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Gene deficient mice could not switch sleep schedules

Finding the brain region responsible still elusive

This region sits close to the area of the brain that manages ordinary circadian responses to light and dark. The study shows that mice lacking a particular gene that acts in the DMH do not adjust to changes in feeding schedule. Reinstating the gene restored the behaviour. But some researchers in the field have serious concerns about the work. “On the face of it, it’s almost the final nail in saying DMH is the pacemaker, but under the surface there are people who strongly disagree,” says neuroscientist Masashi Yanagisawa of University of Texas Southwestern Medical Center in Dallas, who was not involved in the work.

This study’s results conflict with other research indicating that the DMH may have no special role and that food-related circadian rhythms persist even after the DMH has been disabled.

The brain region responsible for food-related rhythms may well continue to be elusive.

To investigate the role of the DMH, Saper and his colleagues looked at mice that lacked a particular clock gene called Bmal1.

They observed that mice without this gene slept intermittently and seemed to follow no regular schedule, a sign that their circadian clock no longer functioned. To test the ability of the mice to switch their sleep schedules to match up with mealtimes, the researchers stopped offering food overnight and restricted meals to a short 4-hour window during the day.

Ordinary mice were able to switch their sleep schedules almost immediately to match, but the Bmal1-deficient mice could not. Injecting a virus containing the gene into the DMH seemed to restore the mice’s ability to switch their sleep schedule to match the new feeding schedule.

“Potentially it has substantial benefit for people,” says Saper, who anticipates that more work in the area will help produce medication that can rapidly alter sleep schedules in humans.

Such drugs could benefit people adjusting to jet lag, a process that often takes days.

The results build on previous work by Yanagisawa that show oscillations in the DMH only when feeding conditions are restricted, suggesting that a period of fasting followed by an unusual mealtime might allow the DMH to overpower the main circadian clock and rejig sleep schedules.

But implicating DMH as the food clock depends on measuring ‘food anticipation’ — factors like body temperature and increased movement that signal metabolic changes in advance of a meal. Some groups who have deactivated the DMH by creating a lesion have seen no change in this behaviour, indicating that other parts of the brain may be responsible.

At the recent Society for Research on Biological Rhythms conference in Florida, other researchers reported that Bmal1-deficient mice still maintain food-entrained rhythms.

“I think this paper’s going to have a very short half-life,” says Ralph Mistleberger, who studies circadian rhythms at Simon Fraser University in Burnaby, British Columbia. Mistleberger notes that Bmal1-deficient mice are not particularly healthy, and that the extent of the study’s food restrictions may stress the mice so much as to skew the results.

So while researchers are making headway, 80 years after food anticipatory behaviour was first observed, in rats, finding the brain region responsible may continue to prove elusive.

Although the DMH may have some role, Mistleberger says, the mechanism is more likely to be a brain-wide network phenomenon or perhaps “a completely novel clock, one that doesn’t rely on the same set of clock genes, or at least not in the same way.”

Gene deficient mice could not switch sleep schedules

Finding the brain region responsible still elusive

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