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.

项目摘要 针对胰高血糖素样肽1受体（GLP-1R）系统的药物通常是针对该系统的 治疗II型糖尿病。不幸的是，我们尚未完全了解这些药物如何在目标中起作用 中枢神经系统或大脑GLP-1如何调节饮食行为。在这个建议中，我们将描述 GLP-1RS在中央杏仁核（CEA）中使用神经回路，遗传和行为的功能作用 实验室小鼠的方法。在AIM 1中，我们将在CEA中使用GCAMP7的纤维光度法与 1）CEA GLP-1和2）局部删除GLP-1R激动剂的局部CEA给药以确定功能 CEA GLP-1R在调节活性和对周围应用GLP-1R激动剂的神经反应中的作用。 在AIM 2中，我们将使用CEA GLP-1RS的特定地点遗传缺失，并将其与高精度相结合， 使用微型喂养装置对饲料进行纵向评估，可用于小鼠归乡 并适用于操作喂养。使用这项技术，我们将衡量食欲和完美的行为 在几周内整个光周期内的自由或操作条件下。我们还将确定CEA是否 GLP-1R是使用两个使用两个激动剂的厌食症的厌食性效应 单独的范例：禁食引起的参考和间歇性获得高脂饮食。使用这两个Benge 在存在或不存在的情况下，饮食范式将在外围施用Exendin-4（潜在的GLP-1R激动剂） CEA GLP-1R。我们假设CEA GLP-1R是需要的 CEA上的外围施用的GLP-1R激动剂，并且CEA GLP-1R的激活足以诱导 体内CEA神经活动的强大变化。在行为上，我们假设CEA GLP-1RS约束 可口食品的动机和食欲，这些受体的删除将部分抑制 外围GLP-1R激动剂对暴饮暴食样食物摄入的影响。从长远来看，我们希望理解 大脑内源性GLP-1R系统的贡献可能为肥胖症提供更有效的治疗方法 和II型糖尿病。