Circuit mechanisms underlying the discrimination and recall of memories along the hippocampal CA3 axis in behaving mice.

Objetivo

The ability to form novel memories without overwriting existing ones (pattern separation) and to retrieve memories from previous experiences (pattern completion) are vital cognitive abilities, largely attributed to neuronal network computations of the hippocampal CA3 area. Despite extensive theoretical work on CA3 circuit functions, little progress has been made in identifying the synaptic, cellular and network mechanisms allowing CA3 to support both apparently opposing mnemonic processes. Current theories suggest that gra-dients in recurrent connectivity between principal cells, in the distribution of the major afferent inputs streams and the strength of GABAergic synaptic inhibition along the proximal-to-distal CA3 axis underlie this functional dichotomy. However, experimental evidence that intra-regional heterogeneities in CA3 sup-port these key mnemonic functions has so far been difficult to obtain in vivo due to technical limitations. ReMember-CA3 overcomes this challenge by establishing simultaneous 2-Photon imaging of neuronal population activity along the CA3 axis. Here, we aim first to visualize CA3 principal cell activity and its main afferent inputs from the entorhinal cortex and the dentate gyrus during spatial learning in virtual reali-ties. Second, we will examine the role of the main afferent input pathways in setting the balance between memory separation during novel context learning and memory recall along the CA3 axis. Third, by applying holographic manipulation and retrograde tracing, we will uncover the role of recurrent connectivity in memory retrieval. Finally, by applying machine-learning methods, we will define the information content of memory traces and its relation to behavior in proximal vs distal CA3. This innovative multidisciplinary approach will provide new insights into the circuit mechanisms of experience-dependent formation, discrimination and retrieval of memories in CA3 along its transverse axis.