MEMORY CONSOLIDATION DRIVES THE ENHANCEMENT OF REMOTE COCAINE MEMORY VIA PREFRONTAL CIRCUIT

Abstract Background Forming memories are essential for survival, guiding our behaviors based on past experience. The expression of most these memories typically gradually weakens over time as an adaptive process of forgetting. Whereas, in some types of maladaptive memories, such as the drug-cue associated memories which account for the risk of drug relapse, their expression is progressively enhanced from recent memory to remote during prolonged time. Aims & Objectives To investigate the neural circuit underpinnings of the enhancement of remote cocaine-cue associated memory during abstinence. Method We used cocaine self-administration model in rats, together with Ca2+ imaging, immunofluorence, chemogenetic interventions, circuit tracing, and three-dimensional reconstruction of dendritic spine morphologies. Results We found a progressive increase in the response of prelimbic cortex (PrL) CaMKⅡ neurons to cues during 30-day abstinence. Dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, and chronic inhibition of BLA-PrL circuit during abstinence day 1 to 14 could prevent cocaine seeking on day 30. Discussion & Conclusion These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependently increase in activity and maturation of PrL CaMKⅡ neurons receiving a sustained BLA input. We propose that the BLA may function as a cache that integrates the strong association between cocaine and related cues, and during system consolidation BLA can convey this information to PrL for long-term storage. Remarkably, during the early period post- training, more mature and stable dendritic spine plasticity which occurred in PrL neurons receiving BLA input possibly makes the association information abnormally consolidated, inducing stronger response when cue exposure at remote time and leading to enhancement of remote cocaine memory.