Jetlag-resistant mice

03 October 2013
Posted by Chris Smith.

Mice that don't suffer jetlag have been developed by scientists in An old style alarm clockJapan, a breakthrough that might enable weary travellers to settle into new time zones more quickly.

Almost all organisms, including even plants and bacteria, have internal clocks that usually tick to a 24hour "circadian" rhythm that dictates patterns of higher or lower metabolic activity, sleep, feeding and growth.

For the majority of people, the only time this clock noticeably announces its presence is during international travel, when jetlag kicks in, or when shiftworkers struggle to stay awake at the right times.

The master clock, which calls time for the rest of the body, is based in the brain's "suprachiasmatic nucleus". Here a cluster of 10-20,000 nerve cells use a genetic "domino effect" in which a cyclical sequence of genes switch each other on and off in turn, taking about a day to complete the loop.

As the levels of these genes rise and fall, the activity of the nerve cells changes, altering the behaviour of other brain circuits and the levels of "wake-up" hormones, like cortisol, in the blood. It's these patterns that take time to adjust and re-align to new time zones when jetlag kicks in.

But how is this resyncronisation achieved, and which genes are involved? To find out, Kyoto University scientist Yoshiaki Yamaguchi and his colleagues first established which genes were switched on in the suprachiasmatic nucleus.

In experimental mice, they set about switching off these genes, initially one at a time, and monitoring the responses of the animals to being jetlagged.

One pair of genes, called V1a and V1b, which encode a receptor for the nerve transmitter chemical AVP, showed a profound effect. Mice lacking both of them were resistant to the effects of jetlag.

In their study, published in Science, the Japanese team shifted the animals forwards 8 hours from an established 12 hour light-dark cycle, similar to a person flying from England to Australia.

Normal mice took 8 days before they were waking up at the right time again, but the animals lacking Va1 and Vb1 genes recovered their normal sleep-wake cycles within 1 day, and, metabolically, their livers were back to normal in 5 days. Control mice took 10 days for their metabolism to reset to their new time zone.

The AVP signal detected by the V1a and V1b receptors, the scientists speculate, is involved in syncing up the activities of the body clock nerve cells in the suprachiasmatic nucleus; using AVP as a signal, the clock nerves share the time signal amongst themselves, making it harder to perturb.

By knocking out the V1a and V1b genes, this resilience is lost, making the clock much easier to re-entrain.

According to Yamaguchi and his colleagues, this may pave the way for making a drug that can temporarily block the clock signal, overcoming jetlag. "Our results identify AVP signaling as a possible therapeutic target for the management of circadian rhythm misalignment..."

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