Physical approaches for modelling circadian rhythms: from cells to networks

NIETO, P.S.; ROMÁN DEBRÁS, M.D.; REVELLI, J.A.; GARBARINO-PICO, E.; CONDAT, C.A.; GUIDO, M. E.; TAMARIT, F.A.

CABA

Workshop; Workshop Internacional Programa Raíces (MINCyT): La matemática como herramienta para entender la biología / la biología como fuente de problemas matemáticos; 2015

científicos argentinos residentes en Argentina y en el Noreste de Estados Unidos.

Predictable environmental changes have been critical for the temporal organization of most living beings. Organisms have developed endogenous circadian clocks, which generate most of the daily variations in their molecular biology, biochemistry, physiology and behavior with a period close to 24 h. At the single cell level, the circadian clockwork is based on a set of clock genes, whose protein products (clock proteins) are necessary components for the generation and regulation of circadian rhythms. Most clock genes are expressed in a circadian fashion as a consequence of their mutual interaction and regulation, commonly called the molecular clock mechanism, which is based on interconnected transcriptional-translational feedback loops (TTFL). Recent studies have demonstrated that the translation of several clock proteins are tightly regulated and highlighted the role of translational regulation in the circadian dynamics. In the present work we show the effects of different translational kinetics on the dynamics of the molecular clock. Changes in the kinetics of PER translation may be one important consequence derived from the PER translational regulation. Importantly, this level of regulation was not considered in previous theoretical studies of the circadian clock. In mammals, the circadian system is composed of a hierarchy of oscillators that function at the cellular, tissue and systems levels. Circadian clocks exist throughout the body, in individual cells and organs, and these clocks are kept synchronized by the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Lack of the fine circadian system organization has wide-ranging influences on metabolism, mood, addictive behaviors, immune system, among others. The SCN is comprised of a diverse population of cells (neurons and glia) which function coordinately in order to drive physiological and behavioral circadian rhythms. SCN cells are circadian clocks able to communicate with each other, sync their activity and hence become -as a whole- a biological clock both precise and robust. Although the SCN oscillators function in a unified manner when coupled, this does not mean that they are completely synchronous. In fact, the expression of clock proteins within a SCN slice, displayed a specific spatio-temporal pattern, characterized by the heterogeneity of their phase peaking. Importantly, the gene expression dynamics display a consistent (not-random) spatio-temporal pattern, suggesting that they emerge as a consequence of the precise interactions between the SCN cells. The mechanisms by which these phase relationships are established are not well understood, but certainly depend on the integration of multiple intercellular signals present in the SCN, which ultimately define the underlying functional connectivity of the SCN. In this work we use a model of circadian cellular oscillators coupled through different network architectures in order to simulate the dynamical behavior observed in SCN slices.