Brain-wide Epigenetic Mapping of Memory Engram Cells
A memory engram is thought to be the physical substrate of the memory trace within the brain, which is generally depicted as a neuronal ensemble activated by learning to fire together during encoding and retrieval. Nowadays, emerging evidence supports the postulation that memory engram exhibits a multiscale organization both at a brain network level and at an epigenetic state. However, as engram cells have mainly been visualized in a limited number of brain regions, functionally connected engram ensemble complex distributed across the entire brain have only started to be illustrated. Furthermore, as epigenetic mechanisms underlying memory formation and storage have mainly been studied at heterogeneous whole tissue level, engram cell-specific epigenetic modifications have only started to be elucidated. To fill these loopholes, my project aimed to generate a composite image of whole brain fear memory engram epigenetics (which I refer to as "epi-engram") throughout memory consolidation. By applying iDISCO+ optical clearing, light sheet microscopy and semi-automated 3D colocalization analysis, we overcome the technical bottleneck of whole mount multiple immunostaining to visualize activity-tagged neurons in the TRAP2-tdTomato mouse line, concomitantly with the neuronal activation marker cfos, and various histone phospho-methylation or phospho-acetylation marked-neuronal ensembles. Doing so, my result thus far has revealed that contextual fear memory encoding specifically triggers an increase in recruitment of cfos+ H3S10pK9me3+ and cfos+ H3S28pK27me3+ epi-engram cells, which indicates the association with heterochromatin during transcriptional activation, among memory-related brain regions. Ultimately, we hope that such brain-wide epi-engram mapping will demonstrate how memory consolidation is orchestrated by chromatin states within engram cells.
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