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

家长助学金摘要 靶向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 大脑或大脑GLP-1RS如何调节饮食行为。在本提案中，我们将描述功能 用神经回路、遗传学和行为学方法研究GLP-1RS在杏仁中央核(CEA)的作用 实验室小白鼠。父母的拨款方案将测试GLP-1RS神经元在 CEA-GLP-1RS在食物摄取中的内源性作用以及CEA-GLP-1RS在 调节外周给药激动剂的作用。 父母的资助将描述：CEA GLP-1Rs在调节神经活动和神经功能方面的功能作用 对外周应用的GLP-1R激动剂的反应(目标1)，并确定是否需要CEA GLP-1R 外周给药GLP-1R激动剂使用两种不同范例的厌食效应：空腹- 诱导性再喂养和间歇性高脂饮食(目标2)。具体地说，我们将利用体内的钙纤维 光度法结合1)CEA GLP-1RS的局部缺失和2)GLP-1R的CEA局部给药 激动剂。CEA-GLP-1RS位点特异性基因缺失联合纵向评估 使用适合可操作饲喂的微型饲喂装置进行饲喂(目标2)。 在功能上，我们假设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的直接激活是 足以在体内诱导CEA神经活动的强劲变化。在行为上，我们假设CEA GLP-1Rs驱动对美味食物动机和胃口行为，而这些受体的缺失将 部分抑制外周应用GLP-1R激动剂对暴饮性食物摄入的影响。这个 父母建议的意义在于辨别大脑内源性GLP-1R系统的贡献 更好地为肥胖症和II型糖尿病提供更有效的治疗方法。 最重要的假设是CEA GLP-1RS在内源性功能上限制了大量的食物 摄入量，对美味食物的动力，以及外周厌食效应的部分需要 GLP-1R激动剂对食物摄入量的影响。

Summary of Parent Grant Drugs that target glucagon-like peptide 1 receptor (GLP-1R) systems 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 brain 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. The parent grant proposal will test the functional requirements of GLP-1Rs neurons in mediating its activation, the endogenous role of CeA GLP-1Rs in food intake, and the role of CeA GLP-1Rs in mediating the actions of peripherallyadministered agonists. The parent grant will characterize: the functional role of CeA GLP-1Rs in regulating neural activity and neural responses to peripherally applied GLP-1R agonists (Aim 1) and 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 (Aim 2). Specifically, we will utilize in vivo Ca2+ fiber photometry in combination with 1) local deletion of CeA GLP-1Rs and 2) local CeA administration of GLP-1R agonists. Site-specific genetic deletion of CeA GLP-1Rs in combination with longitudinal assessment of feeding using miniaturized feeding devices adapted for operant feeding (Aim 2). Functionally, we hypothesize that CeA GLP-1Rs are required for the neurophysiological effects of peripherally administered GLP-1R agonists on the CeA and that direct activation of CeA GLP- 1Rs is sufficient to induce robust changes in CeA neural activity in vivo. Behaviorally, we hypothesize that CeA GLP-1Rs drive motivation and appetitive behavior for palatable food and that deletion of these receptors will partially suppress the effects of peripherally administrated GLP-1R agonists on binge-like food intake. The significance of the parent proposal is to discern the contribution of the brain’s endogenous GLP-1R system to better inform more effective treatments for obesity and type II diabetes. The overarching hypothesis is that CeA GLP-1Rs function endogenously to constrain large volume food intake, motivation for palatable food, and are partially required for the anorexigenic effects of peripheral GLP-1R agonists on food intake.