SCN

Is Circadian Rhythm the Rhythm of Life?

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Pre-ovulatory hormone surge and ovulation may be controlled by novel circadian hiearchy.

Studies in rodents have revealed a novel circadian hierarchy critical for the coordination of pre-ovulatory luteinizing hormone (LH) surge and ovulation.

The research in hamsters and mice suggests that the suprachiasmatic nucleus (SCN) has dual roles in the regulation of ovulation, reported Lance Kriegsfeld, PhD, of the University of California Berkeley, and colleagues, published online April 14.

Circadian rhythms in mammals are generated by a brain clock located in the SCN of the anterior hypothalamus, and this research expands on earlier work examining how SCN communicates timing information throughout the body, they wrote inEndocrinology.

“Based on our findings, we propose that the SCN signals the kisspeptin and systems via direct neuronal projections to positively drive the LH surge,” the researchers wrote. “Concurrently, the SCN directly and perhaps more likely, indirectly, signals the RFamide-related peptide 3 (RFRP-3) system to coordinate the suppression of estradiol negative feedback with this positive drive.”

Circadian clock timing has been shown to be critical in mammalian reproduction, and evidence suggests that this timing is regulated by gonadotropins.

Research has shown that women with irregular work or sleep cycles can have reduced fertility and an increased chance for spontaneous abortions, Kriegsfeld’s group explained.

“The circadian system coordinates the timing of ovulation and sexual behavior to coincide with an individual’s species-specific temporal niche, with the pre-ovulatory LH surge occurring in the early morning in women and diurnal rodents and late afternoon in nocturnal rodents,” the researchers wrote. They added that in species with spontaneous ovulation, the timing of the LH surge is controlled by the master circadian pacemaker in the SCN of the anterior hypothalamus.

Estrogen negative feedback is responsible for restraining the GnRH neuronal system for most of the ovulatory cycle, but immediately before ovulation this feedback is removed to allow stimulation of the pre-ovulatory GnRH/LH surge by the circadian clock in SCN.

Kriegsfeld and colleagues examined the neurochemical pathway by which SCN controls RFRP-3 activity. They also attempted to determine if the RFRP-3 system exhibits time-dependent responsiveness to SCN signaling to time LH surge.

“We found that RFRP-3 cells in female Syrian hamsters (Mesocricetus auratus) receive close appositions from vasopressin (AVP)-ergic and SCN-derived vasoactive intestinal polypeptide (VIP)-ergic terminal fibers,” they wrote. “Central VIP administration markedly suppressed RFRP-3 cellular activity in the evening, but not the morning, relative to saline controls, whereas AVP was without effect at either time point. Double-label in situ hybridization (ISH) for Rfrp-3 and the VIP receptors VPAC1 and VPAC2, revealed that the majority of RFRP-3 cells do not co-express either receptor in Syrian hamsters or mice, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly.”

The research showed that both the GnRH and RFRP-3 systems maintain their own circadian time to ensure the precise coordination of the “stimulation and disinhibition of the reproductive axis,” they noted.

“Given that epidemiological and experimental findings indicate a pronounced negative impact of circadian disruption on female reproductive health, systematically uncovering the mechanisms underlying the circadian control of the female reproductive axis has potential clinical implications,” they wrote.

Study reveals why the body clock is slow to adjust to time changes.

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New research in mice reveals why the body is so slow to recover from jet-lag and identifies a target for the development of drugs that could help us to adjust faster to changes in time zone.

With funding from the Wellcome Trust and F. Hoffmann La Roche, researchers at the University of Oxford, University of Notre Dame and F. Hoffmann La Roche have identified a mechanism that limits the ability of the body clock to adjust to changes in patterns of light and dark. And the team show that if you block the activity of this gene in mice, they recover faster from disturbances in their daily light/dark cycle that were designed to simulate jet-lag.

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Nearly all life on Earth has an internal circadian body clock that keeps us ticking on a 24-hour cycle, synchronising a variety of bodily functions such as sleeping and eating with the cycle of light and dark in a solar day. When we travel to a different time zone our body clock eventually adjusts to the local time. However this can take up to one day for every hour the clock is shifted, resulting in several days of fatigue and discombobulation.

In mammals, the circadian clock is controlled by an area of the brain called the suprachiasmatic nuclei (SCN) which pulls every cell in the body into the same biological rhythm. It receives information from a specialised system in the eyes, separate from the mechanisms we use to ‘see’, which senses the time of day by detecting environmental light, synchronising the clock to local time. Until now, little was known about the molecular mechanisms of how light affects activity in the SCN to ‘tune’ the clock and why it takes so long to adjust when the light cycle changes.

To investigate this, the Oxford University team led by Dr Stuart Peirson and Professor Russell Foster, used mice to examine the patterns of gene expression in the SCN following a pulse of light during the hours of darkness. They identified around 100 genes that were switched on in response to light, revealing a sequence of events that act to retune the circadian clock. Amongst these, they identified one molecule, SIK1, that terminates this response, acting as a brake to limit the effects of light on the clock. When they blocked the activity of SIK1, the mice adjusted faster to changes in light cycle.

Dr Peirson explains: “We’ve identified a system that actively prevents the body clock from re-adjusting. If you think about, it makes sense to have a buffering mechanism in place to provide some stability to the clock. The clock needs to be sure that it is getting a reliable signal, and if the signal occurs at the same time over several days it probably has biological relevance. But it is this same buffering mechanism that slows down our ability to adjust to a new time zone and causes jet lag.”

Disruptions in the circadian system have been linked to chronic diseases including cancer, diabetes, and heart disease, as well as weakened immunity to infections and impaired cognition. More recently, researchers are uncovering that circadian disturbances are a common feature of several mental illnesses, including schizophrenia and bipolar disorder.

Russell Foster, Director of the recently established Oxford University Sleep and Circadian Neuroscience Institute supported by the Wellcome Trust, said: “We’re still several years away from a cure for jet-lag but understanding the mechanisms that generate and regulate our circadian clock gives us targets to develop drugs to help bring our bodies in tune with the solar cycle.Such drugs could potentially have broader therapeutic value for people with mental health issues.”

Source: Cell.