Dual-engram architecture within a single striatal cell type distinctly controls alcohol relapse and extinction

Relapse remains a major obstacle in treating alcohol and drug addiction and is thought to be driven by persistent drug-associated memories formed during use. Extinction training reduces relapse and is proposed to generate a competing memory, yet where and how these opposing memories are stored is unknown. Here, we show that two anatomically and functionally distinct engram ensembles within the same striatal cell type, direct-pathway medium spiny neurons (dMSNs), encode these opposing memories in mice. Operant alcohol learning recruits a broadly distributed dMSN ensemble that encodes relapse-promoting alcohol memories. By contrast, operant extinction recruits a striosome-enriched dMSN ensemble that encodes an extinction memory to suppress relapse. We further demonstrate that relapse-promoting memory is embedded in persistently strengthened corticostriatal synapses engaged during learning and that mimicking this synaptic strengthening is sufficient to drive relapse-like behavior. Together, these findings reveal a dual-engram architecture within dorsostriatal dMSNs governing relapse and extinction.