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: 10414117
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414117
• 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。 中枢神经系统或大脑GLP-1 R如何调节饮食行为。在本提案中，我们将描述 GLP-1 R在中央杏仁核（CeA）中的功能作用，使用神经回路、遗传和行为 在实验室老鼠的方法。在目标1中，我们将使用CeA中GCaMP 7的纤维光度法， 1)CeA GLP-1的局部缺失和2）GLP-1 R激动剂的CeA局部给药，以确定功能性 CeA GLP-1 R在调节神经活动和对外周应用GLP-1 R激动剂的神经反应中的作用。 在目标2中，我们将使用CeA GLP-1 R的位点特异性遗传缺失与高精度相结合， 使用可用于小鼠家庭的小型喂食装置对喂食进行纵向评估 并且适于操作性喂养。利用这项技术，我们将测量食欲和消费行为， 在几周的整个光照周期中在自由或操作条件下进行。我们还将确定， GLP-1 R是外周给药GLP-1 R激动剂的促凋亡作用所必需的，使用两种 单独的范例：禁食诱导的再喂养和间歇性获得高脂肪饮食。利用这两个狂欢式的 进食模式将在存在或不存在的情况下外周给予Exendin-4，一种强效GLP-1 R激动剂 GLP-1 R的影响。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，并且CeA GLP-1 R的激活足以诱导 体内CeA神经活性发生强烈变化。从行为学上讲，我们假设CeA GLP-1 R抑制了 对美味食物的动机和食欲行为，这些受体的缺失将部分抑制 外周GLP-1 R激动剂对暴食样食物摄入的影响。从长远来看，我们希望了解 大脑内源性GLP-1 R系统的贡献可能为肥胖症的更有效治疗提供信息 和II型糖尿病