Targeting Maladaptive Memory Circuits in Heroin Addiction: a Review of Non-Pharmacological Interventions for Cognitive Recovery.

Opioid use disorder, notably heroin addiction, is characterized by severe deficits in learning and memory, which contribute critically to high relapse rates. This review synthesizes recent preclinical and clinical evidence positing that addiction pathologically co-opts the brain’s natural memory systems. We focus on dysregulated plasticity within a core network comprising the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), hippocampus (HPC), and basolateral amygdala (BLA). A key advancement is the identification of sparse, stable neuronal ensembles—‘addiction engrams’—within these circuits that physically encode drug-associated memories. We critically evaluate non-pharmacological interventions, including exercise, neuromodulation, and environmental enrichment, for their potential to normalize circuit dynamics and disrupt these maladaptive ensembles. Furthermore, we highlight emerging evidence indicating that the neuroadaptations underlying addiction and treatment response are significantly influenced by sex-specific mechanisms. We conclude that elucidating these sex differences and developing personalized intervention protocols based on individual neural circuitry and temporal dynamics are crucial steps toward effective cognitive rehabilitation in opioid addiction.