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

家长补助金摘要 靶向胰高血糖素样肽1受体（GLP-1 R）系统的药物通常用于 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-1 R如何调节饮食行为。在本建议中，我们将描述功能 GLP-1 R在中枢杏仁核（CeA）中的作用，采用神经回路、遗传和行为方法， 实验室老鼠母基金提案将测试GLP-1 Rs神经元的功能要求， 介导其活化，CeA GLP-1 Rs在食物摄入中的内源性作用，以及CeA GLP-1 Rs在 介导外周给药激动剂的作用。 母基金将描述：CeA GLP-1 R在调节神经活动和神经功能中的功能作用。 对外周应用GLP-1 R激动剂的反应（目的1），并确定是否需要CeA GLP-1 R 使用两种不同的范式：空腹- 诱导再喂食和间歇性高脂肪饮食（目标2）。具体来说，我们将利用体内钙离子纤维 光度法联合1）CeA GLP-1 R局部缺失和2）GLP-1 R局部CeA给药 激动剂CeA GLP-1 R的位点特异性遗传缺失联合纵向评估 使用适于操作性喂食的小型化喂食装置喂食（目标2）。 在功能上，我们假设CeA GLP-1 Rs是神经生理学效应所必需的。 外周给药GLP-1 R激动剂对CeA的作用，CeA GLP-1 R的直接激活是 足以在体内诱导CeA神经活性的强烈变化。从行为学上讲，我们假设CeA GLP-1 R驱动对可口食物的动机和食欲行为，这些受体的缺失将 部分抑制外周给药GLP-1 R激动剂对暴食样食物摄入的影响。的 母提案的重要性在于识别脑内源性GLP-1 R系统的贡献 以更好地为肥胖和II型糖尿病提供更有效的治疗方法。 总体假设是CeA GLP-1 R内源性抑制大量食物 摄入量，可口食物的动机，并部分需要外周血的促氧化作用 GLP-1 R激动剂对摄食量的影响。

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.