3051-LB: Central Amygdala Glucagon-Like Peptide 1 Receptor Neurons Integrate Endogenous GLP-1 and Encode Consummatory Valence through Diverse Outputs

Introduction and Objective: Pharmacotherapies targeting GLP-1 receptors (GLP-1Rs) are transforming diabetes treatment. Despite the rapid adoption of GLP-1 analogs in the clinic, our understanding of the endogenous GLP-1 and GLP-1R system, particularly in the limbic system, has not kept pace Methods: behavior, electrophysiology, tissue clearing/light sheet microscopy, fiber photometry, chemogenetics, optogenetics Results: We used Glp1r-Cre; Gcg-FlpO mice to label GLP-1R neurons in the central amygdala (CeA, Glp1r CeA) and GLP-1-producing neurons in the nucleus of the solitary tract (Gcg NTS) with eGFP and TdTomato respectively. We then used tissue clearing combined with light sheet microscopy to quantify proximity of Glp1r CeA soma to Gcg NTS axons and whole brain outputs of Glp1r CeA and Gcg NTS neurons. We identified Glp1r CeA axons in thalamic, hypothalamic, midbrain, and brain stem nuclei. Using optogenetic-assisted mapping in ex vivo brain slices and electrophysiology, we detected functional inhibitory connections in a subset of these nuclei. Within the CeA, Glp1r CeA neurons inhibit 50% of recorded medial CeA (CeM) cells and bath application of GLP-1 enhances this inhibition. We then used immunofluorescence to detect GLP-1R protein on CeM neurons. Consistent with the presence of GLP-1R protein in the CeA, bath application of GLP-1 resulted in persistent inward currents and significant depolarization. Using fiber photometry in Glp1r CeA neurons, we observed the activation of these neurons in response to aversive stimuli/ tastants, or ramping during appetitive behavior. Food consumption; however, was coupled with a decrease Glp1r CeA neuron activity. Finally, we used chemogenetic inhibition and observed that activation or inhibition of Glp1r CeA neurons reduced or increased high fat diet consumption respectively. Conclusion: We conclude that Glp1r CeA neurons integrate endogenous GLP-1 inputs and serve as a brake on palatable food intake through a diverse axon output network. Disclosure M. Duran: None. J. Willis: None. S. Pochana: None. N. Dalvi: None. K. Habegger: Research Support; Current; Eli Lilly and Company. Consultant; Current; Glyscend Inc. Consultant; Ended; Merck Sharp Current; Abvance, Genuiti. Board Member; Current; Abvance. Stock/Shareholder; Current; Glyscend Inc., Abvance. Advisory Panel; Current; Boehringer Ingelheim International GmbH. A. Hardaway: None. A. Polamarasetty: None. M. Rodriguez: None. Funding R01DK140308K01DK115902R03DK129561