient to promote weight loss behaviors. I will also use new NtsR1flox mice to selectively delete NtsR1 from the VTA, thus determining its necessity for control of body weight. These data will reveal how VTA NtsR1 neurons modify body weight, and may guide the use of new agonists that selectively target this population for treating obesity. Simultaneously, I will learn cutting-edge skills bridging neuroscience and pharmacology that are necessary for my development into an independent academic faculty member studying disease pathogenesis and treatment.