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 neuroprotective- and neurodegenerative-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.One sentence summaryThe hippocampus contains neurons corresponding to positive and negative engrams, which are segregated by their molecular, cellular, and projection-specific features.

Population dynamics underlying associative learning in the dorsal and ventral hippocampus

“…Consequently, a downstream recipient of these signals could not only decode whether reward is forthcoming, but at the same time the identity of the cue that preceded it, which may be important for updating cue value. Alternatively, it is possible that outcome and cue identity signals present during the trace period are each routed to distinct downstream targets (Beyeler et al, 2016;Namboodiri et al, 2019;Otis et al, 2017), consistent with vCA1 circuitry, where specialized functions are parsed across vCA1 projection pathways (Ciocchi et al, 2015;Jimenez et al, 2018Jimenez et al, , 2020Shpokayte et al, 2020;Xia and Kheirbek, 2020;Xu et al, 2016). Similar to differences in single-cell place field properties across the DV axis, where dCA1 spatial representations are more circumscribed and vCA1 representations generalize across large swaths of space (Jung et al, 1994;Kjelstrup et al, 2008), our cross-time-bin population analysis suggests a more rapid turnover of population activity patterns (neural states) in dCA1 compared to vCA1.…”

Different encoding of reward location in dorsal and intermediate hippocampus

“…17 The different encoding of reward anticipation in dCA1 and iCA1 affects how the signal can be relayed downstream. The reward-anticipatory subpopulation in iCA1 could include nucleus accumbens-projecting neurons controlling appetitive memory [11][12][13]15,36 and exclude those controlling aversion or fear. [36][37][38] In dCA1, the ramping-up population activity resembles that seen in the dopaminergic system.…”

“…The reward-anticipatory subpopulation in iCA1 could include nucleus accumbens-projecting neurons controlling appetitive memory [11][12][13]15,36 and exclude those controlling aversion or fear. [36][37][38] In dCA1, the ramping-up population activity resembles that seen in the dopaminergic system. 39 Such signal could indiscriminately excite downstream targets of dCA1 or recruit specific projection neurons, including the nucleus accumbens-projecting neurons that support spatial appetitive memory.…”

Different encoding of reward location in dorsal and ventral hippocampus

“…vCA1 neurons have divergent outputs 33 . The rewardanticipatory subpopulation could target neurons controlling expression of appetitive memory 11,12,14,[34][35][36] , while avoiding those controlling aversion or fear 27,35,37,38 . In dCA1, the ramping-up of population activity in reward-anticipation resembles that seen in the dopaminergic system 39 .…”