Blocking a hormone helps mice beat lengthy jet lag

Brain molecule steadies the beat of circadian clock, while stopping it allows for quick reset

A molecular timekeeper called vasopressin steadies the rhythm of the body’s daily cycles and may hamper acclimatization to new time zones. Mice rapidly recover from a laboratory form of jet lag when researchers block the hormone in the brain, a new study shows.

Fluctuations in physiology and behavior move to the beat of the circadian clock. Crossing time zones or working night shifts throws the body out of sync, leading to sleep and digestive problems, says neuroscientist Hitoshi Okamura of Kyoto University, who led the study. “When we face this situation,” he says, “we are forced to suffer.”

The tick-tocks of the mammalian circadian clock emanate from a tiny cluster of cells called the suprachiasmatic nucleus, located deep in the brain. Researchers have long known that the suprachiasmatic nucleus sets the clock, but which cells and molecules orchestrate its action have remained unclear.

Because neurons in the suprachiasmatic nucleus pump out vasopressin, Okamura and colleagues thought the molecule might help run the clock. The team genetically engineered mice to lack cell-surface proteins that detect the hormone in the brain.

Then the team shifted the animals’ schedule of light and darkness forward by eight hours, equivalent to the time zone change on a trip from New York to Moscow. Normal mice took eight to 10 days to adjust their active periods to the new time zone. But the mice engineered not to respond to vasopressin acclimated in just two to four days, the researchers report in the Oct. 4 Science.

The team noted that genes that normally turn on or off with circadian rhythms also realigned to the new time zone much faster in the engineered mice than in normal mice. This quick readjustment occurred in genes in the brain as well as in the liver and kidney. The findings give an extraordinarily detailed view of circadian oscillations throughout the body, says neuroscientist Joseph Takahashi of the University of Texas Southwestern Medical Center in Dallas. “This is a beautiful experiment,” he adds.

The team also examined the activity of neurons taken from the suprachiasmatic nucleus. Neurons from the normal mice adhered to a strict, highly coordinated firing schedule, whereas the timing of those from the engineered mice was more easily perturbed.“Vasopressin maintains a strong order,” Okamura says, “and this is why we get jet lag.”

The researchers could also hasten mice’s recovery from jet lag with experimental drugs that block the effects of vasopressin in the brain. Okamura envisions using such inhibitors to treat people’s jet lag symptoms. While temporarily weakening the circadian clock with drugs is not natural, neither is international travel, he says. “Evolution didn’t expect jet lag.”

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