Understanding jet lag may help develop drugs to help with time zone changes

A study using jet lagged mice helps researchers determine what makes people slow to adjust to jet lag and may help develop medication to make the transition easier.

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.

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."

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Jet lagged mice used to study sleep disorders

A study using jet lagged mice helped researchers study different sleep disorders.

Many factors keep us from getting a good night’s sleep. Prime culprits include overnight flights across the ocean, graveyard shifts, and stress-induced insomnia. A new study from McGill and Concordia Universities gives hope, however, that these common sleep disturbances may one day be put to bed.

The Earth’s rotation is responsible for creating day and night, and the daily rhythms of all living beings. Mammals have a “circadian clock” in their brains that drive the daily rhythms in sleep and wakefulness, feeding and metabolism, and many other essential processes. Until now, however, the inner workings and molecular processes of this complex brain clock have eluded scientists.

The findings, published in Neuron, identify how a fundamental biological process called protein synthesis is controlled within the body’s circadian clock. The researchers hope their work will help shed light on future treatments for disorders triggered by circadian clock dysfunction, including jet lag, shift work disorders, and chronic conditions like depression and Parkinson’s disease.

“To understand and treat the causes and symptoms of circadian abnormalities, we have to take a closer look at the fundamental biological mechanisms that control our internal clocks,” says Dr. Shimon Amir, professor in Concordia University’s Department of Psychology.

Amir worked with Dr. Nahum Sonenberg, a James McGill professor in the Dept. of Biochemistry, Faculty of Medicine, at the Goodman Cancer Research Centre at McGill University, to study how protein synthesis is controlled in the brain clock. “We identified a repressor protein in the clock and found that by removing this protein, the brain clock function was surprisingly improved,” explains Dr. Sonenberg.

The circadian clocks of all mammals are similar, so the team was able to use mice to conduct their experiments. The mouse model used lacked this specific protein, known as 4E-BP1. The protein blocks the important function of protein synthesis. The mice that lacked this protein were able to overcome disruptions to their circadian clocks more quickly, the team found.

“In modern society, with the frequency of trans-time zone travel, we often deal with annoying jet lag problems, which usually require a couple of weeks of transition,” says Dr.Ruifeng Cao, a postdoctoral fellow who works with Drs. Sonenberg and Amir, “However, by inducing a state like jet lag in the mice lacking that protein, we found they were able to adapt to time zones changes in about half of the time required by regular mice.”

The research team also found, in mice lacking the protein 4E-BP1,there was a small increase in another small protein necessary for brain clock function, vasoactive intestinal peptide or VIP. This indicates to the researchers the functioning of the circadian clock could be improved by genetic manipulations, opening doors on new ways to treat circadian clock-related disorders.

“A stronger clock function may help improve many physiological processes, such as aging,” says Cao. “In addition, understanding the molecular mechanisms of biological clocks may contribute to the development of time-managing drugs,” Amir concurs, noting that “the more we know about these mechanisms, the better able we will be to solve problems associated with disruptions to our bodies’ internal clocks”.

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