Leloup2004 - Mammalian Circadian Rhythm models for 23.8 and 24.2 hours timeperiod

  public model
Model Identifier
BIOMD0000000975
Short description
We extend the study of a computational model recently proposed for the mammalian circadian clock (Proc. Natl Acad. Sci. USA 100 (2003) 7051). The model, based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, and Clock genes, can give rise to sustained circadian oscillations in conditions of continuous darkness. These limit cycle oscillations correspond to circadian rhythms autonomously generated by suprachiasmatic nuclei and by some peripheral tissues. By using different sets of parameter values producing circadian oscillations, we compare the effect of the various parameters and show that both the occurrence and the period of the oscillations are generally most sensitive to parameters related to synthesis or degradation of Bmal1 mRNA and BMAL1 protein. The mechanism of circadian oscillations relies on the formation of an inactive complex between PER and CRY and the activators CLOCK and BMAL1 that enhance Per and Cry expression. Bifurcation diagrams and computer simulations nevertheless indicate the possible existence of a second source of oscillatory behavior. Thus, sustained oscillations might arise from the sole negative autoregulation of Bmal1 expression. This second oscillatory mechanism may not be functional in physiological conditions, and its period need not necessarily be circadian. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark (LD) cycles. Long-term suppression of circadian oscillations by a single light pulse can occur in the model when a stable steady state coexists with a stable limit cycle. The phase of the oscillations upon entrainment in LD critically depends on the parameters that govern the level of CRY protein. Small changes in the parameters governing CRY levels can shift the peak in Per mRNA from the L to the D phase, or can prevent entrainment. The results are discussed in relation to physiological disorders of the sleep-wake cycle linked to perturbations of the human circadian clock, such as the familial advanced sleep phase syndrome or the non-24h sleep-wake syndrome.
Format
SBML (L2V4)
Related Publication
  • Modeling the mammalian circadian clock: sensitivity analysis and multiplicity of oscillatory mechanisms.
  • Leloup JC, Goldbeter A
  • Journal of theoretical biology , 10/ 2004 , Volume 230 , pages: 541-562 , PubMed ID: 15363675
  • Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
  • We extend the study of a computational model recently proposed for the mammalian circadian clock (Proc. Natl Acad. Sci. USA 100 (2003) 7051). The model, based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, and Clock genes, can give rise to sustained circadian oscillations in conditions of continuous darkness. These limit cycle oscillations correspond to circadian rhythms autonomously generated by suprachiasmatic nuclei and by some peripheral tissues. By using different sets of parameter values producing circadian oscillations, we compare the effect of the various parameters and show that both the occurrence and the period of the oscillations are generally most sensitive to parameters related to synthesis or degradation of Bmal1 mRNA and BMAL1 protein. The mechanism of circadian oscillations relies on the formation of an inactive complex between PER and CRY and the activators CLOCK and BMAL1 that enhance Per and Cry expression. Bifurcation diagrams and computer simulations nevertheless indicate the possible existence of a second source of oscillatory behavior. Thus, sustained oscillations might arise from the sole negative autoregulation of Bmal1 expression. This second oscillatory mechanism may not be functional in physiological conditions, and its period need not necessarily be circadian. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark (LD) cycles. Long-term suppression of circadian oscillations by a single light pulse can occur in the model when a stable steady state coexists with a stable limit cycle. The phase of the oscillations upon entrainment in LD critically depends on the parameters that govern the level of CRY protein. Small changes in the parameters governing CRY levels can shift the peak in Per mRNA from the L to the D phase, or can prevent entrainment. The results are discussed in relation to physiological disorders of the sleep-wake cycle linked to perturbations of the human circadian clock, such as the familial advanced sleep phase syndrome or the non-24h sleep-wake syndrome.
Contributors
Vijayalakshmi Chelliah, Kausthubh Ramachandran

Metadata information

isDescribedBy
BioModels Database BIOMD0000000083
BioModels Database BIOMD0000000078
PubMed 15363675
BioModels Database BIOMD0000000073
BioModels Database BIOMD0000000074
is
BioModels Database MODEL0478895291
BioModels Database MODEL0478895291
BIOMD0000000975
hasTaxon
Taxonomy Homo sapiens
isDerivedFrom
Taxonomy Homo sapiens
BioModels Database BIOMD0000000083
Gene Ontology entrainment of circadian clock by photoperiod
BioModels Database MODEL0478895291
BioModels Database BIOMD0000000078
BioModels Database BIOMD0000000074
BioModels Database BIOMD0000000073
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model

Curation status
Curated


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Model files

Leloup2004_Set1.xml SBML L2V4 file of model of mammalian circadian rhythms for 23.8 and 24.2 hours timeperiod with Set 1 parameters 289.58 KB Preview | Download

Additional files

Leloup2004_CircadianRhythmsSet4.xml SBML L2V4 file of model of mammalian circadian rhythms for 23.8 and 24.2 hours timeperiod with Set 4 parameters 478.67 KB Preview | Download
Leloup2004_Set1.cps COPASI 4.29 (Build 228) file of model of mammalian circadian rhythms for 23.8 and 24.2 hours timeperiod with Set 1 parameters 331.90 KB Preview | Download
Leloup2004_Set1.omex COMBINE archive of model of mammalian circadian rhythms for 23.8 and 24.2 hours timeperiod with Set 1 parameters 29.83 KB Preview | Download
Leloup2004_Set1.sedml SED-ML file of model of mammalian circadian rhythms for 23.8 and 24.2 hours timeperiod with Set 1 parameters 2.82 KB Preview | Download

  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: 23-Apr-2009 14:17:12
  • Last Modified: 10-Nov-2020 03:09:35
Revisions
  • Version: 5 public model Download this version
    • Submitted on: 10-Nov-2020 03:09:35
    • Submitted by: Kausthubh Ramachandran
    • With comment: Automatically added model identifier BIOMD0000000975
  • Version: 2 public model Download this version
    • Submitted on: 14-Jan-2011 14:11:12
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Leloup2004_CircadianRhythms
  • Version: 1 public model Download this version
    • Submitted on: 23-Apr-2009 14:17:12
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Leloup2004_CircadianRhythms

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Curator's comment:
(added: 10 Nov 2020, 02:57:31, updated: 10 Nov 2020, 02:57:31)
Fig 2A is reproduced here using Set 1 parameters (associated XML file - Leloup2004_Set1.xml). Output had to be suppressed for the first 18 hours to reproduce the figure. The numerical simulation data was taken from the COPASI plot and plotted in Microsoft Excel 2016. Fig 2C (not shown here) was reproduced using Set 4 parameters after suppressing output for the first 4 hours. (associated XML file - Leloup2004_CircadianRhythmsSet4.xml)