Extinction Training Suppresses Alcohol Relapse by Inhibiting Acquisition-Recruited Striatal Ensembles and Engaging Striosomal Neurons

Relapse to alcohol use is frequently triggered by re-exposure to alcohol-associated cues, and extinction-based interventions reduce relapse vulnerability. However, the cellular mechanisms through which extinction suppresses alcohol seeking remain unclear. Using a mouse model of operant alcohol self-administration, we examined how extinction training alters activity of defined striatal direct-pathway medium spiny neuron (dMSN) populations in the dorsomedial striatum (DMS). Extinction significantly reduced cue-induced reinstatement and decreased reactivation of acquisition-recruited dMSN ensembles during relapse. Chemogenetic activation of acquisition-recruited dMSN ensembles during extinction impaired extinction learning and enhanced subsequent reinstatement, even in the absence of manipulation at test, indicating that suppression of these ensembles is required for effective extinction. In contrast, selective activation of striosomal dMSNs during extinction accelerated extinction learning and further reduced reinstatement without affecting locomotor activity. These findings demonstrate that extinction suppresses alcohol seeking through coordinated modulation of distinct striatal dMSN populations, involving both reduced engagement of acquisition-related ensembles and recruitment of striosomal circuits. Together, these findings provide mechanistic insight into how extinction reshapes striatal circuitry to suppress relapse-related behavior and highlight defined striatal dMSN populations as potential substrates for enhancing extinction-based interventions.