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Journal Club: “Sandman” molecule controls when fruit flies wake up

Scientist are beginning to discover the features of a sleep homeostat that controls when fruit flies fall asleep and wake. Credit: Centre for Neural Circuits and Behaviour/ University of Oxford

Scientist are beginning to discover the features of a sleep homeostat that controls when fruit flies fall asleep and wake. Credit: Centre for Neural Circuits and Behaviour/ University of Oxford

Sleep cuts people off from the outside world, which entails considerable risks and costs that scientists reason must be counterbalanced by a vital but enigmatic benefit. Now scientists have discovered what makes a switch flip in the brains of fruit flies to wake them up, findings that could help researchers solve the mystery of sleep.

Previous research suggests that sleep is governed by two systems—the circadian clock and the sleep homeostat. Decades of research have shed light on the circadian clock, which helps organisms set their daily activities based on when day and night start and stop. However, very little is known about the sleep homeostat. Mutant fruit flies whose circadian rhythms ran abnormally fast or slow helped scientists begin understanding the circadian clock about 45 years ago, but a similar Rosetta stone for understanding the sleep homeostat—a group of about two dozen sleep-promoting neurons in the fruit fly brain—was only unearthed a few years ago.

“The homeostat measures something—and we don’t know what that something is—that happens in our brains while we are awake, and when that something hits a ceiling, we go to sleep,” says study senior author Gero Miesenböck, a neuroscientist at the University of Oxford in England.

“The system is reset during sleep, and the cycle begins anew when we wake up,” Miesenböck says. “If we knew what the sleep homeostat responds to, we would have an important clue to the vital function of sleep, perhaps even the smoking gun.”

To learn more about the sleep homeostat, Miesenböck and his colleagues investigated sleep-promoting fruit fly neurons. Previous research found that when these neurons are artificially stimulated, the insects go to sleep, and when these brain cells are less active, the result is insomnia.

To switch the sleep-promoting neurons on and off, the scientists relied on optogenetics, a technique that Miesenböck helped develop in 2002. The insects were genetically engineered so that pulses of light would activate or deactivate production of the brain chemical dopamine.

When dopamine is released, the researchers found the sleep-promoting neurons in these fruit flies became silent, and they rapidly woke up. When dopamine levels fell, these neurons became active and the insects went to sleep.

The scientists discovered a molecule they named Sandman that appears to control the activity of the sleep-promoting neurons. When these neurons are electrically active and the fruit flies are asleep, Sandman is kept inside these neurons. However, when dopamine is released, Sandman inserts into the cell membrane. Sandman is an ion channel that lets potassium ions flow out of the cells, which stifles the electrical activity of these neurons, waking the insects.

“You get goosebumps when the fog finally lifts and you see how simple and elegant the underlying mechanism is,” Miesenböck says.

Neuroscientist Luis de Lecea at Stanford University, who did not participate in this study, says, “It’s an incredibly elegant study that provides many clues regarding the mechanisms underlying the cycle of sleep-to-wake transitions.”

The sleep-promoting neurons seen in fruit flies are similar to certain neurons seen in mammals, Miesenböck says. “It is not inconceivable that some of the same molecular machinery is used, with potential practical implications,” Miesenböck says, such as new classes of sleep-inducing drugs.

Future research will aim “to identify the signals and processes that impinge on the Sandman switch,” Miesenböck says. While Miesenböck and his colleagues have found that dopamine can flip this switch off, researchers should also look for what can switch it on, says neuroscientist Paul Shaw at the Washington University School of Medicine in St. Louis, who did not take part in this research. Future research can also uncover what other conditions can turn this switch off, de Lecea says.

The scientists detailed their findings online Aug. 3 in the journal Nature.

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