Modeling feedback loops of the Mammalian circadian oscillator

Biophys J. 2004 Nov;87(5):3023-34. doi: 10.1529/biophysj.104.040824. Epub 2004 Sep 3.


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 to characterize the differential roles of negative and positive feedback loops. The oscillations that are obtained have a 24-h period and are robust toward 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-erbalpha-/- 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 that 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- erbalpha -/- mutant mice.

Publication types

  • Comparative Study
  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adaptation, Physiological / physiology
  • Animals
  • Biological Clocks / physiology*
  • Cell Cycle Proteins
  • Circadian Rhythm / physiology*
  • Computer Simulation
  • Cryptochromes
  • Feedback / physiology*
  • Flavoproteins / metabolism*
  • Mammals
  • Mice
  • Models, Biological*
  • Nuclear Proteins / metabolism*
  • Period Circadian Proteins
  • Signal Transduction / physiology*
  • Transcription Factors
  • Transcriptional Activation / physiology


  • Cell Cycle Proteins
  • Cry2 protein, mouse
  • Cryptochromes
  • Flavoproteins
  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Transcription Factors