Synaptic computations of the hippocampal CA3 circuitry

Description du projet

Comprendre les mécanismes impliqués dans la consolidation de la mémoire dans le cerveau

L’hippocampe est responsable de la consolidation de la mémoire à court terme et de la navigation spatiale. Cependant, on sait peu de choses sur la connectivité synaptique et le traitement des signaux dans cette région du cerveau. Des chercheurs travaillant sur le projet CIRCA3, financé par l’UE, se consacrent à découvrir comment les neurones pyramidaux situés dans l’aire CA3 de l’hippocampe forment un réseau interconnecté. L’accent sera mis sur les mécanismes qui sous‑tendent le traitement des données de CA3 en étudiant les connexions synaptiques individuelles. Les résultats apporteront une compréhension essentielle sur la fonction de l’hippocampe, ce qui aura d’importantes conséquences cliniques notamment pour la compréhension de la maladie d’Alzheimer.

Objectif

The hippocampus is critical for learning and memory, and the unique wiring of its CA3 area has inspired theories for neuronal mechanisms of memory storage and retrieval. CA3 pyramidal neurons form an interconnected network which could store unique experiences in specific ensembles of coactive cells. While an attractive hypothesis, many critical facets of CA3 networks remain unknown. CA3’s principal synaptic input arrives from dentate gyrus granule cells, via the powerful mossy fibre synapse. Little is known about the connectivity of individual granule cells to CA3 neurons, while their activity in vivo is very sparse, and they appear to predominantly target inhibitory interneurons rather than pyramidal neurons. Therefore, due to the technical challenge of identifying functionally connected neurons, whether the circuit properties of CA3 are sufficient for its proposed memory function is unclear. This project aims to determine the circuit mechanisms underlying information processing in CA3 at the level of individual synaptic connections. It will employ simultaneous multicellular patch-clamp recordings from CA3 neurons to identify locally connected neuronal ensembles in hippocampal slices, while driving sparse granule cell input in realistic activity patterns using optogenetic stimulation. This project will determine the synaptic connectivity of individual mossy fibre inputs into CA3 cell ensembles, characterise the role of feedforward inhibition in controlling pyramidal neuron activity, and reveal how the unique properties of each synaptic connection contributes to signal processing. Together, this study will provide an insight into the synaptic mechanisms of the hippocampus’ critical memory storage functions. The fellowship will facilitate rigorous scientific development of the researcher, including critical training in state-of-the-art circuit investigation techniques that will enable pursuit of an innovative research career, defined by the highest quality science.