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Sleepyhead. Losing sleep disrupts one molecular circuit inside mouse neurons, causing them to forget.

Why Sleepyheads Forget

Red-eye flights, all-night study sessions, and extra-inning playoff games all deprive us of sleep and can leave us forgetful the next day. Now scientists have discovered that lost sleep disrupts a specific molecule in the brain's memory circuitry, possibly leading to treatments for tired brains.

Neuroscientists studying rodents and humans have found that sleep deprivation interrupts the storage of episodic memories: information about who, what, when, and where. To lay down these memories, neurons in our brains form new connections with other neurons or strengthen old ones. This rewiring process, which occurs over a period of hours, requires a rat's nest of intertwined molecular pathways within neurons that turn genes on and off and fine-tune how proteins behave.

Neuroscientist Ted Abel of the University of Pennsylvania and colleagues wanted to untangle these molecular circuits and pinpoint which one sleep deprivation disrupts. The researchers started by studying electrical signals in slices of the hippocampus--the brain's memory center--from sleep-deprived mice. They tested for long-term potentiation (LTP), a strengthening of connections between neurons that neuroscientists think underlies memory. When the scientists tried to trigger LTP in these brain slices with electrical stimulation or chemicals, they found that methods that fired up cellular pathways involving the molecule cyclic adenosine monophosphate (cAMP) didn't work. Brain cells from sleep-deprived mice also held about 50% less cAMP than did cells from well-rested mice. In the brain, cAMP acts as a molecular messenger, passing signals between proteins that regulate activity of genes responsible for memory formation.

So how does sleep deprivation diminish levels of this important signaling molecule? The researchers measured 40% more of the enzyme PDE4A5 in the brains of sleep-deprived mice than in normal mouse brains. PDE4A5 is a type of phosphodiesterase (PDE) enzyme and chews up cAMP.

To confirm that extra enzyme led to sleep deprivation's effects on memory, the scientists next tried to counteract it with rolipram, a drug that inhibits PDE4A5 and other similar PDEs. Applying rolipram to brain slices from sleep-deprived mice restored LTP. The researchers then tested the animals' memories by conditioning them to associate a small electric shock with a specific cage. Mice kept awake for 5 hours--about half a full night's sleep for the rodents--lacked a specific memory for the conditioning cage. But sleep-deprived mice that received shots of rolipram after their training remembered just as well as well-rested animals, the scientists report tomorrow in Nature. "The animals lost about half of their sleep in a 24-hour period and they don't know it," Abel says. He and colleagues are now working to find molecules that knock out only PDE4A5.

The findings begin to answer a "long-standing mystery" about the specific cellular pathways disrupted by sleep deprivation, says David Dinges, a neuroscientist at the University of Pennsylvania who wasn't involved in the study. "Scientists like me can only describe what is affected [by sleep deprivation] at the behavioral level in humans," Dinges says. Linking observed memory deficits to the PDE4A5 enzyme "suggests a potential target for alleviating the effects of sleep deprivation in humans," says neuroscientist Sam Deadwyler of Wake Forest University in Winston-Salem, North Carolina.