We present a computational model for the @entity1 circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, @entity8713 , Clock, and Rev-Erb alpha genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erbalpha and @entity8713 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in @entity1 , such as advanced or delayed @entity25 , whereas the lack of entrainment by light-dark cycles can be related to the non-24h @entity25 . The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of @entity8713 expression.

Toward a detailed computational model for the XXXX circadian clock.

@entity1 :: ('9606', 'Species') :: ['mammalian', 'humans'] @entity8713 :: ('406', 'Gene') :: ['Bmal1'] @entity25 :: ('MESH:D012893', 'Disease') :: ['sleep phase syndrome', 'sleep-wake syndrome']
@entity1 :: (9606,Species) :: ['mammalian']
