A coordinated and enhanced brain network supports the persistence of long-term cocaine memory.

The persistence of drug memories accounts for the high risk of drug relapse, which is a major challenge in the treatment of substance use disorders. However, the neurobiological underpinnings, especially the dynamic changes of brain networks underlying long-term drug memories, remain unclear. Here we utilized cocaine conditioned place preference (CPP) in rats combined with c-Fos mapping in multiple brain regions and network analysis to assess dynamic patterns of neural activity and functional memory networks following the recall of short-term and long-term cocaine memory. Furthermore, we employed chemogenetic interventions to disrupt the core nodes within the long-term memory network. Our results showed that the recall of long-term cocaine memory is characterized by more extensive and stronger neuronal activation, greater interregional co-activation, and a more coordinated and stable brain network, compared to short-term cocaine memory. Within this reorganized network, the retrosplenial cortex (RSC) emerged as a key hub. Chronic inhibition of RSC disrupted the network and impaired the recall of the long-term memory. These findings demonstrate that the persistence of cocaine memory is encoded by a large-scale reorganization toward a more integrated and stable brain state, and identify the RSC as a critical cortical node orchestrating this process, offering a potential target for relapse prevention strategies.