Drug-Related Engrams and Their Role in the Persistence and Recurrence of Drug-Related Behaviors

Memory is a cornerstone of human behavior, and addiction offers a compelling model of its persistence and plasticity. The scope of engram research has rapidly expanded to include addiction-related phenomena. Addiction-related memories, like strong aversive memories, are often highly resistant to extinction and can continue to drive relapse long after drug use has ceased. These enduring behavioral effects suggest that drug engrams, sparsely distributed neural ensembles encoding drug-associated experiences, are stabilized by powerful synaptic and molecular plasticity. At the same time, their very malleability may hold the key to developing new treatments. This minireview synthesizes emerging findings on drug engrams, highlighting the specialized circuits, molecular mechanisms, and behavioral consequences tied to addiction-related memory traces. We focus on how engram tagging and reactivation techniques have revealed addiction-specific ensembles across several brain regions and important pathways that promote or attenuate drug-seeking behavior. We also discuss how direct manipulation of drug engrams may hold promise for weakening the influence of drug-associated cues and other relapse triggers, while enhancing protective circuits to reduce relapse risk. Still, fundamental questions remain such as how do drug engrams evolve during the transition from recreational use to addiction? Addressing these questions will be critical for developing circuit-informed, lasting interventions that target the memory systems sustaining addiction.