A stochastic oscillator model simulates the entrainment of vertebrate cellular clocks by light

Vojtěch Kumpošt,Ralf Mikut,Daniela Vallone,Srinivas Babu Gondi,Lennart Hilbert,Nicholas S Foulkes

doi:10.1038/s41598-021-93913-2

Vojtěch Kumpošt, Ralf Mikut + Show 4 more

Open Access

https://doi.org/10.1038/s41598-021-93913-2

Copy DOI

Abstract

The circadian clock is a cellular mechanism that synchronizes various biological processes with respect to the time of the day. While much progress has been made characterizing the molecular mechanisms underlying this clock, it is less clear how external light cues influence the dynamics of the core clock mechanism and thereby entrain it with the light–dark cycle. Zebrafish-derived cell cultures possess clocks that are directly light-entrainable, thus providing an attractive laboratory model for circadian entrainment. Here, we have developed a stochastic oscillator model of the zebrafish circadian clock, which accounts for the core clock negative feedback loop, light input, and the proliferation of single-cell oscillator noise into population-level luminescence recordings. The model accurately predicts the entrainment dynamics observed in bioluminescent clock reporter assays upon exposure to a wide range of lighting conditions. Furthermore, we have applied the model to obtain refitted parameter sets for cell cultures exposed to a variety of pharmacological treatments and predict changes in single-cell oscillator parameters. Our work paves the way for model-based, large-scale screens for genetic or pharmacologically-induced modifications to the entrainment of circadian clock function.

Highlights

The circadian clock is a cellular mechanism that synchronizes various biological processes with respect to the time of the day
Light is perceived by a dedicated circadian photoreceptor, the non-visual opsin melanopsin which is expressed in intrinsically photosensitive retinal ganglion cells in the r etina[5]
Information on external light levels is relayed indirectly via the retinohypothalamic tract (RHT) to the central clock located in the suprachiasmatic nucleus (SCN) within the hypothalamus, resulting in induced expression of the per[1] and per[2] clock genes, which in turn sets the phase of the SCN clock

Summary

Introduction

The circadian clock is a cellular mechanism that synchronizes various biological processes with respect to the time of the day. Unlike mammalian cells which require transient pharmacological treatments to synchronize cell culture c locks[24,25], in the case of zebrafish cells, the clocks can be regulated non-invasively by changing lighting conditions These light-responsive cell lines are suitable for high-throughput screening as well as studies of the transcriptional control mechanisms mediating light entrainment[26]. In this regard, many bioluminescent reporter systems have been established in zebrafish cell lines and enable the non-invasive assessment of dynamic changes in clock gene transcription at high temporal resolution over the course of light exposure protocols[27]. This model is based on the consideration of two interlocked feedback loops and a large number of parameters, making reliable fitting and readjustment of model parameters to limited experimental data difficult

Methods

Results

Conclusion