Sleep is one of many biological mysteries scientists seek to explore and explain. Although the timing of sleep is known to be regulated by the body’s biological clock, the nitty gritty mechanics of exactly how that happens remain obscure. Until, perhaps, now: A team of researchers have identified, in fruit flies, the protein made by the gene that promotes and regulates sleep as well as a mutant gene — dubbed "Wide Awake" — that sabotages how the biological clock sets the timing for sleep. "We have now found the first protein ever identified that translates timing information from the body's circadian clock and uses it to regulate sleep," said Dr. Mark N. Wu, an assistant professor of neurology, medicine, genetic medicine, and neuroscience at the Johns Hopkins University School of Medicine. The researchers feel confident the same protein plays a similar role in the human body.

Discovering the Molecular Basis of Sleep

Most of our bodily functions and behaviors, including the sleep and wake, body temperature, hunger, and hormonal cycles, fluctuate in 24-hour cycles. Scientists understand that these circadian cycles are influenced and regulated by the body’s central clock, which is located in two tiny structures in the brain: the suprachiasmatic nuclei (SCN). They sit on both right and left sides at the base of the hypothalamus. Each SCN contains several tens of thousands of neurons (or brain cells), yet each is no larger than a pencil tip. Receiving information from the nearby optic nerve, the SCN synchronize themselves with day and night cycles while sending out molecular signals, transmitted via proteins, to regulate the body as a whole.

To learn more about the molecular processes involved in our sleep cycle, Wu and his research team studied thousands of fruit fly colonies and analyzed their sleep patterns. Flies in each of the separate colonies shared a different set of genetic mutations. The researchers found that one group of flies had a mutation in the gene they called Wide Awake (for short: WAKE) and this particular group had trouble falling asleep each night. In fact, their difficulties resembled humans dealing with sleep-onset insomnia.

After isolating the gene, the team figured out that normally, when working properly, Wake acts as the messenger from the circadian clock to the brain, telling it that it's time to shut down and sleep. Wake levels rise and fall in cycles throughout the day; these patterns help to shut down certain neurons in the brain by making them more responsive to signals from the inhibitory neurotransmitter called GABA. Levels of Wake peak near dusk in good sleepers, and then by night they have subsided enough to promote sleep.

“Although WAKE is expressed in clock neurons and its levels vary throughout the day, WAKE itself is not a core clock molecule, since period length and activity rhythm strength are intact in wake mutants in constant darkness,” wrote the researchers in their paper appearing online in the journal Neuron. “Rather, WAKE is, to our knowledge, the first clock output molecule shown to specifically regulate sleep timing.” Investigating further, the team found the fruit flies with a mutated WAKE gene couldn't get to sleep because they were not getting enough GABA signal to quiet their arousal circuits at night, causing the flies to feel agitated.

"Sometimes we discover things in flies that have no direct relevance in higher order animals," Wu said in a press release. In this case, however, the researchers found the same gene in every animal they studied: worms, mice, rabbits, chickens… and even humans. Importantly, when Wu's team looked to see where WAKE was located in the mouse brain, they found that it was expressed in the suprachiasmatic nucleus, where it could be found in high concentrations.

"In this case, because we found the protein in a location where it likely plays a role in circadian rhythms and sleep, we are encouraged that this protein may do the same thing in mice and people," Wu noted. He and his colleagues believe their discoveries may lead to new treatments for people with insomnia or those working night shifts and other schedules.


Source: Liu S, Lamaze A, Liu Q, Tabuchi M, Yang Y, Wu MN, et al. WIDE AWAKE Mediates the Circadian Timing of Sleep Onset. Neuron. 2014.