title: Emergence of rich-club topology and coordinated dynamics in development of hippocampal functional networks in vitro.
abstract: 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.
authors: Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge CB2 3EB, United Kingdom, manuel.schroeter@gmail.com etb23@cam.ac.uk.
authors: Manuel S
authors: http://orcid.org/0000-0002-9347-9203
authors: MS
authors: Schroeter
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Physiological Laboratory, Cambridge CB2 3EG, United Kingdom.
authors: Paul
authors: http://orcid.org/0000-0002-6159-4223
authors: P
authors: Charlesworth
authors: Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors: Manfred G
authors: http://orcid.org/0000-0002-4494-0753
authors: MG
authors: Kitzbichler
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Physiological Laboratory, Cambridge CB2 3EG, United Kingdom.
authors: Ole
authors: http://orcid.org/0000-0002-2258-5455
authors: O
authors: Paulsen
authors: Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge CB2 3EB, United Kingdom, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge CB21 5HH, United Kingdom, and GlaxoSmithKline, Immuno Psychiatry, Alternative Discovery and Development, Stevenage SG1 2NY, United Kingdom manuel.schroeter@gmail.com etb23@cam.ac.uk.
authors: Edward T
authors: http://orcid.org/0000-0002-8955-8283
authors: ET
authors: Bullmore
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017711:Nonlinear Dynamics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D026941:Sodium Channel Blockers; D013779:Tetrodotoxin
keywords: development; electrophysiology; hippocampus; hubs; network