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Development of a Two-Dimension Manifold to Represent High Dimension Mathematical Models of the Intracellular Mammalian Circadian Clock

Biomathematical Modeling Unit, Division of Sleep Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, Premananda.Indic{at}umassmed.edu

Katherine Gurdziel

Biomathematical Modeling Unit, Division of Sleep Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA

Richard E. Kronauer

Biomathematical Modeling Unit, Division of Sleep Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, Division of Engineering and Applied Sciences, Harvard University, Cambridge, MA

Elizabeth B. Klerman

Biomathematical Modeling Unit, Division of Sleep Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA

A new focus for mathematical models of the circadian pacemaker involves the encapsulation within the models of detailed biological processes responsible for generating those circadian rhythms. Representing greater biological detail requires more mathematical equations, which pose a greater challenge for the analysis of such systems. Development of a method that retains the predominant dynamics while still providing biologically detailed information is advantageous. Two high-dimension mathematical models of intracellular mammalian circadian pacemakers, Leloup-Goldbeter and Forger-Peskin, with 19 and 73 differential equations, respectively, have been published. The authors projected each of these high-dimension models onto their respective manifold using proper orthogonal functions (POFs) obtained from the empirical decomposition of the model’s phase space to obtain a 2-dimension model. The resulting 2-dimension model, represented by 2 differential equations, predicts most of the salient characteristics of a biological clock including ~24-h oscillations, entrainment to an LD cycle, phase response curves, and the amplitude recovery dynamics that emerge following amplitude suppression. The manifold representation simplifies the mathematical analysis, since only 2 variables need to be observed and analyzed to understand the behavior of the biological clock. This reduced model derived from a model based on biological variables can be used for the development and analysis of mathematical models of the coupled mammalian oscillators to understand the dynamics of the integrated circadian pacemaker.

Key Words: circadian rhythm • mammalian clock models • model reduction • proper orthogonal functions • eigenvalue decomposition • manifold models

Journal of Biological Rhythms, Vol. 21, No. 3, 222-232 (2006)
DOI: 10.1177/0748730406287357


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