May 22, 2023

A Simplified Method Assessing the Synchronization Properties of the Body Clockwith Internal and External Rhythms
The circadian clock or the biological clock adjusts to periodic signals originating internally and externallyfrom the body. Examining the entrainment attributes of the circadian clock involves measuring phase
responses to various stimuli at numerous intervals, a time-consuming and expensive process. A team ofresearchers from the University of Tsukuba has put forward a methodology that simplifies this process. By
employing mathematical modeling and a single measurement of desynchronized cells, they have proposed a
new approach for evaluating the entrainment properties of the clock.

Tsukuba, Japan— Numerous organisms are equipped with circadian clocks (internal body clocks) that
help them adapt to daily environmental changes in light and temperature. For synchronizing the clockphase (timing) with these environmental rhythms, the circadian clock alters its phase in response tosynchronizing stimuli such as light and temperature. This is known as a phase response. It is important tonote that the magnitude of this response varies, depending on the phase of the stimulus received. These
diverse phase responses are collectively represented in a single graph called the phase response curve(PRC), which illuminates the relationship between the circadian clock and the internal and external
synchronizing stimuli. However, traditional methods of obtaining a PRC require multiple measurementsof the phase response to stimuli at different times of day, a process that is both time-consuming andexpensive.
In this study, we adapted a previously developed PRC estimation method, originally used in the context ofthe plant circadian clock, for use in the mammalian clock. This innovative method involves measuring thephase response to stimuli in a desynchronized state (also known as a singularity response, SR), where eachcell’s timing varies. This allows for the evaluation of the circadian clock’s response characteristics todiverse stimuli. We demonstrated that SR can be observed in mouse- and rat-cultured cells and that thePRC for temperature and chemical stimuli can be assessed from a single measurement. Additionally,measurements using tissue cultures derived from mice showed that the phase response to identicalsynchronizing stimuli varies depending on the tissue involved. These results are expected to be applied fordeveloping therapeutic drugs for jet lag and circadian rhythm disorders.

Correspondence
Assistant Professor Arisa Hirano
Professor Takeshi Sakurai

1International Institute for Integrative Sleep Medicine (WPI-IIIS)/ Institute of Medicine, University ofTsukuba
URL: https://sakurai-lab.com/english/
Funding
This study was partially supported by Grants-in-Aid for JSPS Fellows (No.22J00270 to K.M.), for
Scientific Research (22K15157 to K.M.) and for Specially Promoted Research (17H06096 to Y.F.)
provided by the Japan Society for the Promotion of Science (JSPS), Moonshot Research
Development Program (JP21zf0127003 to A.H.) provided by Japan Agency for Medical Research andDevelopment (AMED) and Research grant (A.H.) (The Naito Foundation, Japan).
Article“Singularity response reveals entrainment properties in mammalian circadian clock” Naturecommunications, May 17, 2023.
DOI: 10.1038/s41467-023-38392-x
Keywords
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Computational biology
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Mathematical biology

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