Coelho, C. A. O. | bioRxiv Science

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↗

bioRxiv2017

Network supporting contextual fear learning after hippocampal damage has increased dependence on retrosplenial cortex

Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear conditioning (CFC). Although the content learned in the latter have been discussed, the compensating regions were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using inter-regional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belonging to the SHAM network. These results suggest that dHPC network engaged in CFC learning is partially different, and engage alternative hubs. We next tested if pre-training lesions of dHPC and one of the new dHPC network hubs (perirhinal, Per; or disgranular retrosplenial, RSC, cortices) would impair CFC. Only dHPC-RSC, but not dHPC-Per, impaired CFC. Interestingly, only RSC showed a consistently higher centrality in the dHPC network, suggesting that the increased centrality reflects an increased functional dependence on RSC. Our results provide evidence that, without hippocampus, the RSC, an anatomically central region in the medial temporal lobe memory system might support CFC learning and memory.\n\nAUTHOR SUMMARYWhen determined cognitive performances are not affected by brain lesions of regions generally involved in that performance, the interpretation is that the remaining regions can compensate the damaged one. In contextual fear conditioning, a memory model largely used in laboratory rodents, hippocampal lesions produce amnesia for events occurred before, but not after the lesion, although the hippocampus is known to be important for new learning. Addressing compensation in animal models has always been challenging as it requires large-scale brain mapping. Here, we quantified 30 brain regions and used mathematical tools to model how a brain network can compensate hippocampal loss and learn contextual fear. We described that the damaged network preserved general interactivity characteristics, although different brain regions were identified as highly important for the network (e.g. highly connected). Further, we empirically validated our network model by performing double lesions of the hippocampus and the alternative hubs observed in the network models. We verified that double lesion of the hippocampus and retrosplenial cortex, one of the hubs, impaired contextual fear learning. We provide evidence that without hippocampus, the remaining network relies on alternative important regions from the memory system to coordinate contextual fear learning.

neuroscience↗