Project Summary/Abstract The staggering prevalence of obesity presents major public health and economic consequences. Effective anti- obesity drugs are desperately needed to combat the obesity epidemic, as behavioral strategies offer limited success. Analogs of the endogenous satiety signal glucagon-like peptide-1 (GLP-1) suppress food intake and body weight and are FDA-approved for obesity treatment. However, GLP-1 analogs (e.g. semaglutide) are burdened by side effects, namely nausea and emesis. Therefore, increasing the therapeutic potential of GLP-1 receptor (GLP-1R) agonists requires characterization of the central mechanisms that mediate both the food intake-suppressive and nausea/emesis effects of GLP-1. Preliminary data in the rat indicate that GLP-1Rs in the locus coeruleus (LC), a source of norepinephrine (NE) output in the brain, are pharmacologically and physiologically relevant for the food intake and illness-like effects of GLP-1. However, the circuit by which endogenous GLP-1 signaling in the LC contributes to food intake suppression and nausea/emesis remains unclear. Additionally, the functional relevance of LC GLP-1Rs to the food intake suppressive and nausea/emesis effects of the semaglutide is not known. The main goal of the proposed 5- year research career development plan is to facilitate the applicant’s transition to a tenure-track Assistant Professor with independent R01 funding. To this end, the proposed research will train the applicant in a variety of approaches to identify the behavioral, cellular, and circuit-level mechanisms behind LC GLP-1R induced anorexia and illness-like behaviors. Aim I will utilize pharmacological, chemogenetic and RNAi-mediated GLP-1R knockdown strategies in the rat and musk shrew, a preclinical model that has an emetic profile similar to humans, to reveal a circuit by which endogenous GLP-1 signaling in the LC contributes to food intake suppression, nausea and emesis. Aim II will take a translational approach by determining the real-time calcium signaling dynamics of LC NE neurons to semaglutide as well as the pharmacological relevance of LC GLP-1Rs to the food intake suppression, nausea/emesis and calcium signaling evoked by systemic semaglutide. Aim II will use also cutting-edge single nucleus RNA sequencing and bioinformatic analysis to probe semaglutide-induced changes in the LC NE neuron transcriptome to reveal the fingerprint of LC neurons and regulation of LC NE neuron genes by semaglutide. Results from these experiments will inform the development of more efficacious and tolerated obesity treatments and will provide the applicant with a unique set of skills and pilot data to encourage her transition to research independence.