Cognition and behavior

Publication date: 14/05/2025

Authors: Sangyoon Y. Ko, Yiming Rong, Adam I. Ramsaran et al.

Journal: Nature

Commentary: Episodic memories are not permanently stored as exact representations of past experiences. Instead, with time they progressively lose their precision and become more “gist-like”, allowing acquired knowledge to be flexibly generalized and used to guide behaviour in novel but related situations. How this transformation emerges at the cellular and circuit level has remained largely unclear. In this study, Ko and colleagues demonstrate that hippocampal engram circuits undergo a progressive reorganization that supports the emergence of generalized memory representations. Using contextual fear conditioning in mice, the authors show that memory retrieval is initially highly context-specific but progressively generalizes to similar environments over time. By permanently tagging hippocampal engram neurons activated during learning and tracking their reactivation during remote recall, they found that CA3 and CA1 engram populations originally encoding the conditioning experience become progressively reactivated even in related, although non-identical, contexts. This progressive “promiscuous” reactivation provides a compelling cellular correlate of gist memory formation. To understand how hippocampal memories become more generalized over time, the authors examined structural changes within engram circuits and observed a time-dependent reorganization of hippocampal connectivity. Specifically, remote gist-like memories were associated with reduced feed-forward inhibition in DG-to-CA3 circuits, together with increased connectivity and synaptic clustering between CA3 and CA1 engram neurons. Together, these circuit changes are likely to promote the promiscuous reactivation of hippocampal engram populations in related contexts during remote recall. Importantly, this restructuring of hippocampal engram circuits was bidirectionally modulated by hippocampal neurogenesis. Preventing neurogenesis maintained precise memories and blocked engram reorganization, whereas increasing neurogenesis accelerated both circuit remodelling and memory generalization. These findings further suggest that physiological levels of neurogenesis may support adaptive memory generalization, whereas excessive remodelling could potentially contribute to forgetting. Overall, this work suggests that memories are not simply weakened with time but are dynamically restructured within hippocampal circuits to generate flexible representations that can support adaptive behaviour in changing environments.

Commented by: Maria Italia

DOI: 10.1038/s41586-025-08993-1