Penn Researchers Find Molecular Key to Exhaustion Following Sleep Deprivation

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Media Contact:Kim Menard | Kim.Menard@uphs.upenn.edu | 215-662-6183March 8, 2013

It happens to everyone: You stay up late one night to finish an assignment, and the next day, you’re exhausted. Humans aren’t unique in that; all animals need sleep, and if they don’t get it, they must make it up.

The biological term for that pay-the-piper behavior is “sleep homeostasis,” and now, thanks to a research team at the Perelman School of Medicine, University of Pennsylvania, one of the molecular players in this process has been identified – at least in nematode round worms.

David Raizen, MD, PhD, assistant professor of Neurology, and his colleagues report in Current Biology that even in Caenorhabditis elegans, a tiny nematode worm that feeds on bacteria, loss of sleep is “stressful.”

The researchers forced the animals to stay awake during a developmental stage when they normally sleep, called “lethargus.” These sleep-deprived worms, like college students after an all-nighter, exhibited signs of sleep homeostasis – they were harder to wake up compared to control worms.

While nematode worms do not sleep as vertebrates do, lethargus is a sleep-like state, says Raizen, characterized by episodic reversible immobility, elevated arousal thresholds, and homeostasis.

On the molecular level, loss of sleep in the worm was associated with migration of the stress-related DNA-binding protein DAF-16, also called FOXO, from the cell cytoplasm into the nucleus. Here, the protein activates expression of stress-related genes. Knocking out that DAF-16 gene eliminated the animals’ homeostatic response – the equivalent of giving an up-all-night college student a free pass on sleep deprivation.

“You might think that is a good thing,” Raizen says, “but a good percentage of DAF-16 mutants died” – as many as half of the worms in some cases. That, Raizen says, suggests that the movement of DAF-16 into the nucleus is not merely a consequence of sleep deprivation, but rather a key to the homeostatic response.

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