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

中央杏仁核胰高血糖素样 Peptode-1 受体的功能和行为特征

• 批准号: 10286169
• 负责人: James Andrew Hardaway
• 金额: $ 11.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286169
• 关键词: Acute; Adult; Agonist; Amygdaloid structure; Animals; Appetitive Behavior; Behavior; Behavioral; Binding Sites; Biological Assay; Biology; Body Weight decreased; Brain; Brain region; Centers for Disease Control and Prevention (U.S.); Clinical; Consummatory Behavior; Coupled; Data; Desire for food; Developed Countries; Devices; Diabetes Mellitus; Disease; Dose; Drug Prescriptions; Drug Targeting; Eating; Eating Behavior; Emotional; Fasting; Feeding behaviors; Fiber; Food; Future; GCG gene; GLP-I receptor; Genetic; Glucagon; High Fat Diet; Home; Hyperphagia; Hypothalamic structure; Immunohistochemistry; Infusion procedures; Insulin; Laboratory mice; Lateral; Light; Measures; Mediating; Metabolism; Modeling; Motivation; Mus; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Obesity; Output; Palate; Pancreas; Patients; Peripheral; Pharmaceutical Preparations; Phase; Photometry; Public Health; Research; Role; Site; Stimulus; Structure of terminal stria nuclei of preoptic region; Synapses; System; Technology; Testing; Work; blood glucose regulation; cohort; diabetic; effective therapy; exenatide; feeding; glucagon-like peptide 1; in vivo; liraglutide; miniaturize; mortality; neural circuit; neural patterning; neurophysiology; novel; obesity treatment; protein kinase C-delta; receptor; receptor expression; receptor function; reduced food intake; relating to nervous system; response; therapeutic target

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.

项目概要 靶向胰高血糖素样肽 1 受体 (GLP-1R) 系统的药物通常用于治疗以下疾病： II型糖尿病的治疗。不幸的是，我们尚未完全了解这些药物如何作用于靶点 中枢神经系统或大脑 GLP-1R 如何调节饮食行为。在本提案中，我们将描述 利用神经回路、遗传和行为研究 GLP-1R 在中央杏仁核 (CeA) 中的功能作用 实验室小鼠的方法。在目标 1 中，我们将结合使用 CeA 中 GCaMP7 的光纤光度测定法 1) CeA GLP-1 的局部缺失和 2) GLP-1R 激动剂的局部 CeA 给药以确定功能 CeA GLP-1R 在调节神经活动和对外周应用的 GLP-1R 激动剂的神经反应中的作用。 在目标 2 中，我们将结合高精度使用 CeA GLP-1R 的位点特异性遗传删除， 使用可在小鼠笼中使用的小型饲喂装置进行饲喂的纵向评估 并适应操作性喂养。使用这项技术，我们将测量食欲和完成行为 在几周的整个光周期中，在自由或操作条件下。我们还将确定 CeA 是否 使用两种方法进行外周给药的 GLP-1R 激动剂的减食欲作用需要 GLP-1R。 不同的范例：禁食诱导的再进食和间歇性摄入高脂肪饮食。使用这两个狂欢般的 无论存在或不存在，饮食模式都会外周施用Exendin-4（一种有效的 GLP-1R 激动剂） CeA GLP-1R。我们假设 CeA GLP-1Rs 是神经生理学作用所必需的 在 CeA 上外周施用 GLP-1R 激动剂，并且 CeA GLP-1R 的激活足以诱导 体内 CeA 神经活动的剧烈变化。在行为上，我们假设 CeA GLP-1Rs 限制 对美味食物的动机和食欲行为，删除这些受体将部分抑制 外周 GLP-1R 激动剂对暴食样食物摄入的影响。从长远来看，我们希望能够理解 大脑内源性 GLP-1R 系统的贡献可能为更有效的肥胖治疗提供信息 和二型糖尿病。