Circuit Mechanisms of Retrospective Memory-Linking

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

Project Summary The central goal of this proposal is to investigate the circuit mechanisms of memory linking, specifically how aversive memories retrospectively update and link to past neutral memories during post-encoding offline periods to influence future behavior, such as avoiding dangerous situations. Memories are encoded in a sparse neural ensemble during learning and then stabilized by offline reactivation that occurs primarily during sleep. We predict that hippocampal ensemble reactivation during sharp-wave ripples (SWRs) stabilizes recent memories and integrates recent experiences with past memories. We will experimentally test these predictions by recording and manipulating ensemble activity along the dorsoventral hippocampus during the offline period when memories are being stabilized and integrated across time. We will test the hypothesis that a strong aversive experience leads to ensemble reactivation of both a recent aversive memory and a past neutral memory during SWRs in the offline period, thus linking the two memories. Importantly, we will assess how the magnitude of the aversive experience impacts hippocampal ensemble reactivation of recent and previously encoded memories during SWRs. We will next test the hypothesis that ensemble reactivation of a past neutral event during SWRs is necessary for memory integration to occur. We will use immediate-early gene tagging methods to tag specific memory ensembles and then use our closed-loop optogenetics system to selectively inhibit hippocampal ensemble reactivation during SWRs to prevent linking. This proposal will provide novel insight into how ensemble reactivation during SWRs along the dorsoventral hippocampus support integrating memories across time.