Insight into behavioural rhythms without circadian clock

Scientists have found behaviour rhythms remaining in mice, after “switching off” the 24-hour canonical circadian rhythm and day-night cycle of light.

The circadian rhythm is the 24-hour cycle of physiology and behaviour in living beings. Circadian clocks are responsible for keeping time; the main clock in the brain gathers time-of-day information from daylight and synchronises the circadian rhythm to the 24-hour light-dark cycle.

Researchers were interested in investigating what happens after removing genes responsible for the circadian rhythm and the 24-hour day-night cycle. The behaviour of mice with genetically inactivated circadian clocks were monitored in constant darkness at The University of Texas Southwestern Medical Centre, and the measured data was analysed at Lancaster University.

Professor Shin Yamazaki of The University of Texas Southwestern Medical Centre said: “The project came about due to my longstanding interest in understanding the origin and nature of circadian rhythmicity as a fundamental process that governs daily rhythms at all levels of biology, including sleep, behaviour, metabolism, physiology, and gene expression. Precise control of this process is critical to life.”

The mice were kept in the dark for 272 days, the longest known recording to date. The number of running wheel turns were collected every minute. The long recording period and frequent collection of data is important, to see short patterns in behaviour, and patterns that emerge over time.

A unique set of mathematical methods based on a sound understanding of the physics of living systems were used to analyse the running wheel behaviour data. The toolbox MODA, developed by the Nonlinear and Biomedical Physics team led by Professor Aneta Stefanovska, is available in MatLab and Python. MODA includes methods to see what rhythms emerge over time, whether these rhythms interact, and if the rhythms are influenced by some outside forces.

Professor Stefanovska said: “There are many rhythms in the body including the circadian 24-hour rhythm, and they are all, in a way, imperfect clocks acting on many timescales and mutually influencing each other. That is why analysis methods are needed that are capable of unwinding cyclic processes as they evolve in time rather than just obtaining their averages. Shin’s experiments provide excellent examples of open systems acting far from equilibrium that we can study in practice.”

Although all known sources of the circadian rhythm were removed, it was identified that four rhythms remained in the behaviour, all with cycles less than 24-hours. These were approximately 17 hours, 8 hours, 4 hours, and 20 minutes. Interestingly, the 17-hour and 8-hour rhythms alternated in approximately 20 days interval. This is believed to be the first observation of an autonomous ~3-weeks ultradian rhythm in rodents. All rhythms interacted with each other, but particularly the 17-, 8- and 4-hour rhythms were found to strongly influence the 20-minute rhythm.

Megan Morris of Lancaster University said: “While the 17-hour rhythm is most likely another non-canonical circadian behavioural clock, the other three rhythms are ultradian rhythms, related to various physiological functions. Ultradian rhythms are robust to external stimuli, unlike the circadian system. However, their origin, mechanism and significance are poorly understood.”

Researchers believe that thorough investigation into the timekeeping mechanism is essential, as its disruption, through e.g., sleep deprivation or cycle disturbance, may contribute to the onset of diseases such as cancer, diabetes and obesity and mood disorders such as depression.

/Public Release. This material from the originating organization/author(s) may be of a point-in-time nature, edited for clarity, style and length. The views and opinions expressed are those of the author(s).View in full here.