Investigating the impact of adolescent intermittent ethanol on GLP-1R function in central amygdala - fproject summary/abstract: alcohol use disorder (AUD) is a major public health burden, with…

Investigating the impact of adolescent intermittent ethanol on GLP-1R function in central amygdala - fproject summary/abstract: alcohol use disorder (AUD) is a major public health burden, with adolescent alcohol exposure increasing risk for developing AUD in adulthood. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as promising potential therapeutic candidates for AUD, with clinical trials demonstrating reduced alcohol consumption in patients. However, nothing is currently known about how adolescent alcohol exposure affects GLP-1R system maturation and function. This knowledge GAP is critical, because GLP-1R agonists are increasingly prescribed for metabolic disorders, yet their effects on neural function in individuals with adolescent alcohol history remain unknown. The central amygdala (CEA) is particularly relevant, as IT serves as the primary behavioral output of the extended amygdala, mediates negative affective states associated with AUD, and expresses GLP-1R. This project will determine how adolescent intermittent ethanol (AIE) exposure produces persistent alterations in GLP-1R regulation of amygdala circuits. Aim 1 will use whole-cell patch- clamp electrophysiology combined with chemogenetic activation and activity-dependent labeling in c-FOS lacz transgenic rats to examine how AIE alters GLP-1R modulation of excitatory and inhibitory transmission in the CEA. Aim 2 will use bulk RNA sequencing to identify transcriptional changes in the CEA following AIE and adult GLP-1R agonist administration, correlated with anxiety-like behaviors. X-GAL staining will map functional connectivity between GLP-1R activated CEA neurons and downstream brain regions to determine whether AIE decouples amygdala output pathways. Finally, candidate genes identified through RNA sequencing will be functionally validated using targeted pharmacological manipulations during electrophysiology recordings. We hypothesize that AIE will disrupt CEA GLP-1R signaling in a circuit-specific manner, reducing GLP-1R function on ethanol-activated projection neurons, ultimately increasing gabaergic tone and decoupling functional connectivity. This integrated approach will establish causal links between AIE-induced molecular changes and altered GLP-1R mediated control of CEA circuits. Together, these studies will investigate the impact of adolescent alcohol history on adult GLP-1R function and treatment efficacy using GLP-1R agonists. Furthermore, this proposal will generate preliminary data for a future K99/R00 application to further investigate the interactions between ethanol history and GLP-1R, of which very little is known. Finally, the comprehensive team of sponsors and collaborators which we have chosen to guide this project will assist in developing my conceptual, technical, and professional skillset as i become an independent researcher.