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

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, alternative regions supporting CFC learning 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.