Decoding the Neural Circuit Underlying Context-Cue Association in Retrieval of Morphine Reward Memory

Context-induced relapse is a major challenge in treating drug use disorders, yet the neural circuits underlying drug memory retrieval remain unclear. A glutamatergic projection from the ventral CA1 (vCA1) to the dorsomedial prefrontal cortex (dmPFC) is identified as a critical pathway for morphine reward memory retrieval. In vivo monitoring and ex vivo electrophysiology show that vCA1 inputs engage distinct dmPFC neuronal populations and differentially regulate local parvalbumin (PV+) and somatostatin (SST+) interneurons, thereby reshaping cortical output during memory retrieval. Pathway-specific inhibition abolishes cue-induced memory retrieval, which is restored by local NMDA administration, whereas blockade of NMDA receptors in the dmPFC impairs retrieval during pathway activation, supporting a critical role for NMDA receptor signaling in memory retrieval driven by vCA1 input. Beyond reward memory, chronic inhibition of the vCA1-dmPFC pathway attenuates somatic withdrawal and the development of analgesic tolerance without affecting the acute analgesic effect of morphine. Together, these findings reveal a cell-type-specific hippocampal-prefrontal mechanism regulating opioid-associated maladaptive behaviors and provide a potential circuit-level strategy to reduce addiction-related consequences while preserving morphine analgesia.