Abstract
Molecular mechanisms responsible for 24 h circadian oscillations, entrainment to external cues, encoding of day length and the time-of-day effects have been well studied experimentally. However, it is still debated from the molecular network point of view whether each cell in suprachiasmatic nuclei harbors two molecular oscillators, where one tracks dawn and the other tracks dusk activities. A single cell dual morning and evening oscillator was proposed by Daan et al., based on the molecular network that has two sets of similar non-redundant per1/cry1 and per2/cry2 circadian genes and each can independently maintain their endogenous oscillations. Understanding of dual oscillator dynamics in a single cell at molecular level may provide insight about the circadian mechanisms that encodes day length variations and its response to external zeitgebers. We present here a realistic dual oscillator model of circadian rhythms based on the series of hypotheses proposed by Daan et al., in which they conjectured that the circadian genes per1/cry1 track dawn while per2/cry2 tracks dusk and they together constitute the morning and evening oscillators (dual oscillator). Their hypothesis also provides explanations about the encoding of day length in terms of molecular mechanisms of per/cry expression. We frame a minimal mathematical model with the assumption that per1 acts a morning oscillator and per2 acts as an evening oscillator and to support and interpret this assumption we fit the model to the experimental data of per1/per2 circadian temporal dynamics, phase response curves (PRC's), and entrainment phenomena under various light-dark conditions. We also capture different patterns of splitting phenomena by coupling two single cell dual oscillators with neuropeptides vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP) as the coupling agents and provide interpretation for the occurrence of splitting in terms of ME oscillators, though they are not required to explain the morning and evening oscillators. The proposed dual oscillator model based on Daan's hypothesis supports per1 and per2 playing the role of morning and evening oscillators respectively and this may be the first step towards the understanding of the core molecular mechanism responsible for encoding the day length.
Highlights
The circadian clock in the mammalian suprachiasmatic nuclei (SCN) is the master endogenous oscillator with a period close to 24 h oscillations that can persist even in the absence of external cues like light-dark (LD) cycles and temperatures
For the single cell dual oscillator model that we described in earlier sections, the phase differences observed between per1 and per2 in WT under constant light condition (LL) was found to be very small and splitting was not seen in the simulations
We simulated the single cell dual oscillator model of mammalian circadian rhythms based on the hypothesis proposed by Daan et al, [15]
Summary
The circadian clock in the mammalian suprachiasmatic nuclei (SCN) is the master endogenous oscillator with a period close to 24 h oscillations that can persist even in the absence of external cues like light-dark (LD) cycles and temperatures. Maintaining a constant phase relationship with the external cues is important to keep the circadian clock synchronized with the local time. With the advent of new biological techniques, the molecular mechanisms of gene expressions and the regulations responsible for the generation of circadian oscillations are well characterized and the time-of-day effects to the external cues are well studied in the models of fungal species Neurospora, fruit fly Drosophila, plant Arabidopsis thaliana and mammalian mice models [3,4,5]. Circadian rhythms of all the species are tightly regulated by the interlinked multiple negative and positive feedback loops that guides circadian pacemakers to function under various conditions [6]
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