Functional and Behavioral Characterization of Central Amygdala Glucagon Like Peptode-1 Receptors

项目摘要 针对胰升糖素样肽1受体(GLP-1R)系统的药物通常用于治疗 治疗II型糖尿病。不幸的是，我们还没有完全了解这些药物是如何作用于靶点的 中枢神经系统或大脑GLP-1RS如何调节饮食行为。在这份提案中，我们将描述 GLP-1RS在中央杏仁核(CEA)中的神经回路、遗传和行为功能作用 在实验室小鼠中的方法。在目标1中，我们将使用CEA中GCaMP7的纤维光度法结合 1)CEA GLP-1的局部缺失和2)GLP-1R激动剂的CEA局部给药 CEA GLP-1RS在外周应用GLP-1R激动剂调节神经活动和神经反应中的作用。 在目标2中，我们将使用CEA GLP-1RS的位点特异性基因缺失结合高精度， 使用可用于小鼠家庭的微型喂养装置进行喂养的纵向评估 并适应于可操作的进食。使用这项技术，我们将测量食欲和消费行为 在整个光周期中处于自由或工作状态下，持续数周。我们还将确定CEA是否 外周应用GLP-1R激动剂的厌食效应需要GLP-1R，使用两种 不同的范例：禁食诱导的再喂养和间歇性地获得高脂肪饮食。利用这两种狂欢 进食模式将在存在或不存在的情况下对Exendin-4进行外围管理，Exendin-4是一种有效的GLP-1R激动剂 CEA-GLP-1RS。我们推测CEA、GLP-1受体是发挥神经生理作用所必需的。 外周应用GLP-1R激动剂对CEA和CEA GLP-1Rs的激活足以诱导 体内CEA神经活性的强劲变化。在行为上，我们假设CEA GLP-1RS约束 对美味食物动机和胃口行为，这些受体的缺失将部分抑制 外周GLP-1R激动剂对暴食性食物摄入量的影响从长远来看，我们希望了解 大脑内源性GLP-1R系统的作用可能为肥胖症的更有效治疗提供信息 和II型糖尿病。

Project Summary Drugs that target the glucagon-like peptide 1 receptor (GLP-1R) system are commonly prescribed for the treatment of type II diabetes. Unfortunately, we do not yet fully understand how these drugs work on targets in the central nervous system or how brain GLP-1Rs regulate eating behaviors. In this proposal we will characterize the functional role of GLP-1Rs in the central amygdala (CeA) using neural circuit, genetic, and behavioral approaches in laboratory mice. In Aim 1, we will use fiber photometry of GCaMP7 in the CeA in combination with 1) local deletion of CeA GLP-1 and 2) local CeA administration of GLP-1R agonists to determine the functional role of CeA GLP-1Rs in regulating neural activity and neural responses to peripherally applied GLP-1R agonists. In Aim 2, we will use site-specific genetic deletion of CeA GLP-1Rs in combination with high precision, longitudinal assessment of feeding using miniaturized feeding devices that can be used in the mouse homecage and adapted for operant feeding. Using this technology, we will measure appetitive and consummatory behavior under free or operant conditions throughout the light cycle over several weeks. We will also determine if CeA GLP-1Rs are required for the anorexigenic effects of peripherally administered GLP-1R agonists using two separate paradigms: fasting-induced refeed and intermittent access to high fat diet. Using these two binge-like eating paradigms will peripherally administer Exendin-4, a potent GLP-1R agonist, in the presence or absence of CeA GLP-1Rs. We hypothesize that CeA GLP-1Rs are required for the neurophysiological effects of peripherally administered GLP-1R agonists on the CeA and that activation of CeA GLP-1Rs is sufficient to induce robust changes in CeA neural activity in vivo. Behaviorally, we hypothesize that CeA GLP-1Rs constrain motivation and appetitive behavior for palatable food, and that deletion of these receptors will partially suppress the effects of peripheral GLP-1R agonists on binge-like food intake. Over the long-term we hope to understand the contribution of the brain’s endogenous GLP-1R system that may inform more effective treatments for obesity and type II diabetes.