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

项目摘要 腹侧被盖区（VTA）的多巴胺（DA）神经元调节摄食和身体活动， 这些行为的中断促进了世界范围内的肥胖流行。虽然VTA DA的子集 神经元促进或抑制进食，缺乏分子标记来区分这些人群， 阻止了支持减肥行为的靶向治疗的发展。本提案的目的是 确定是否一个新的分子定义的表达神经降压素受体1的腹侧被盖区DA神经元亚群， （NtsR 1）可能有助于支持减肥;我将这些称为“VTA NtsR 1神经元”。有趣的是， 神经降压素只支持双重减肥行为时，注射到腹侧被盖区，虽然NtsR 1神经元， 分布在整个大脑中。此外，NtsR 1基因敲除小鼠破坏了DA信号传导，过度消耗 可口的食物，并成为超重，这表明一些NtsR 1神经元是必要的调节 体重因此，我假设含有DA的腹侧被盖区NtsR 1神经元特异性地刺激体重减轻 通过NtsR 1依赖机制的行为。为了验证这一点，我将使用DREADD技术， 实验性地激活腹侧被盖区NtsR 1神经元，并确定它们是否足以促进体重减轻 行为。我还将使用新的NtsR 1flox小鼠选择性地从VTA中删除NtsR 1，从而确定其 必须控制体重。这些数据将揭示VTA NtsR 1神经元如何改变体重， 可能指导选择性靶向这一人群治疗肥胖症的新激动剂的使用。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.