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Abstract

When exploring new environments animals form spatial memories that are updated with experience and retrieved upon re-exposure to the same environment. The hippocampus is thought to support these memory processes, but how this is achieved by different sub-networks such as CA1 and CA3 remains unclear. My doctoral work aims at studying the CA1 and CA3 network dynamics when animals experience neutral or noxious novel environments and interpreting the underlying function of CA1 and CA3 during memory encoding and recall. In chapter 1, to understand how hippocampal spatial representations emerge and evolve during familiarization with a neutral novel environment, we performed 2-photon calcium imaging in mice running in new virtual environments and compared the trial-to-trial dynamics of place cells in CA1 and CA3 over days. We found that place fields in CA1 emerge rapidly but tend to shift backward from trial-to-trial and remap upon re-exposure to the environment a day later. In contrast, place fields in CA3 emerge gradually but show more stable trial-to-trial and day-to-day dynamics. These results reflect the different roles of CA1 and CA3 in spatial memory processing during familiarization with new environments and constrain the potential mechanisms that support them. In chapter 2, to study the network dynamics in CA1 and CA3 during contextual fear memory formation and recall, we implemented a novel behavioral and imaging paradigm for CFC in virtual reality where simultaneous two-photon calcium imaging of the hippocampal CA1 and CA3 was performed. We observed CFC behaviors in head-fixed mice in virtual reality similar to freely moving animals. We identified co-activated neuronal ensembles independently within CA1 and CA3 and also across CA1 and CA3 during contextual fear memory formation and recall. Interestingly, across regions co-activate events were associated with fear memory encoding and recall, suggesting synchronized activity across hippocampal sub-networks is a feature of memory encoding and recall in the hippocampus. Overall, my thesis provide the field with a new method to access CA1 and CA3 neurons simultaneously with two-photon imaging. Moreover, we investigated the CA1 and CA3 network dynamics when neutral or fearful novel memory formed and recalled. We found distinct CA1 and CA3 place field dynamics during neutral memory formation and recall, indicating distinct role of CA1 and CA3 in memory processing. On the other hand, we found synchronized CA3-CA1 co-activation events associated with contextual fear memory formation and recall, indicating the cross-network connection is also critical for memory formation and recall.

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