Dorsal hippocampal CA3 to CA1 circuit maintains contextual cocaine memories in a rat model of drug relapse.

Exposure to a cocaine-associated environment triggers drug craving and relapse by prompting the retrieval of drug-related long-term memories. Upon retrieval, memory traces enter a labile state during which they can be modified until their reconsolidation into long-term memory stores. Disrupting labile memory traces is a promising therapeutic approach for treating neuropsychiatric disorders characterized by maladaptive memories, including substance use disorder. The dorsal hippocampus cornu ammonis 3 (dCA3) is a critical regulator of cocaine-memory strength, and the dorsal CA1 (dCA1) has been implicated in similar processes. Therefore, we tested the hypothesis that monosynaptic input from dCA3 to dCA1 is necessary for maintaining cocaine-memory strength, using circuit-specific optogenetic inhibition. Rats underwent cocaine self-administration training then extinction training in two distinct environmental contexts to acquire contextual cocaine and extinction memories, respectively. They were briefly re-exposed to the cocaine-predictive context then received intermittent dCA3-dCA1 circuit-specific photoinhibition or no photoinhibition immediately after the session (when memories were expected to be labile) or 6 h later (post reconsolidation). dCA3-dCA1 circuit photoinhibition immediately, but not 6 h, after memory retrieval, attenuated drug-seeking behavior in the cocaine-predictive context 72 h later. This effect was opsin-, light-, and context-dependent, and it positively correlated with a decrease in dCA1 neuronal activation at test. This effect was also more robust in female rats, consistent with sex-dependent compensatory synaptic plasticity. Together, these findings suggest that dCA3-dCA1 circuits encode labile cocaine memories, underlie their reconsolidation, or support subsequent long-term memory retrieval.