|
By
Michael Purdy
Dec.
11, 2006 -- Scientists have identified the first biochemical
marker linked to sleep loss, an enzyme in saliva known
as amylase, which increases in activity when sleep deprivation
is prolonged.
Researchers
hope to make amylase the first of a panel of biomarkers
that will aid diagnosis and treatment of sleep disorders
and may one day help assess the risk of falling asleep
at the wheel of a car or in other dangerous contexts.
"As we prepare for the holiday season and
long drives to distant relative's houses, I hope this
finding will get people thinking about the dangers and
costs of sleep deprivation," says lead author Paul
J. Shaw, Ph.D., assistant professor of neurobiology.
"If you're feeling sleepy on your way over the
river and through the woods to grandmother's house,
it's much better to pull over and find a place where
you can sleep for a while than to continue on and risk
a serious accident."
The
study appears this week in the online edition of Proceedings
of the National Academy of Sciences. Shaw's lab
was the first to show that fruit flies enter a state
of inactivity comparable to sleep. They demonstrated
that the flies have periods of inactivity where greater
stimulation is required to rouse them. Like humans,
flies deprived of sleep one day will try to make up
for the lost time by sleeping more the next day, a phenomenon
referred to as increased sleep drive or sleep debt.
To
identify a marker for sleep debt, Shaw decided to look
in saliva. Easily accessible, saliva contains many of
the substances found in blood and urine, making it an
increasingly popular target for diagnostics. Saliva
was also an attractive target for Shaw's lab because
the brain areas that regulate sleep drive are known
to send signals to the brain areas that regulate salivation.
To start his search, Shaw subjected the flies
to different kinds of sleep deprivation and used microarrays
to look for changes in activity in many different genes.
Amylase levels consistently changed after sleep loss.
Amylases are a family of enzymes found in the saliva
that break down starch.
To
verify amylase's connection to sleep loss, Shaw's lab
monitored its activity level after sleep deprivation
in different fruit fly lines genetically altered to
modify their sleep drive. In one key test, amylase did
not increase in a fly modified to endure sleep deprivation
longer than normal flies without incurring sleep debt.
When scientists kept the same mutant flies awake for
extended nine or 12 hour stretches that normally cause
them to incur sleep debt, their amylase levels increased.
"This
helped prove that the increases in amylase activity
level we were seeing weren't just triggered by wakefulness,"
Shaw says. Humans kept awake for 28 hours also had increased
amylase levels versus controls allowed to sleep normally.
Shaw's
lab previously showed that they can use caffeine and
methamphetamine to keep flies awake. Caffeine inflicts
sleep debt, causing flies to sleep for extended periods
when it wears off, while methamphetamine does not. When
they monitored fly amylase levels in response to these
drugs, they found caffeine drove amylase activity up
while methamphetamine did not.
Flies
dosed with the herbicide paraquat did not have increased
amylase levels, suggesting changes in amylase activity
were not related to stress. Flies lacking the gene for
amylase had normal sleep and waking cycles, showing
that while amylase is tightly linked to sleep drive,
it is not actively involved in its regulation.
"We're very pleased with how tightly amylase levels
correlate with sleep debt, but for a good diagnostic
test we're likely going to need more than one biomarker,"
Shaw says. "So we're going to continue to use the
processes that we've developed to look for other substances
that change in connection with the level of sleep debt."
Stephen
L. Duntley, M.D., associate professor of neurology and
director of the Washington University Sleep Medicine
Center, is a frequent research collaborator with Shaw.
"Despite the tremendous medical and public
health consequences of sleep debt, its measurement in
humans relies upon unreliable subjective rating scales
and expensive, often impractical sleep laboratory testing,"
Duntley says. "Simple, easily accessible biomarkers
for sleep debt in humans would revolutionize our ability
to conduct research on the causes and consequences of
sleep deprivation and provide clinicians with valuable
new tools for diagnosing and assessing treatment efficacy
in patients with sleep disorders."
According
to Shaw, sleepiness biomarkers will also prove useful
to studies of sleep in animals. "Cetaceans
like killer whales, for example, are known to go for
extended periods of time without sleep, and we'd like
to know more about how that works and whether they incur
sleep debt," Shaw says. "Until now, the main
way to study sleep deprivation's effects on the brain
has been to attach electrodes, which can be a bit awkward
when your target is a killer whale. Hopefully the markers
we develop will make these kinds of phenomena much easier
to study."
Seugnet
L, Boero J, Gottschalk L, Duntley SP, Shaw PJ. Identification
of a biomarker for sleep drive in flies and humans.
Proceedings of the National Academy of Sciences, early
edition.
|
