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

Cesar A O Coelho,Maria Gabriela M Oliveira,Tatiana L Ferreira,João R Sato,Juliana C Kramer-Soares,Daniel Bush

doi:10.1371/journal.pcbi.1006207

Abstract

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.

Highlights

Brain lesions provide evidence primarily about the extent to which a brain function can persevere in the absence of the damaged region
In contextual fear conditioning (CFC), hippocampal lesions reveal a complex relation to contextual memory, as they result in profound retrograde amnesia, but often result in no anterograde amnesia [post-lesion events; 3, 4, 5] under defined circumstances [6], suggesting that new learning can be supported by the reminiscent regions
Experiment 1—Network underlying contextual fear learning in the absence of dorsal hippocampal lesion (dHPC)

Summary

Introduction

Brain lesions provide evidence primarily about the extent to which a brain function can persevere in the absence of the damaged region. The CFC learning after hippocampal lesion inspired cognitively-oriented hypotheses about the content learned by non-hippocampal regions These accounts differ on whether the contextual representation without hippocampus is fragmented [elemental; 10, 11] or is— still—a configural representation [reviewed in 12], it is well accepted that learning under hippocampal loss is likely to be 1) different in terms of content learned, 2) less efficient and 3) more prone to generalization and decay over time [12,13,14]. Parahippocampal cortices were pointed out as putative candidates [11], the regions supporting CFC learning after hippocampal lesion have not been empirically addressed Investigating how these regions learn and store CFC information can help to understand the dynamics of hippocampal function and its interactions within the memory systems

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Discussion

Conclusion