MemoPlasticGenomics · Epigenetic and transcriptional basis of memory engram plasticity

Neuroplasticity underlies learning and memory formation, which allows for accumulation of knowledge. There is an emerging view that a sparse ensemble of neurons, termed as engram cells, represent memory substrate and explain how memory is formed and retrieved. Extensive studies have been carried out to reveal molecular mechanisms regulating structural and synaptic plasticity of memory engram cells. However, there are still fundamental questions remaining to be solved regarding epigenetic and transcriptional basis of recent and remote memory formation, and heterogeneous identity specification of engram cells. To address these issues, I will carry out state-of-the-art genomics/epigenomics analysis of engram cells that are permanently labelled during recent and remote fear memory consolidation. Firstly I will reveal epigenetic and transcriptional mechanisms regulating active-silent state shifts of engram cells during systems memory consolidation in the hippocampus and neocortical regions. Next I will address heterogeneity of engram cells and reveal how a subset of engram cells may become functionally relevant during memory consolidation and retrieval. To particularly address the latter issue, on top of existing sequencing technologies, I will also apply a novel “time machine”-like retrospective whole-genome history tracing approach to obtain molecular profiles of a given timepoint in the past, and overcome the critical limitation of current snapshot-type technologies. To validate relevance of my findings, I will also carry out functional analysis including gene knocking-down and optogenetics approaches. My interdisciplinary research program will shed new light on how environmental cues, including cell-to-cell interaction mediated by neuronal activity and signalling molecules, can be integrated with intrinsic cellular states at the chromatin epigenetic level to regulate neuroplasticity underlying memory engram cell state and/or identity specification.