de Snoo, M. | Search bioRxiv

bioRxiv2025

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 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

neuroscience↗

bioRxiv2023

Neurogenesis-mediated circuit remodeling reduces engram reinstatement and promotes forgetting

Post-training increases in hippocampal neurogenesis are associated with forgetting of hippocampus-dependent memories in adult mice. This form of forgetting might be due to increased numbers of new neurons, remodeling of hippocampal circuitry or some combination of both. Here we tested the hypothesis that neurogenesis-mediated forgetting is caused by remodeling of hippocampal circuits by engineering mice in which adult-generated granule cells hypo- or hyper-integrate into hippocampal circuits. Using gene deletion, opto- and chemogenetic strategies, we find that hypo-integration of newborn neurons prevents post- training exercise-induced forgetting of contextual fear memories. Conversely, inducing hyper- integration of newborn neurons following contextual fear conditioning is sufficient to produce forgetting. Because these interventions did not affect survival of newborn neurons, these findings suggest that neurogenesis-mediated remodeling of hippocampal circuits represents a continuous and active form of interference that alters accessibility of engrams underlying hippocampal memories. Consistent with this, using engram-labeling approaches, we found that exercise-induced forgetting was associated with reduced engram reactivation.

neuroscience↗