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

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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.