summary: Research has revealed new molecular pathways that help control homeostasis and sleep rhythms in the brain.
sauce: University of Tsukuba
Most organisms exhibit a circadian rhythm, an internal clock that repeats approximately every 24 hours. Now, Japanese researchers have discovered new details about the molecular processes that govern sleep/wake rhythms in mice.
In a recently published study, researchers from the University of Tsukuba reveal that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays an important role in circadian behavior. Did.
Through changes in the suprachiasmatic nucleus (SCN), the brain’s master clock that synchronizes various rhythms in the body, animals can adapt to the circadian light-dark cycle both behaviorally and physiologically. increase. However, the biological activity within her SCN that induces time-specific arousal has not been fully characterized. The research team aimed to address this.
“Most animals show peak activity at certain points in the circadian cycle,” explains Professor Tadashi Yanagisawa, lead author of the study. “Since the SCN is known to regulate sleep and wakefulness at specific times of the day, we wanted to investigate the distinct neurons that control this process.”
To do this, the researchers genetically engineered levels of SIK3 in specific neuronal groups in the mouse SCN. Next, we examined sleep and circadian behavior in mice, including the times and periods during which mice showed activity with respect to the light-dark cycle.
“We found that SIK3 in the SCN can influence the length of the circadian cycle and the timing of peak wakefulness activity without changing the amount of sleep per day,” says Yanagisawa.
The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (a key target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Here, they found that the SIK3-HDAC4 pathway regulates circadian cycle length via NMS-producing neurons and contributes to sleep/wake rhythms.
The length of behavioral periods and the timing of peak activity are important components of circadian rhythms. Given the similarities of circadian rhythm systems in different mammals, new information about how this system works in mice may lead to new treatments for sleep and circadian rhythm disorders in humans. .
Funding: This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research, World Premier International Research Center Initiative (WPI). (KAKENHI), Japan Science and Technology Agency (JST), Basic Research in Evolutionary Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 Grant, University of Tsukuba Basic Research Support Project Type A , funded by the World’s Leading Innovative Science and Technology Research and Development Program (FIRST Program).
About this Circadian Rhythm Research News
author: press office
sauce: University of Tsukuba
contact: Press Office – University of Tsukuba
image: image is public domain
Original research: closed access.
“SIK3–HDAC4 in the suprachiasmatic nucleus regulates the timing of dark onset and circadian arousal in mice]Masashi Yanagisawa and others PNAS
overview
SIK3–HDAC4 in the suprachiasmatic nucleus regulates the timing of dark onset and circadian arousal in mice
Mammals exhibit a circadian cycle of sleep and wakefulness under the control of the suprachiasmatic nucleus (SCN). This includes strong arousal phase-locked to the onset of dark in experimental mice.
Here, we show that salt-inducible kinase 3 (SIK3) deficiency in γ-aminobutyric acid (GABA)-ergic neurons or neuromedin S (NMS)-producing neurons delays peak wakefulness phase and behavioral circadian cycle under both 12 h. We will demonstrate that it extends the Light: 12 hours of darkness (LD) and constant darkness (DD) without changing the amount of sleep you get each day.
In contrast, the induction of gain-of-function mutant alleles Sik3 GABAergic neurons showed high activity onset and short circadian periods. Loss of her SIK3 in neurons that produce arginine vasopressin (AVP) lengthened the circadian cycle, but the peak phase of wakefulness was similar to control mice.
Heterozygous deficiency of the SIK3 substrate histone deacetylase (HDAC) 4 shortened the circadian cycle, whereas mice harboring HDAC4 S245A, which is resistant to phosphorylation by SIK3, delayed the peak phase of wakefulness. I was. Expression of a phase-delayed core clock gene was detected in the liver of mice lacking her SIK3 in GABAergic neurons.
These results suggest that the SIK3–HDAC4 pathway regulates circadian cycle length and timing of arousal through NMS-positive neurons in the SCN.
