Hippocampal cells multiplex positive and negative engrams

Abstract

The hippocampus is involved in processing a variety of mnemonic computations including the spatiotemporal components, as well as the corresponding emotional dimensions, of contextual memory.^1–3 Recent studies have demonstrated vast structural and functional heterogeneity along the dorsal-ventral axis⁴ of the hippocampus, and while much is known about how the dorsal hippocampus processes spatial-temporal content, much less is known about whether or not the ventral hippocampus (vHPC) partitions positive and negative experiences into distinct sets of cells.^4–9 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, albeit physiologically similar, populations that respond to positive and negative experiences. Next, using an RNA Sequencing approach, we find that vHPC positive and negative engram cells display distinct transcriptional programs in which neurodegenerative- and neuroprotective-related gene sets are enriched, respectively. Additionally, while optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive behavior, tagged vHPC terminals projecting to the amygdala and nucleus accumbens, but not the prefrontal cortex, have the capacity to drive preference and avoidance when stimulated, as well as to “switch” or “reset” their capacity to drive either, thereby demonstrating their flexible contributions to behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally distinct populations of cells processing positive and negative 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 putative avenues for future therapeutic interventions.