Aging disrupts transcriptional programs for memory updating in the dorsal hippocampus and reveals a required role for Tent5a in reconsolidation.

UNLABELLED: Existing memories can be updated with new information through a process known as reconsolidation, though the molecular mechanisms underlying this process are poorly understood. Additionally, memory updating is impaired with aging, but little is known about how this impairment occurs. Here, we used a hippocampus-dependent memory updating task alongside transcriptomics to identify which genes are upregulated in the dorsal hippocampus specifically during a memory update in both young adult mice, which show successful memory updating, and in old mice, which do not. In young mice, we observed that distinct transcriptional programs were activated by reconsolidation-dependent memory updating and memory retrieval without new information. In old mice, similar transcriptional programs were engaged by both memory updating and memory retrieval. From our sequencing results, we identified Tent5a as a novel regulator of reconsolidation-mediated memory updating, and we demonstrate that hippocampal expression of Tent5a is necessary for this process. Together, these results expand our understanding of both the underlying transcriptional mechanisms of memory updating and how these mechanisms go awry in the aged brain. SIGNIFICANCE STATEMENT: Many studies have examined the transcriptional mechanisms that contribute to memory formation, typically relying on highly controlled exposures to isolated stimuli. However, memories are not formed in isolation, and the brain constantly integrates new experiences into existing memories and information stores to drive optimal behavior. This process of memory updating is preferentially impaired with aging yet has received relatively little attention in the scientific literature. Here we compared gene expression during memory updating in the dorsal hippocampus of young adult mice (which successfully update memories) and old mice (which do not). These results expand our understanding of how transcriptional mechanisms change with age and how these changes contribute to age-related deficits in understudied aspects of cognition, like memory updating.