Ventral striatum control of spatial memory consolidation in the hippocampus

New representations, such as those formed during the exploration of novel environments, are initially encoded by the hippocampus (HPC) in a labile form and can subsequently be either lost or stabilized into long-term memory. Reward-related signals from the ventral striatum (VS) have been proposed to contribute to this stabilization process by prioritizing which information is consolidated into lasting memory traces [1][2]. One possible mechanism through which the VS could modulate memory stabilization in the HPC involves a polysynaptic pathway through ventral pallidum (VP) and ventral tegmental area (VTA). This hypothesis is supported by evidence showing that VTA projections to HPC can bidirectionally modulate memory [3][4]. However, direct evidence demonstrating that VS serves as the source of the triggering signal to the VTA–HPC pathway is still lacking. Moreover, because VTA is—together with VP—one of the main targets of VS efferent projections, it remains possible that VS-to-HPC modulation of memory occurs through a more direct VS–VTA pathway. To test this hypothesis, we first investigated the existence of a disynaptic pathway form the VS to the HPC via the VTA, next we verified the possibility that the modulation of this pathway could regulate memory stabilization in the HPC. To this end, we injected AAV1-hSyn-Cre in transgenic mice expressing a Cre-dependent reporter (tdTomato), which has anterograde trans-synaptic properties, into the VS. Simultaneously, a second AAV enabling Cre-dependent expression of EGFP (AAV-hSyn-DIO-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 VS inputs. Employing the same experimental approach, we examined the functional relevance of this circuit in memory stabilization. An inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) was expressed in VTA neurons in a Cre-dependent manner, ensuring that only VTA neurons receiving projections from the VS selectively expressed the DREADD. We inhibited these VTA projections by administering Clozapine-N-oxide (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 after training, indicating disrupted long-term memory consolidation (two-way ANOVA repeated measure: quadrant preference F(3,42)=10.1, p<0.0001; interaction F(3,42)=3.0, p=0.041; CNO: N=7, SAL: N=9). Following the same paradigm, a separate cohort was tested for remote memory after 30 days. Similarly, this manipulation led to an impairment in mice’s ability to locate the platform (two-way ANOVA: quadrant preference F(3,48)=11.6, p<0.0001; interaction F(3,48)=3.0, p=0.038; CNO: N=8, SAL: N=10) (some of the data were presented in a preliminary form at FENS2024 and/or EBBS2025). As control, CNO or saline were injected post-training into the dHPC of mice expressing Cre-dependent EGFP instead of the DREADD. In this case, both CNO and saline-treated animals correctly located the platform during the 24-hour probe test (one-way ANOVA repeated measure SAL: F(3,18)=7.6, p=0.0018; CNO: F(3,30)=7.3, p=0.0008; CNO: N=11, SAL: N=7). Taken together, these findings reveal a VS–VTA–HPC circuit that modulates both long-term and remote memory consolidation. This identifies the VS as a key structure shaping memory persistence through bottom-up regulation of hippocampal activity. 1. Lisman, J. E., & Grace, A. A., 2005. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron, 46(5), 703-713. 2. Del Ferraro, G., Moreno, A., Min, B., Morone, F., Pérez-Ramírez, Ú., Pérez-Cervera, L., ... & Makse, H. A., 2018. Finding influential nodes for integration in brain networks using optimal percolation theory. Nature communications, 9(1), 2274. 3. Tsetsenis, T., Badyna, J. K., Wilson, J. A., Zhang, X., Krizman, E. N., Subramaniyan, M., ... & Dani, J. A., 2021. Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories. Proceedings of the National Academy of Sciences, 118(40), e2111069118. 4. McNamara, C. G., Tejero-Cantero, Á., Trouche, S., Campo-Urriza, N., & Dupret, D., 2014. Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nature neuroscience, 17(12), 1658-1660.