A Central Amygdala GLP-1R Circuit Gates Mesolimbic Dopamine and Hedonic Feeding 8 views

Obesity is driven in part by dysregulated reward processing that promotes the overconsumption of palatable foods beyond metabolic need. Glucagon-like peptide-1 receptor agonists (GLP1RAs) have emerged as transformative obesity therapies, yet the neural circuits through which they modulate reward-driven feeding remain poorly defined. In this dissertation, I investigate the mechanisms by which GLP1RAs engage brain reward circuitry to suppress hedonic food consumption. I identify a population of GLP1R-expressing neurons in the central amygdala (CeA-Glp1r) that receive input from GLP-1-producing neurons in the nucleus of the solitary tract and project to ventral tegmental area dopamine neurons. I demonstrate that activation of this NTS-Gcg → CeA-Glp1r → VTA → NAc circuit selectively suppresses palatable food intake without affecting homeostatic feeding, and that GLP-1RAs acting through this pathway attenuate consumption-associated dopamine release in the nucleus accumbens. Conditional deletion of Glp1r from the CeA diminishes the ability of GLP-1RAs to reduce hedonic intake, establishing these neurons as a required component of GLP-1RA-mediated reward suppression. These findings reveal that GLP1RAs recruit a dedicated amygdalar reward circuit operating alongside canonical homeostatic pathways, providing a mechanistic framework for understanding how these drugs reshape motivated behavior with implications for disorders of dysregulated reward signaling including substance use disorders and binge eating.

PHD (Doctor of Philosophy)

Obesity; Feeding; Neurometabolism; GLP-1R; Reward

English

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2026-07-21