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In this project, we study how rewiring of brain circuits can be induced and how this affects learning and memory. In first publications, we described the capacity of wiring in specific groups of adult neurons and describe some mechanisms behind it. Understanding these mechanisms is a prerequisite for a potential future rewiring of incorrect connections in the brain.
During development, improper neuronal wiring can lead to formation of persistently altered brain circuits and onset of intellectual disabilities. In principle, one could instate proper connections by means of cellular programing and thus facilitate repair of circuits. However, mechanisms that regulate or maintain wiring after development remain largely unknown.
Understanding these biological mechanisms is a prerequisite for an eventual use of rewiring to cure intellectual disabilities. Towards this goal, this project aims to investigate the capacity of wiring in a specific group of adult hippocampal neurons, the dentate granule cells, which are critically involved in certain forms of learning and memory. We published our discovery that a subpopulation of dentate granule cells in adult mice atypically project to the contralateral hippocampus (Egger at al., 2023). We also found that the number and contralateral axon length of commissural granule cells significantly increased in an experimental model of temporal lobe epilepsy, also highlighting the potential relevance of our findings to understanding seizure mechanisms.
In a follow-up study, we aim at enabling circuit rewiring in the adult mouse brain to investigate its consequences on circuit operations, learning and memory. First findings show that axonal wiring can be cell autonomously induced in adult hippocampal pyramidal neurons by molecular programing. Afterwards, synaptic weights are reconfigured both in the hippocampus and in target areas outside the hippocampus. As a next step, we are characterizing network dynamics after circuit rewiring and are testing if rewiring can enhance the behavioral learning and memory performance of the animal without evoking adverse effects.
Outcomes of this project will generate basic knowledge for circuit rewiring and might facilitate the development of therapeutic strategies for intellectual disabilities associated with circuit deficiencies.
Principal Investigators: Csaba Földy, Sebastian Jessberger, Fritjof Helmchen
PhD Students: Matteo Egger (until 07.2023), Natalia Cruz-Ochoa
Collaborators: Wenshu Luo
Platforms: mesoSPIM
Egger M, Luo W, Cruz-Ochoa N, Lukacsovich D, Varga C, Que L, Maloveczky G, Winterer J, Kaur R, Lukacsovich T, Földy C (2023) Commissural dentate granule cell projections and their rapid formation in the adult brain. PNAS Nexus, 2(4):pgad088.
Luo W, Cruz-Ochoa NA, Seng C, Egger M, Lukacsovich D, Lukacsovich T and Földy C (2022) Pcdh11x controls target specification of mossy fiber sprouting. Frontiers in Neuroscience 16:888362.
Underlined: AdaBD researchers
