Researchers find a molecular pathway that controls sleep rhythms and homeostasis

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In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3, or salt-inducible kinase 3) also plays a critical role in circadian behavior.

Animals can adapt to the 24-hour cycle of light and dark in terms of behavior and physiology through changes in the suprachiasmatic nucleus (SCN), which is the brain’s master clock that synchronizes the various rhythms of the body. However, the biological activities within the SCN that induce wakefulness at a specific time have not been fully characterized; the research team set out to address this.

“Most animals show a peak of activity at a specific point in the circadian cycle,” explains the study’s lead author, Professor Masashi Yanagisawa. “Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the various neurons that control this process.”

To do this, the research team genetically engineered SIK3 levels in specific groups of neurons in the SCN of mice. They then examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity regarding the light-dark cycle.

“We found that SIK3 in the SCN can influence the length of the circadian cycle and the timing of peak activation activity, without changing the amount of daily sleep,” says Professor Yanagisawa.

The research team previously reported that SIK3 interacts with LKB1 (a molecule upstream of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have discovered that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons and contributes to the sleep/wake rhythm.

The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans.

This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) World Premier International Research Center Initiative (WPI), Japan Society for the Promotion of Science (JSPS) Grants for Scientific Research ( KAKENHI), Japan Agency for Science and Technology (JST) Basic Research for Evolutionary Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 Grant, Research Support Program University of Tsukuba Type A Basic Program and funding Program for the World’s Leading Innovative R&D in Science and Technology (FIRST Program).