Contribution of the hippocampal subfield CA1, CA3 and the trisynaptic and temporoamonic pathways to the retrieval of memory over half a life time

• Applicant: Professorin Dr. Magdalena Sauvage
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432630241

Whether the retrieval of remote memories depends on the hippocampus or whether it relies on cortical areas remains a major controversy in memory research. Moreover, the extent to which these areas contribute to retrieving precise memories vs. their gist is still unclear. Most studies on this subject compared mechanisms underlying recent and early remote memory retrieval while only a handful has investigated the retrieval of very remote memories. This is a major shortcoming as the contribution of the neocortex is thought to be the highest the older memories become. Importantly, evidence of a functional segregation between the hippocampal subfields CA1 and CA3 has recently accumulated. However, it is not known if CA1 and CA3 contribute to the same extent and to the same aspects of memory retrieval over time. Likewise, the role of the temporoammonic pathway (entorhinal cortex projections to CA1) and that of the trisynaptic loop (entorhinal cortex projections to CA3 through the DG) within this context has not been characterized. We recently reported that CA3 was disengaged for the retrieval of very remote contextual fear memories in mice (i.e. 6 months and one-year old) in contrast to CA1, which was recruited independently of the age of the memory (i.e. one day- to one year-old memories; Lux et. al., ELife, 2016). These findings led us to hypothesize a shift from a recruitment of the temporoammonic and the trisynaptic pathways to a primary involvement of the temporoammonic pathway in memory retrieval over time. The goal of the present proposal is to address these issues. In Project 1, we propose evaluating the extent to which CA1 and CA3 contribute to retrieving precise memories or their gist and if their involvement is truly necessary. Here, we will inactivate cell firing in CA1 or CA3 during the retrieval of recent and very remote contextual fear memories using optogenetics (ArchT) and assess memory performance in the conditioning and a similar(safe) context. In Project 2, we will test that the gradual disengagement of CA3 and the persistent involvement of CA1 during the retrieval of aging memories is a general mechanism by studying if it holds true for non-fear related memories. Here, we will image brain activity in CA1 and CA3 upon recent to very remote object-in-place memory retrieval in mice by detecting the RNA of the immediate-early gene Arc, which is strongly tied to synaptic plasticity and memory function. Finally, in Project 3, we will investigate the extent to which activity patterns observed in CA1 and CA3 during fear memory retrieval originate from the temporoammonic pathway and the trisynaptic loop using optogenetics and mutant mice in collaboration with S. Tonegawa (MIT, USA/RIKEN Japan). By these means, we aim at further characterizing the mechanisms underlying memory consolidation over time, which are relevant for aging, patients with amnesia and stress related pathologies such as post-traumatic stress disorders.

• DFG Programme: Research Grants