Sandman’s role in sleep control [with video]

Sleep-promoting neurons switch between electrical activity and silence as a function of sleep need. The switch is operated by dopamine and involves the antagonistic regulation of two potassium channels.

HFSP Long-Term Fellow Jeffrey Donlea and Program Grant holder Gero Miesenböck and colleagues
authored on Thu, 27 October 2016

Sleep is one of the great biological mysteries. Each night we disconnect ourselves from the world for 7 or 8 hours—a state that leaves us vulnerable and unproductive. Yet, despite these risks and costs, we do not know what sleep is good for. A team of scientists, including the former HFSP Long-Term Fellow Jeff Donlea, are trying to solve this puzzle by understanding the brain mechanisms controlling sleep and waking. A discovery published in the journal Nature brings them one step closer to this goal.

Sleep is governed by two systems—the circadian clock and the sleep homeostat. Gero Miesenböck, whose laboratory undertook the new research, explains, ‘The circadian clock allows us to anticipate predictable changes in the environment that are caused by the Earth’s rotation. As such, it makes sure we do our sleeping when it hurts us least, but it doesn’t speak to the deeper question of why we need to sleep in the first place. That explanation will come from understanding the second controller—the sleep homeostat. 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. The system is reset during sleep, and the cycle begins anew when we wake up.’

The team studied the sleep homeostat in fruit flies—the animal that also provided the crucial first insight into circadian timekeeping, some 45 years ago. Each fly has around two dozen sleep-promoting neurons in an area of the brain called the dorsal fan-shaped body; similar brain cells are also found in other animals and believed to exist in people. These neurons convey the output of the sleep homeostat.

In the new work, the group was able to demonstrate that the sleep-promoting neurons switch between electrically active and silent states as a function of sleep need: if the neurons are active, the fly is asleep, and when they are silent, the fly is awake. A sleeping fly could be shifted into wakefulness by stimulating the release of the messenger chemical dopamine, which turns off the sleep-promoting cells. Diogo Pimentel, one of the two lead authors of the study, said, ‘Being able to operate the sleep switch at will has given us a chance to find out how it works.’  The switch works by regulating tiny pores in the neurons that control their electrical activity. One of these pores—which the researchers called Sandman—is essential for the off switch: flies without Sandman spend most of their lives asleep, some waking up for just 20 minutes each day.

The researchers did not need to physically prod the fly brains to induce the dopamine release that operates the switch. Instead, they genetically engineered select neurons to make them pump out dopamine when illuminated, a technique known as optogenetics and first reported by Miesenböck in 2002. Shining light on the fly brains for 2-10 minutes released enough dopamine to completely flick the switch from sleep to wake mode. A short pulse of light caused instant but transient waking, as if the flies were hitting the snooze button and falling straight back to sleep. ‘You can think of these neurons like an alarm clock,’ says lead author Jeff Donlea, a former member of the Miesenböck group who is now an Assistant Professor of Neurobiology at the University of California, Los Angeles. ‘If the alarm does not persist, you go back to sleep. But if it does, the switch is flicked and you stay awake. A hard switch for sleep control makes sense,' says Miesenböck. ‘You want to be either asleep or awake but not drift through twilight states.’

The team is now planning to test what flicks the sleep-wake switch the other way. ‘If you could figure out what molecules or processes the sleep homeostat responds to, you might have your answer,’ says Diogo Pimentel.

 

Reference
Operation of a homeostatic sleep switch. Pimentel D*, Donlea JM*, Talbot CB, Song SM, Thurston AJ, Miesenböck G. Nature. 2016 Aug 18;536(7616):333-7.

Pubmed link