Epigenetic and transcriptional basis of memory engram plasticity

Introduction

Neuroplasticity underlies learning and memory formation, which allows for the accumulation of knowledge. There is an emerging view that a sparse ensemble of neurons, termed as engram cells, represent the 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.

Research Questions

However, there are still fundamental questions remaining to be solved regarding:

1. Epigenetic and transcriptional basis of recent and remote memory formation.
2. Heterogeneous identity specification of engram cells.

Methodology

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.

Epigenetic and Transcriptional Mechanisms

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.

Heterogeneity of Engram Cells

Next, I will address the heterogeneity of engram cells and reveal how a subset of engram cells may become functionally relevant during memory consolidation and retrieval.

Innovative Approaches

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.

Validation of Findings

To validate the relevance of my findings, I will also carry out functional analysis including gene knocking-down and optogenetics approaches.

Conclusion

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.