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Small World Network Models of Intercellular Coupling In the Mammalian Circadian Clock

Christina Vasalou1, Mark Freeman2, Erik D. Herzog2, and Michael A. Henson1. (1) Department of Chemical Engineering, University of Massachusetts, 686 N. Pleasant Street, Amherst, MA 01003, (2) Department of Biology, Washington University, Box 1137 , 205 Monsanto Office, St. Louis, MT 63130-4899

The suprachiasmatic nucleus (SCN) of the hypothalamus is a multioscillator system that drives daily rhythms in mammalian behavior and physiology. Although intercellular communication within the SCN has been the focus of significant experimental effort, little is known about how SCN cells synchronize to each other to coordinate behavior. We previously developed a multicellular, molecular model of the mammalian circadian clock that incorporated recent data implicating the neurotransmitter vasoactive intestinal polypeptide (VIP) as the key synchronizing agent (To et al., 2007). This model assumed that cells were locally connected and that connection strengths were inversely proportional to the distance between cells due to the effects of VIP diffusion. In this contributon, we consider an alternative connectivity scheme based on small world networks that contain both short and long range synaptic connections for VIP mediated coupling. Individual SCN cells exhibit experimentally observed heterogeneities in uncoupled oscillator phenotype (sustained and damped oscillators) and VIP release characteristics (VIP producing and non-producing cells). We show that the small world network models are able to robustly synchronize despite heterogeneities in individual cells and network connectivity as long as the number of long range connections is sufficiently large. The model is used to investigate the hypothesis that age related circadian dysfunction is attributable to degeneration of the VIP coupling mechanism in the SCN rather than impairment of individual cell function. We find that partial removal of long range connections produces several experimentally observed behaviors including reduced VIP and CREB oscillation amplitudes in individual cells, a decrease in the mean period of the population, a higher percentage of non-oscillating cells, and reduced synchrony. The model thus predicts that loss of a few long range connections in the SCN can have large effects on circadian rhythmicity. Supported by NIH grant 78993.

To, T.-L., M. A. Henson, E. D. Herzog and F. J. Doyle III, A Computational Model for Intercellular Synchronization in the Mammalian Circadian Clock, Biophysical Journal, 92, 3792-3803 (2007).