Contamination of Engram Coactivity Networks During Forgetting

Abstract

Forgetting is a fundamental component of adaptive memory and essential for cognitive flexibility, yet its cellular basis remains unclear. Here we establish a mouse model of retroactive interference (RI) and show that post-learning novelty exploration induces active forgetting of hippocampus-dependent object location memory only within a discrete consolidation window defined by protein synthesis sensitivity. RI imposed within this window reduces engram reactivation and destabilizes a structured coactivity network formed during learning. Mice that forget retrieve reorganized engram with increased edge turnover and reduced training edge survival during recall. During this vulnerable period, RI infiltrates the engram core, whereas after consolidation it remains confined to the network periphery. Over the consolidation window, the engram network progressively matures, acquiring greater density, similarity, and k-core robustness, features that confer resistance to interference. Importantly, blocking RI infiltration rescues memory formation. Together, these findings show that forgetting arises from reorganization of engram topology during consolidation and identify engram core contamination as a network-level substrate for forgetting.