Frontiers in Network Physiology · 4 authors, 3 centres
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This mathematical modeling study investigated how two simultaneous zeitgebers (light-dark cycles and rhythmic drug application) synergistically affect the entrainment of mammalian circadian clocks. The central result is that the phase difference between the two zeitgebers strongly modulates entrainment range, amplitude resonance, and transient adaptation times, with synergistic phase differences leading to more robust clock synchronization.
This preclinical study used mathematical modeling based on murine gene expression to investigate the effects of two simultaneous zeitgebers—light-dark cycles and rhythmic drug application targeting Rev-Erbα—on the mammalian circadian clock. The models, featuring at least five clock genes, simulated entrainment under various conditions. Key findings indicate that both zeitgebers can entrain the clock individually or together, but their phase difference critically impacts outcomes. Synergistic phase differences resulted in larger entrainment ranges, amplitude resonances, and shorter transient adaptation times. Modeling also predicted entrainment to non-1:1 period ratios, causing amplitude and phase modulations. The implications suggest potential for optimizing therapeutic timing to strengthen disturbed circadian rhythms in clinical settings.
