Persistent transcriptional programs are associated with remote memory in diverse cells of the medial prefrontal cortex

Abstract

It is thought that memory is stored in engrams, a subset of neurons that undergo learning-induced alterations. The role of gene-expression during learning and short-term memory has been studied extensively, but little is known about remote memory that can persist for a lifetime. Using long-term contextual fear memory as a paradigm, an activity-dependent transgenic model for engram-specific labeling, and single-cell transcriptomics we probed the gene-expression landscape underlying remote memory consolidation and recall in the medial prefrontal cortex. Remarkably, we find sustained activity-specific transcriptional alterations in diverse populations of neurons that persist even weeks after fear-learning and are distinct from those previously identified in learning. Out of a vast plasticity-coding space, we uncover select membrane-fusion genes that could play important roles in maintaining remote memory traces. Unexpectedly, astrocytes and microglia also acquire new persistent gene signatures upon recall of remote memory, suggesting that they actively contribute to memory circuits. Our discovery of novel distinct gene-expression programs involved in long term memory adds an important dimension of activity-dependent cellular states to existing brain taxonomy atlases and sheds light on the elusive mechanisms of remote memory storage.