MECHANISMS AND MODELING OF NETWORKED CIRCADIAN PACEMAKER SYNCHRONIZATION

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The mammalian suprachiasmatic nucleus (SCN), required for daily cycles in behavior and physiology. How the cells of the SCN synchronize to coordinate behavior is largely unknown. We have established a collaborative program combining experimental and computational methods to study large numbers of circadian oscillators, their connections, and the real-time kinetics by which they self-synchronize and respond to perturbations in environmental timing cues. To understand circadian regulation within the brain, we must understand the topology and types of interactions between circadian neurons. Aim 1 will monitor the network of SCN oscillators as they synchronize during fetal development, during entrainment, following a phase shift, and after restoration of cell-cell communication in the adult SCN. Using novel wavelet-based time series analyses, we will estimate the strength and direction of individual connections in the SCN. Aim 2 will use graph theory and spatial statistics to quantify network features of the developing and adult SCN. These analyses will define the mechanisms of synchronization during normal development and following environmental perturbations and the relative contributions of local, regional or global coupling which contribute to period precision. Aim 3 will compare the performance of the SCN networks under the four conditions with both deterministic and stochastic model networks. The computational models will investigate the effects of intrinsic noise and cell-cell heterogeneity on circadian synchronization. Revealing how circadian oscillators interact to generate a coherent rhythmic output will have important clinical implications for prevention and treatment of circadian rhythm disruptions, including mood and sleep disorders.