Neural dynamics underlying brain state-dependent memory functions

Project Summary/Abstract Mental health disorders associated with memory deficits have been on the rise for a few decades, highlighting the need for understanding the brain mechanisms of memory from a systems neuroscience point of view. One of the outstanding problems regarding the mechanisms of memory is how the brain can continuously incorporate new memories while leaving recently acquired knowledge intact. The current accepted model sets that recently acquired memories are reactivated in the hippocampus during sleep, an initial step for memory consolidation, during sharp-wave ripples (SWRs), hippocampal oscillations important for memory and planning. Yet, this process is concomitant with the hippocampal reactivation of prior memories, posing the problem of how to prevent interference between older and recent, initially labile, memory traces. Theoretical work has suggested that consolidating multiple memories while minimizing interference can be achieved by randomly interleaving their reactivation. Alternatively, a temporal micro-structure that promotes the reactivation of different types of memories during specific substates during the overall course of the sleep could exist. Indeed, work in humans suggests that non-rapid eye (NREM) movement and rapid-eye movement (REM) states can be further subdivided into substages that differently correlate with memory processes. To understand this, we propose to simultaneously monitor memory reactivation (using electrophysiology) in combination with brain states and substates (using pupillometry) in naturally sleeping mice after performing a hippocampal dependent memory task. Our preliminary data show that we can successfully record pupillometry and electrophysiology in naturally sleeping mice and distinguish both NREM and REM phases of sleep. Furthermore, our preliminary data suggest that pupil fluctuations can reveal a previously unknown micro-structure of non-REM sleep and associated memory processes, such as memory replay. Specifically, our preliminary data show that memory replay of recent experiences dominated in sharp-wave ripples (SWRs) during contracted pupil substates of non-REM sleep, while replay of prior memories preferentially occurred during dilated pupil substates. Initial experiments show that closed-loop disruption of SWRs during contracted pupil non-REM sleep impaired the recall of recent memories, while the same manipulation during dilated pupil substates had no behavioral effect. We will investigate what are the underlying mechanisms of the distinct pupil associated memory processes during NREM sleep. If successful, the results of this proposal will solve a long-standing question in traditional neuroscience of learning and memory: how the brain can multiplex distinct cognitive processes during sleep to facilitate continuous learning without interference. Applying the concept of isolating pupil-guided cognitive substates to other domains (such as learning or attention) can offer novel insights into our current understanding of cognition. Importantly, using this methodology during pathological conditions can inform current diagnosis pipelines of different mental health conditions associated with memory deficits.