Aging alters the distribution, stability, and transcriptional signature of engram cells

While aging impairs memory precision, its effects on engram dynamics and gene expression remain poorly understood. Here, we used nuclear tagging and FOS-based activity mapping to track neurons activated during contextual fear memory encoding and recall in young and aged mice. Brain-wide quantification revealed age-dependent differences in engram activation, spatial distribution, and functional connectivity between memory-related brain regions. To investigate the molecular basis of these changes, we combined nuclear sorting with single-nucleus RNA sequencing, and identified transcriptional signatures associated with memory recall across neuronal cell types further dissected through the comparison of first- and second-time responder neurons. In aged mice, recall-associated engrams showed reduced reactivation and coordination of activity-dependent transcription, particularly in the dentate gyrus, consistent with increased inhibitory engagement by somatostatin-expressing interneurons. These findings reveal age-related changes in the organization and molecular identity of memory traces, providing mechanistic insight into cognitive decline and potential targets for intervention. Aging affects memory precision, but the exact impact of aging on engrams is not well understood. Here the authors show that aging reduces neuronal reactivation, disrupts coordinated activity-dependent gene expression, and increases inhibitory interneuron engagement in mice.