THE REINSTATEMENT OF AN INFANTILE MEMORY BINDS FORGOTTEN EXPERIENCE TO A NEW ENGRAM

Early-life experiences, especially when traumatic, shape adult behavior despite being forgotten. Rodent studies show that these forgotten memories persist in a latent state beyond infantile amnesia, can influence learning during adulthood, and their supporting neuronal ensembles (the infantile memory engram, iEngram) retain the ability to trigger memory retrieval when artificially reactivated. Yet, the physiological mechanisms by which forgotten infantile memories are naturally reinstated to shape adult behavior remain unknown.
Here, we show that the reinstatement of a forgotten infantile memory is triggered by a precise sequence of contextual reminders, and is supported by a temporally structured process in which hippocampal iEngram neurons act as a dynamic scaffold that binds latent experiences with a new neuronal ensemble. Using engram labeling technology, calcium imaging, and optogenetics, we show that iEngram neurons actively participate in hippocampal network dynamics during adulthood, despite failures in natural recollection of their associated memory. Their activity is central to memory reinstatement, which unfolds in three steps. First, a contextual reminder primes the hippocampal network for increased recruitment of iEngram neurons during a subsequent aversive reminder. This second reminder tags iEngram neurons for offline reactivation, when in step three their repeated co-firing during synchronous network events binds the latent memory with a newly emerging ensemble, reinstating behavioral responses. Our results thus show that infantile memory engrams mediate the enduring influence of early-life experiences on behavior by constraining the formation of new memory traces during offline network events, which can be targeted to prevent traumatic memory reinstatement.