Dorsomedial striatal GABA dynamics organize palatable reward consumption and are reshaped by GLP-1 receptor agonism

Abstract

Palatability and metabolic state strongly shape food consumption, making it important to understand the neural mechanisms that integrate these influences. Glucagon-like peptide-1 (GLP-1) receptor agonists are potent modulators of food intake and increasingly used therapeutic options, yet the circuit mechanisms underlying their effects remain unclear. Dorsal striatal inhibitory circuits contribute to reward-guided behavior and feeding, but how they encode ongoing consumption or are altered by GLP-1 receptor agonism is unknown. Using fiber photometry in mice, we found that dorsomedial striatal (DMS) GABA signals decreased at consumption onset, scaled with palatability, predicted licking, and were enhanced by food deprivation. GLP-1 receptor agonist semaglutide reduced intake, disrupted coupling between DMS GABA and licking, enhanced rebound signals preceding pauses, and increased DMS ensemble synchrony. Optogenetic excitation of DMS GABAergic interneurons reproduced key semaglutide-induced changes in consumption structure. These findings suggest that DMS GABA dynamics, as a state-dependent regulator of palatable consumption, are reshaped by GLP-1 receptor agonism.