title: Coupling Controls the Synchrony of Clock Cells in Development and Knockouts.
abstract: In mammals, a network of coupled neurons within the hypothalamus coordinates physiological rhythms with daily changes in the environment. In each neuron, delayed negative transcriptional feedbacks generate oscillations, albeit noisy and unreliable ones. Coupling mediated by diffusible neuropeptides lends precision and robustness to circadian rhythms. The double knockout of Cryptochrome Cry turns adult mice arrhythmic. But, remarkably, double knockout neonates continue to show robust oscillation much like wild-type neonates and appear to lose rhythmicity with development. We study quantitatively dispersed neurons and brain slices from wild-type and Cry double knockout mice to understand the links between single cell rhythmicity and intercellular coupling. We quantify oscillator properties of dispersed cells using nonlinear regression and study bifurcations diagrams of network models. We find that varying just three parameters-oscillator strength, strength of coupling, and timing of coupling-can reproduce experimentally observed features. In particular, modeling reveals that minor changes in timing of coupling can destroy synchronization as observed in adult slices from knockout mice.
authors.affiliation: Department of Mechanical Engineering, Ritsumeikan University, Shiga, Japan. Electronic address: isao@fc.ritsumei.ac.jp.
authors.forename: Isao T
authors.initials: IT
authors.lastname: Tokuda
authors.affiliation: Photonic Bioimaging Section, Research Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ono
authors.affiliation: Institute for Theoretical Biology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Bharath
authors.initials: B
authors.lastname: Ananthasubramaniam
authors.affiliation: Department of Chronomedicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Sato
authors.initials: S
authors.lastname: Honma
authors.affiliation: Department of Chronomedicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Honma
authors.affiliation: Institute for Theoretical Biology, Humboldt University of Berlin, Berlin, Germany.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000235:genetics*; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D056931:Cryptochromes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism / Q000502:physiology
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes