Brain dynamics underlying long-term memory consolidation

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Abstract The hippocampus has a well-established role in the initial formation and storage of memory. However, little is understood about brain mechanisms that support the re-organization and transfer of memories into longer-term cortical storage. A detailed understanding of hippocampal- to-cortical consolidation is critical to shed light on the regulation of long-term memories, and how they may become too transient (as in Alzheimer’s, Parkinson’s, Traumatic Brain Injury) or too persistent (as in PTSD). One challenge has been the difficulty inherent to tracking the real-time cellular resolution activity of multiple brain regions throughout the weeks-to-months long consolidation window. Toward this, we have recently developed a head-fixed behavioral paradigm, compatible with longitudinal imaging, where mice learn to form and main contextual associations for at least one month. We have also found that learning of this task requires the hippocampus, while memory consolidation requires the entorhinal and prefrontal cortex. Using methods to perform multi-region longitudinal neural activity recordings, together with anatomically-defined optogenetic inhibition during imaging, we propose to dissect the real-time contributions of the hippocampal-entorhinal-prefrontal pathway in memory consolidation. Specifically, we aim to characterize a new behavioral model of memory consolidation (aim 1), and perform longitudinal imaging to identify prefrontal cortex brain activity patterns unique to consolidated memories (aim 2). Finally, we will identify how entorhinal projections stabilize such activity patterns in prefrontal cortex during consolidation (aim 3). Together, we will contribute to our understanding of how some memories are progressively re-organized and stabilized across the brain for long-term storage.