Reorganization of cortical memory ensembles across time

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Project Summary Memory of a single event can last a lifetime. Certain experiences can guide behavior minutes, months, and years after the event has transpired. For this to happen, the brain must encode the relevant information from the event, retain it for an indeterminate amount of time, then retrieve that memory when given appropriate cues. Previous work has shown that retrieval of a fearful experience is behaviorally similar across recent and remote retrieval times of a memory, yet the neural circuits mediating that memory are importantly different across the memory timeline. In short, behavior remains stable while neural activity is dynamic. Evidence suggests that memories are reorganized across time – increasingly involve a distributed cortical network. Although we have identified several independent cortical regions that participate in remote memory, our understanding of how they interact at the and the nature of these changes is lacking My preliminary data indicates that an uninvestigated medial prefrontal cortex (mPFC) projection coordinates remote but not recent memory via projections to association cortex. Further exploration is needed to determine the specific activity patterns in these circuits during memory retrieval over time. These discoveries would reveal fundamental principles by which the brain organizes and retrieves salient experiences across time. The overall goal of this proposal is to investigate the cell-type specific changes that occur in mPFC ensembles as fear memories reorganize from recent to remote and to determine the nature of this reorganization. Based on published work from my mentor and my preliminary findings, my project will focus on the connection between mPFC and auditory association areas. To address these questions, I will use circuit-specific, optogenetic approaches to establish necessity and sufficiency of a mPFC–cortical association circuit for remote memory. This will address the functional role of these mPFC projection neurons. I will then use freely-moving calcium imaging to record the activity of these cells at both recent and remote memory timepoints in order to examine how these mPFC neurons encode and behavior and task variables across memory timepoints. Finally, with a combined viral-genetic approach, I will label activity-dependent ensembles while employing whole-brain circuit mapping to understand the anatomical relationship between recent and remote ensembles and their downstream connections. Together, these aims will reveal novel insights into the time-dependent changes in memory organization and enhance our understanding of mPFC function in organizing cortical networks, potentially identifying improved circuits to target for treatment of fear disorders (e.g. Post Traumatic Stress Disorder).