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A Multiscale Model for Intercellular Synchronization in Circadian Neural Networks for Design of Chronotherapeutic Strategies


An interdisciplinary team of chemical engineers, biologists, computer scientists and statisticians has developed an integrated experimental, modeling, and computational program to decipher the molecular mechanisms responsible for mammalian circadian rhythm generation and synchronization. In collaboration with researchers at Washington University and UCSB, ICE IGERT trainee, Christina Vasalou, of the Henson lab at the University of Massachusetts Amherst has integrated a systems biology approach with computational neuroscience techniques to elucidate the intracellular architecture that accounts for the robustness of the circadian clock both at a single cell and network level.

Circadian rhythms are approximate 24 hour cycles in biochemical, physiological and behavioral processes observed in a diverse range of organisms including Cyanobacteria, Neurospora, Drosophila, mice and humans. In mammals, the dominant circadian pacemaker that drives daily rhythms is located in a brain region referred as the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN produces autonomous 24h cycles in gene expression, firing frequency and neurotransmitter release and conveys its signal to distinct organs and targets across the brain.

Due to this well-defined regulatory network, a number of physiological and behavioral responses, such as hormone secretion, sleep-wake cycles, body temperature, cardiovascular regulation and respiration, fluctuate in course of the day. Circadian variations affect a number of physiological processes and thus have become the point of interest in the evolving field of chronotherapeutics. Mechanisms that determine the drug disposition, including absorption, distribution, metabolism and elimination, have been shown to vary over the course day. Thus, the efficacy of a drug can be closely correlated to its administration time, as optimal dosing time can help reduce toxicities and improve overall effects.

In their new study, C. Vasalou and M. A. Henson developed a multicellular model characterized by a high degree of heterogeneity with respect to uncoupled rhythmic behavior (intrinsic and damped oscillators with a range of periods), neurotransmitter release (vasoactive intestinal peptide (VIP) and gamma-aminobutyric acid (GABA)), and intercellular coupling (short and long range connections) to investigate possible mechanisms that underlie network synchronization and behavior. This model has incorporated the effects of the circadian gene regulatory pathway, cellular electrophysiological properties and other intracellular signaling mechanisms responsible for cell-to-cell communication. This work, published in PLoS Computational Biology, suggests a possible system architecture that accounts for the robustness of the circadian clock and provides a novel multiscale framework which captures characteristics of the SCN at both the electrophysiological and gene regulatory levels.

Address Goals

One of the primary challenges in circadian biology is the construction of computational models that can adequately couple molecular processes occurring in 24h timescales with electrical events that occur in a millisecond timescale. Detailed cell models with molecular descriptions of gene expression and neural firing coupled by intracellular signaling pathways are not currently available for any circadian system. This model provided a new approach to integrate two distinct timescales, has enabled better understanding of the intracellular architecture underlying the circadian clock and has led to novel predictions concerning the role of various cellular components.