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bioRxiv · 10.1101/2025.06.05.658072

Neurogenesis-dependent transformation of hippocampal memory traces during systems consolidation

Golbabaei, A.·Coelho, C. A. O.·de Snoo, M.·Josselyn, S.·Frankland, P.
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Abstract

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 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, here we 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 (freezingA {equiv} freezingB 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 monitored the resolution of these artificially-generated memories at recent versus remote post-conditioning delays by testing mice in contexts A and B. Hippocampal engrams for a fear conditioning event were initially high-resolution (recent delay: freezingA >> freezingB) but lost resolution with time (remote delay: freezingA {equiv} freezingB). In contrast, cortical engrams were initially low-resolution and remained low-resolution over time (recent and remote delay: freezingA {equiv} freezingB). Transformation of hippocampal engrams was dependent on adult hippocampal neurogenesis. Eliminating hippocampal neurogenesis arrested hippocampal engrams in a recent-like, high-resolution state where mice continued to exhibit discriminative freezing at remote delays. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/658072v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1aec109org.highwire.dtl.DTLVardef@36e20org.highwire.dtl.DTLVardef@1332e46org.highwire.dtl.DTLVardef@123215d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Golbabaei, A., Coelho, C. A. O., de Snoo, M., Josselyn, S., Frankland, P.. 2025-06-06. Neurogenesis-dependent transformation of hippocampal memory traces during systems consolidation. https://doi.org/10.1101/2025.06.05.658072

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