NUCLEUS ACCUMBENS CONTROL OF VTA MODULATION OF HIPPOCAMPAL MEMORY CONSOLIDATION

New memory traces are first encoded by the hippocampus (HPC) in an unstable manner. Only a subset of the information encoded undergoes stabilization into long-term memory, suggesting the existence of a mechanism governing which memory trace to consolidate for long-term storage. Reward-related signals from the nucleus accumbens (NAc) have been proposed to contribute to this process. To test this hypothesis, we injected AAV1-hSyn-Cre, which has anterograde trans-synaptic properties, in the NAc of transgenic mice expressing a Cre-dependent reporter. Simultaneously, a second AAV that enables Cre-dependent expression of EGFP was injected into the VTA. This approach allowed visualization of EGFP-positive fibers in the dorsal HPC (dHPC) originating from labeled VTA neurons directly receiving NAc inputs. Employing the same experimental approach, we examined the functional relevance of this circuit in memory stabilization. An inhibitory DREADDs was expressed in VTA neurons in a Cre-dependent manner, ensuring the expression of the DREADDs only in VTA neurons that receive NAc-projections. We inhibited these VTA projections by administering CNO into the dHPC immediately after a massed training protocol of the Morris Water Maze in CD1 mice. This manipulation significantly impaired animals’ ability to locate the hidden platform 24 hours and 30 days after training, indicating disrupted recent and remote memory consolidation. Taken together, these findings reveal a NAc–VTA–HPC circuit that modulates both recent and remote memory consolidation. Our results identify the nucleus accumbens as a key structure shaping memory persistence through bottom-up regulation of hippocampal activity.