A team led by researchers from RIKEN has revealed how daily or circadian rhythms in mammals can be reinforced, shifted or disrupted by exposure to a burst of bright light. The work solves a 30-year-old mystery, and may well find application in the treatment of circadian disorders such as jet lag, lack of alertness in shift workers, delayed sleep phase syndrome and some forms of mental illness.
A network of genes ensures the rhythms of organisms—sleep and wakefulness, changes in body temperature and the secretion of certain proteins—are attuned to daily cycles. These genes generate proteins that interact in complex interlocking feedback loops to produce the rhythms. Groups of cells exhibiting circadian rhythms are found in many parts of the body.
The researchers found that a critical light pulse at midnight can uncouple and randomize the circadian cycles of individual cells thus damping the rhythm of the whole group of cells. Their data did not support a more popular hypothesis, that the pulse suppresses the rhythms of all the cells simultaneously.
In a recent paper in Nature Cell Biology (1), the researchers from RIKEN’s Center for Developmental Biology in Kobe and several Japanese universities outline how they created light-sensitive circadian clocks in mouse fibroblast cells in the laboratory. The team introduced the light receptor melanopsin together with a bioluminescent reporter compound that emits light when the key clock gene PER2 is active. The system can be used to track the phase and amplitude of circadian rhythms by measuring the average output of light over time.
The researchers then plotted the impact on phase and amplitude of pulses of light of differing lengths introduced at different times during the cycle. From this work, they determined which pulses were most effective in disrupting the rhythm altogether.
The team next measured individual cells within a group, and found that disruptive light pulses desynchronize their cycles with respect to one another, but without damping each individual cycle. A computer model developed to mimic this desynchronization process generated results which closely matched the experimental data.
The researchers also showed light could desynchronize the activity of key clock genes in live rats. This was linked with a decrease in general movement in 30% of the rats.
The team hopes to apply its findings to human behavior, says Hiroki Ueda, the research team leader. “Our mathematical model could lead to a deeper understanding and better treatment of circadian rhythm disorders.”
Reference
1. Ukai, H., Kobayashi, T.J., Nagano, M., Masumoto, K., Sujino, M., Kondo, T., Yagita, K., Shigeyoshi, Y. & Ueda, H.R. Melanopsin-dependent photo-perturbation reveals desynchronization underlying the singularity of mammalian circadian clocks. Nature Cell Biology 9, 1327–1334 (2007).
