Repeated experience drives multiscale engram reorganization to shape memory strength and precision

Abstract

How memories are shaped by repeated experiences remains unclear. Reorganization of memory engram could underlie memory transformation. Here, by combining c-Fos-based engram cell tagging with optogenetics, spine imaging, and reactivation analyses in the dentate gyrus (DG) and medial prefrontal cortex (mPFC), we discovered a distinct system-wide engram reorganization following repeated learning; that is, a reshuffling of engram cells in the DG, as well as the rapid maturation of mPFC engram cells, forming a dual engram distributed within the hippocampal-mPFC network. These mPFC engram cells were crucial for relearning-dependent enhancement of memory precision. In addition, we found that reactivation of DG engram cells during retraining is critical for engram reorganization-dependent memory strengthening. These findings establish a causal link between engram reorganization and memory transformation by relearning.