Neurogenesis-dependent transformation of hippocampal memory traces during systems consolidation

Memories for events (i.e., episodic memories) change qualitatively with time. Systems consolidation theories posit that organizational changes accompany qualitative shifts in memory resolution, but they differ as to the locus of this reorganization. Whereas some theories favor inter-regional changes in organization (e.g., hippocampus → cortex; multiple trace theory), others favor intra-regional reorganization (e.g., within-hippocampus; trace transformation theory). Using an engram-tagging and manipulation approach in mice, we here provide evidence that intra-regional changes in organization underlie shifts in memory resolution. We establish that contextual fear memories lose resolution as a function of time, with mice exhibiting conditioned freezing in both the training apparatus (context A) and a second apparatus (context B) at more remote delays (i.e., freezing_A ≡ freezing_B at remote delay). By tagging either hippocampal (dentate gyrus) or cortical (prelimbic cortex) neuronal ensembles in context A, and then pairing their optogenetic activation with shock (in context C), we tracked time-dependent changes in the resolution of either "context-only" or "context-shock" engrams by testing mice in contexts A and B. Hippocampal context-only or context-shock engrams were initially high resolution (i.e., recent delay: freezing_A >> freezing_B) but lost resolution with time (i.e., remote delay: freezing_A ≡ freezing_B). In contrast, cortical context-only or context-shock engrams were initially low resolution and remained low resolution over time (i.e., recent and remote delay: freezing_A ≡ freezing_B). Transformation of hippocampal engrams was dependent on adult hippocampal neurogenesis. Eliminating hippocampal neurogenesis arrested hippocampal engrams in a recent-like, high-resolution state in which mice continued to exhibit discriminative freezing at remote delays.