'You Are Getting Sleepy,' Said The Scientist To The Fruit Fly

We've all been caught in that hazy tug of war between wakefulness and sleep. But the biology behind how our brains drive us to sleep when we're sleep-deprived hasn't been entirely clear.

For the first time scientists have identified the neurons in the brain that appear to control sleep drive, or the growing pressure we feel to sleep after being up for an extended period of time. The findings, published online Thursday by the journal Cell, could lead to better understanding of sleep disorders in humans. And perhaps, one day, if the work all pans out, better treatments for chronic insomnia could be developed.

To explore which brain areas might be involved in sleep drive, Johns Hopkins neuroscientist Dr. Mark Wu and his colleagues turned to fruit flies, that long tinkered-with subject of scientific inquiry. Despite our rather obvious physical distinctions, humans and fruit flies – or Drosophila – have a good deal in common when it comes to genes, brain architecture and even behaviors.

Included in the study were over 500 strains of fly, each with unique brain activation profiles (meaning certain circuits are more active in certain flies). By employing a genetic engineering technique in which specific groups of neurons can be activated with heat, the researchers were able to monitor the firing of nearly all the major circuits in the fruit fly brain and monitor the resulting effects on sleep.

Moreover, the neurons of interest were engineered to glow green when activated allowing specific cells to be identified with fluorescent microscopy. Wu found that activating a group of cells called R2 neurons, which are found in a brain region known as the ellipsoid body, put fruit flies to sleep, even for hours after the neurons were "turned off."

Next, using more generic tinkering, Wu engineered R2 neurons that can produce tetanus toxin in order to deactivate the cells by preventing the release of neurotransmitters (in other words cutting off communication with neighboring neurons). Flies that weren't sleep deprived but whose R2 neurons expressed the toxic compound slept their usual amount. However sleep-deprived flies — their lab vials were mechanically shaken through the night — also with silenced R2 neurons experienced, on average, 66 percent less rebound sleep.

The authors took this to mean that the flies felt less tired following inadequate sleep. Cutting off R2 activity appeared to suppress sleep drive in the sleep deprived.

"We didn't know circuits for sleep drive even existed," Wu tells Shots in an email. "If we can find the analogous circuits in humans, we might be able to induce more powerful and long-lasting changes in sleep or wakefulness in patients that suffer from severe pathologic sleepiness or severe insomnia."

As Wu explains, for years sleep has been primarily attributed to the release of chemicals involved in arousal and circadian rhythm control, namely adenosine and melatonin. And these compounds certainly appear to play a role in sleep. However once released they are are transient; scientists have wondered how then they contribute to prolonged sleep.

By using a technology called synaptic tagging with recombination – or STaR – that allows for the communication between two neurons to be visualized in live animals, Wu's group found that R2 neurons in sleep-deprived flies showed an increase in neurotransmitter release. The increased neuronal activity was still evident two hours after sleep-disruption ended, possibly explaining how extended sleep is maintained. Following 24 hours of recovery sleep, the increased activity in R2 neurons subsided back to normal.

"The current view has been that the increase in sleep pressure with extended wakefulness is caused by an increase in the concentration of chemicals in the brain that induce sleep," says Frank A.J.L. Scheer, a sleep scientist at Harvard Medical School and Brigham and Women's Hospital.

"However, these chemicals typically have a short half life on the order of minutes, while the buildup and dissipation of sleep pressure is on the order of hours," he continues. "[Dr. Wu's] elegant study in fruit flies shows that homeostatic sleep pressure is partially encoded by changes in how well neurons are connected."

Scheer says the findings provide a new model of how sleep is regulated in the brain. Yet he does express some reservations. "Whether and how it translates to the mammalian system, including humans, is currently unknown," he cautions.

Wu is upfront that applying his findings to humans is, for now, speculative. Still, the prospects are exciting. He envisions using sleep-drive neuron stimulation much in the way deep brain stimulation is now used for movement disorders such as Parkinson's disease. Iin other words, influencing neuronal activity with an implanted stimulator that monitors and controls sleep drive, boosting it or suppressing it as needed.

It's not hard to imagine the potential drawbacks of convincing the brain and body that they're not tired when in fact they are. Normally our brains alert us to sleep for a reason: to rest our cellular machinery; to restore energy reserves; to consolidate memories. What would be the consequences – health or otherwise – of, say, an overly ambitious, overworked surgeon stifling her innate sleep drive?

Given the early stages of this work, Wu doesn't appear concerned. He believes that a better understanding of mechanisms behind sleep drive could in the future help doctors treat patients with an overactive desire to sleep.

"I envision that sleep drive treatments would be used in patients with very severe disease who are resistant to existing therapies," he said.

Bret Stetka is a writer based in New York and an editorial director at Medscape. His work has appeared in Wired, Scientific American and on The Atlantic.com. He graduated from University of Virginia School of Medicine in 2005. He's also on Twitter: @BretStetka.