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.

项目总结