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Biophys. J. BioFAST: First Published September 3, 2004. doi:10.1529/biophysj.104.040824
© 2004 by the Biophysical Society.

A more recent version of this article appeared on November 1, 2004.
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BIOPHYSICAL THEORY AND MODELING

Modeling Feedback Loops of the Mammalian Circadian Oscillator

Sabine Becker-Weimann 1, Jana Wolf 1, Hanspeter Herzel 1 and Achim Kramer 2*

1 Humboldt-University Berlin
2 University Hospital Charité

* To whom correspondence should be addressed. E-mail: achim.kramer{at}charite.de.

Submitted on January 28, 2004
Revised on March 15, 2004
Accepted on 16 August 2004


  Abstract
The suprachiasmatic nucleus governs daily variations of physiology and behavior in mammals. Within single neurons, interlocked transcriptional/translational feedback loops generate circadian rhythms on the molecular level. We present a mathematical model that reflects the essential features of the mammalian circadian oscillator in order to characterize the differential roles of negative and positive feedback loops. The oscillations that are obtained have a 24-hour period and are robust towards parameter variations even when the positive feedback is replaced by a constantly expressed activator. This demonstrates the crucial role of the negative feedback for rhythm generation. Moreover, it explains the rhythmic phenotype of Rev-erb{alpha}-/- mutant mice, where a positive feedback is missing. The interplay of negative and positive feedback reveals a complex dynamics. In particular, the model explains the unexpected rescue of circadian oscillations in Per2Brdm1/Cry2-/- double mutant mice (Per2Brdm1 single mutant mice are arrhythmic). Here, a decrease of positive feedback strength associated with mutating the Per2 gene is compensated by the Cry2-/- mutation which simultaneously decreases the negative feedback strength. Finally, this model leads us to a testable prediction of a molecular and behavioral phenotype: circadian oscillations should be rescued when arrhythmic Per2Brdm1 mutant mice are crossed with Rev-erb{alpha}-/- mutant mice.

Key Words: circadian rhythms, mathematical model, mutant mice, period, robustness, suprachiasmatic nucleus




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Copyright © 2004 by the Biophysical Society.