Hippocampal cells multiplex positive and negative engrams

The hippocampus is involved in processing a variety of mnemonic computations specifically the spatiotemporal components and emotional dimensions of contextual memory.[1][1]–[3][2] Recent studies have demonstrated vast structural and functional heterogeneity along the dorsal-ventral axis[1][1], [5][3] of the hippocampus. The ventral hippocampus has been shown to be important in the processing of emotion and valence.[6][4]–[9][5] Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated cell populations and projections that respond to appetitive and aversive experiences. Next, using RNA sequencing and DNA methylation sequencing approaches, we find that vHPC appetitive and aversive engram cells display distinct transcriptional programs and DNA methylation landscapes compared to a neutral engram population. Additionally, while optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive appetitive or aversive behavior in real-time place preference, stimulation of tagged vHPC terminals projecting to the amygdala and nucleus accumbens (NAc), but not the prefrontal cortex (PFC), had the capacity drive preference and avoidance. These terminals can also undergo a “switch” or “reset” in their capacity to drive either, thereby demonstrating their adaptable contributions to behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally distinct populations of cells processing appetitive and aversive memory engrams. Together, our findings provide a novel means by which to visualize multiple engrams within the same brain and point to their unique genetic signatures as reference maps for the future development of new therapeutic strategies. One sentence summary The hippocampus contains neurons that correspond to positive and negative engrams, which are segregated by their molecular, cellular, and projection-specific features. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-3 [3]: #ref-5 [4]: #ref-6 [5]: #ref-9