Abstract
Behavior of human circadian rhythms could be interpreted according to the two oscillator regime: one for circadian pacemaker driving temperature/plasma melatonin rhythm, and the other for rest-activity rhythm, which are tentatively called Osc I and Osc II, respectively. Osc I can be regarded as collective pacemakers in the suprachiasmatic nucleus. On the other hand, Osc II might be synergetically organized by peripheral oscillators. Recently, we have developed a phase oscillator model consisting of mutually coupled Osc I and II, and an extra-oscillator representing an overt rest-activity rhythm. Feedbacks are introduced to the model, which are devised to modulate the coupling strength dependent on a coherence between the oscillators and the overt rest-activity rhythm. Considering these macroscopic oscillators consisting of cellular or molecular oscillators, these feedbacks deliver the macroscopic coherence to a molecular level. At a molecular level, transcription/translation feedback loops involving the clock genes are apparently believed to generate the rhythms. However, accumulated evidence suggests that such transcription/translation loops are open to the intracellular signaling pathways and inter-cellular environments. Based on this knowledge, an oscillator model has been developed for rodent's molecular clock. This model includes the CREB-dependent transcription mechanism, where the phospholyration level of CREB is also under circadian regulation. Our models could provide a novel framework toward integrative modeling of the hierarchical circadian system because of their structure open to the other layers of the hierarchy. [Jpn J Physiol 54 Suppl:S7 (2004)]
