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A developmental engram for the organization of adult hippocampal circuits

Periodic Reporting for period 3 - NeuroPioneers (A developmental engram for the organization of adult hippocampal circuits)

Reporting period: 2018-10-01 to 2020-03-31

Most adult cortical dynamics are dominated by a minority of highly active neurons distributed within a silent neuronal mass. If cortical spikes are sparse, spiking of single distinct neurons can impact on network dynamics and drive an animal’s behavior. It is thus essential to understand whether this active and powerful minority is predetermined and if true to uncover the rules by which it is set during development. We hypothesize that birthdate is a critical determinant of neuronal network function into adulthood. More specifically, we reason that neurons that are born the earliest are primed to participate into adult network dynamics. The goal of this proposal is to challenge this original hypothesis, which is considerably fed by our past work aiming at understanding how cortical networks function and assemble during development. We will analyze the structure and function of early born GABA and glutamate neurons, in the adult mouse hippocampus, mainly in vivo, where the extensive and long-range connectivity of these cells is preserved. To this aim, we have translated from the in vitro to the in vivo situation, our multidisciplinary method to investigate structure-dynamics relationship in cortical networks. This project is important because it spans various disciplines ranging from developmental biology to systems neuroscience and complex systems. Given the importance of pioneer, early born cells during development and in memory-associated network dynamics, this project will shed light on the circuit basis of developmental and network disorders, including epilepsy as well as pathologies associated with memory deficits. Pioneer cells will undoubtedly provide a neat opportunity for future targeted therapeutic strategies.
Since the project start, we have identified the functional building blocks of hippocampal function in the form of stable assemblies that are bound together to encode spatio-temporal experience (Malvache et al. 2016). We have also gathered evidence indicating that pioneer GABA or glutamatergic neurons, both in the Dentate Gyrus (Save et al. 2018) as well as in CA1, are major nodes in the functional organization of the adult hippocampus. They display specific intrinsic physiological properties and are integrated into distinct connectivity scheme which support their recruitement in defined network states as imaged in awake mice.
This project is unraveling the developmental scaffolding of hippocampal function. By the end of the project, we should be able to establish causality, in the role of pionner cells, both during development and in coordinating adult CA1 dynamics.