Parameterized resetting model captures dose-dependent entrainment of the mouse circadian clock

Area of Science:

• Chronobiology
• Systems Biology
• Computational Biology

Background:

• Circadian rhythm phase resetting is complex due to time-dependent responses.
• Phase response curves (PRCs) are difficult to quantify because their shape varies with stimulus intensity.
• Previous work introduced singularity response (SR) to simplify circadian clock analysis using amplitude and phase parameters.

Purpose of the Study:

• To develop a comprehensive model for phase resetting in the mouse circadian clock.
• To convert traditional PRCs into simplified SR parameters for easier quantification.
• To validate the SR model's predictive power for combined and pre-treated stimuli.

Main Methods:

• Constructing a comprehensive model by converting mouse circadian clock PRCs into SR parameters.
• Analyzing single-cell PRCs to determine SR amplitude parameter relationships with stimulus concentration.
• Utilizing the Hill equation to model SR amplitude parameters.
• Developing a predictive model for combined and pre-treated stimuli effects.
• Experimentally validating the SR model using mouse cells and tissues.

Main Results:

• SR amplitude parameters for varying stimulus concentrations follow the Hill equation.
• The SR model accurately predicts the combined effects of multiple stimuli on phase response.
• The model also accurately predicts the effects of pre-treatment (background) on phase response.
• Experimental validation confirmed the model's accuracy in mouse cells and tissues.

Conclusions:

• Singularity responses (SRs) simplify the quantification of circadian phase resetting.
• The SR model reveals simple, additive/subtractive rules governing phase response under various conditions.
• This approach enhances the understanding and analysis of circadian clock dynamics.