Wenger, N. H. | Search bioRxiv

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2025

Dorsolateral striatal acetylcholine reorganizes neural ensembles to anticipate threat

Adaptive behavior requires flexible encoding of emotional valence. Although striatal acetylcholine (ACh) signaling is critical for reinforcement learning, its contribution to aversive learning has remained poorly defined. Here, we demonstrate that ACh release in the dorsolateral striatum (DLS) is selectively biased toward negative valence. Using fiber photometry with a genetically encoded ACh sensor, we found that ACh release robustly increased during threat prediction but decreased in anticipation of rewarding outcomes, revealing a bidirectional and valence-specific signature. Optogenetically stimulating ACh release at cue onset accelerated threat learning, impaired extinction, and shifted behavioral responding toward persistent threat expectancy. Concurrent single-cell calcium imaging and optogenetic manipulation revealed that elevated ACh release dynamically reorganized DLS ensemble activity, increasing both excited and inhibited neurons and producing large-scale state-space divergence during threat cues. During extinction, optogenetically sustained ACh release preserved the organization of threat-predictive DLS ensemble activity despite the absence of shock. These findings identify DLS ACh as a valence-specific neuromodulatory signal that reconfigures striatal network dynamics, primes ensembles for impending threat, and biases learning toward threat persistence.

neuroscience↗