Ventral striatum control of spatial memory consolidation in the hippocampus

New representations, such as those formed during exploration of novel environments, are initially encoded by the hippocampus (HPC) in a labile form and can subsequently be lost or stabilized into long-term memory. It has been proposed that rewarding signals from the ventral striatum (VS) contribute to this stabilization process, prioritizing which information is consolidated into lasting memory traces. However, the pathway through which VS signals influence the HPC has remained unclear. Using transgenic mice expressing a Cre-dependent reporter (dTomato), we identified an indirect pathway from the VS to the HPC via the ventral tegmental area (VTA). To this end, we injected AAV1-Cre, which has anterograde trans-synaptic properties, into the VS. Simultaneously, a second AAV was injected into the VTA to enable Cre-dependent expression of the inhibitory DREADD hM4Di and the fluorescent reporter mCitrine. This allowed us to visualize mCitrine-positive fibers in HPC originating from labeled VTA neurons directly receiving VS inputs. To examine the functional relevance of this circuit, we inhibited these VTA neurons by administering CNO into the HPC immediately after training in CD1 mice in the Morris water maze. This manipulation significantly impaired the animals’ ability to locate the hidden platform 24 hours later, indicating disrupted memory consolidation. A separate cohort will be tested for remote memory after 30 days. These findings reveal a VS–VTA–HPC circuit that modulates memory consolidation, highlighting a key role of the VS in shaping the persistence of memories through bottom-up regulation of HPC activity.