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Emergence of rich-club topology and coordinated dynamics in development of hippocampal functional networks in vitro.

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Recent studies demonstrated that the anatomical network of the human brain shows a "rich-club" organization. This complex topological feature implies that highly connected regions, hubs of the large-scale brain network, are more densely interconnected with each other than expected by chance. Rich-club nodes were traversed by a majority of short paths between peripheral regions, underlining their potential importance for efficient global exchange of information between functionally specialized areas of the brain. Network hubs have also been described at the microscale of brain connectivity (so-called "hub neurons"). Their role in shaping synchronous dynamics and forming microcircuit wiring during development, however, is not yet fully understood. The present study aimed to investigate the role of hubs during network development, using multi-electrode arrays and functional connectivity analysis during spontaneous multi-unit activity (MUA) of dissociated primary mouse hippocampal neurons. Over the first 4 weeks in vitro, functional connectivity significantly increased in strength, density, and size, with mature networks demonstrating a robust modular and small-world topology. As expected by a "rich-get-richer" growth rule of network evolution, MUA graphs were found to form rich-clubs at an early stage in development (14 DIV). Later on, rich-club nodes were a consistent topological feature of MUA graphs, demonstrating high nodal strength, efficiency, and centrality. Rich-club nodes were also found to be crucial for MUA dynamics. They often served as broker of spontaneous activity flow, confirming that hub nodes and rich-clubs may play an important role in coordinating functional dynamics at the microcircuit level.



development, electrophysiology, hippocampus, hubs, network, Action Potentials, Animals, Cells, Cultured, Embryo, Mammalian, Female, Hippocampus, Male, Mice, Models, Neurological, Nerve Net, Neurons, Nonlinear Dynamics, Sodium Channel Blockers, Tetrodotoxin

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J Neurosci

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Society for Neuroscience
Medical Research Council (G1000183)
Biotechnology and Biological Sciences Research Council (BB/H008608/1)
Medical Research Council (G0001354)
Wellcome Trust (093875/Z/10/Z)
Wellcome Trust (095844/Z/11/Z)
M.S.S. is supported by a PhD studentship funded by a Core Award from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z) and by the Studienstiftung des deutschen Volkes. Additional support for this study from the Biotechnology and Biological Sciences Research Council (BBSRC Ref BB/H008608/1) is gratefully acknowledged.