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August 05, 1999
Mouse Studies Link Feeding-Behavior Gene with Narcolepsy
Researchers who had bred a group of mice in hopes of learning more
about a brain hormone that stimulates appetite got a bit of a surprise
when they saw that the rodents would suddenly collapse and fall fast
asleep with no provocation. As a result, Howard Hughes Medical
Institute investigator Masashi
Yanagisawa and colleagues at the University of Texas Southwestern
Medical Center in Dallas have an exciting new lead into the genesis of
sleep and the origins of narcolepsy, a severe sleep disorder in
humans.
In 1998, Yanagisawa discovered the orexins, small brain proteins and
their receptors that regulate feeding behavior in mice. To probe the
role that orexins play in regulating appetite, Yanagisawa and his
colleagues developed a strain of knockout mice whose orexin genes do
not function properly. After raising several generations of the mice,
the investigators videotaped the animals as they went about their daily
business, hoping to see how the genetic alteration changed their
behavior.
“The mice would be running around, burrowing, grooming themselves. Then all of a sudden, like a switch flipping, they would turn over on one side. It looked almost like they were dead.”
Masashi Yanagisawa
After scrutinizing hundreds of videotapes of mice scampering,
grooming, eating, and sleeping, Richard Chemelli, a pediatric research
fellow in Yanagisawa’s laboratory, began to feel discouraged
because despite months of observation, the knockout mice did not seem
any different from their normal, or wild-type, counterparts.
"Then we thought, wait a minute, mice are nocturnal. So watching
them during the day is the equivalent of watching human behavior in the
middle of the night. They're asleep," explained Yanagisawa. "So we
started videotaping them in complete darkness using an infrared
camcorder."
Chemelli studied nocturnal surveillance tapes of about 50 knockout
mice and began to notice a bizarre and unexpected pattern of behavior.
"The mice would be running around, burrowing, grooming themselves. Then
all of a sudden, like a switch flipping, they would turn over on one
side. It looked almost like they were dead. Then in a little bit, boom,
they'd jump up like nothing happened. Like a switch again," Yanagisawa
said.
Their observations, which are described in a research article in the
August 20, 1999, issue of Cell, led to the hypothesis that the
missing orexin somehow alters the mouse’s sleep/wake cycle and
causes a condition similar to narcolepsy. In humans, signs of
narcolepsy usually begin during a person's teens or early 20s. With
little or no warning — while driving a car, perhaps, or
interviewing for a job — a narcoleptic person feels irrepressibly
sleepy and quickly falls into deep sleep. Some people with narcolepsy
experience vivid dreams; others describe a sense of paralysis. On
occasion, narcolepsy is accompanied by catalepsy, in which a person
goes limp without losing consciousness. In every case, however, the
attack ends seconds to minutes after it begins. The only known triggers
are sudden emotion, such as surprise, laughter, anger, or fear.
Patients can experience narcoleptic episodes several or many times a
day for life, and while certain drugs can decrease the number of
episodes, there is no cure. Narcolepsy affects males and females
equally, and the condition tends to run in families.
Yanagisawa's team's discovery, along with a paper in the August 6,
1999, issue of Cell that describes research on narcoleptic
doberman pinschers by researchers at Stanford University, are the first
major insights into this life-altering condition that afflicts 125,000
people in the United States. They may also shed light on the control of
normal patterns of sleep and wakefulness as well.
Yanagisawa said his first thought was that the knockout mice were
having seizures. To investigate this, Chemelli and UT Southwestern
psychiatrist Dr. Christopher Sinton fashioned tiny
electroencephalograph (EEG) electrodes, cables, and harnesses to
measure the brainwaves of the mice. The investigators expected that the
needles of the EEG would spike wildly during an attack, signaling that
the mice were having epileptic-like seizures.
The spikes never appeared. However, the animals’ EEGs and
electromyograms (EMGs), which measure muscle activity, were abnormal
during the blackouts. "The simultaneous EEG/EMGs showed that the
animals’ sleep patterns were grossly disturbed in a way remarkably
similar to narcoleptic patients," Yanagisawa said.
Sleep normally progresses from light to deeper stages, then to the
so-called dream or REM (rapid eye movement) phase. A narcoleptic person
lapses directly from wakefulness to REM sleep and back to wakefulness.
This is the characteristic that Yanagisawa's team saw, sometimes a
dozen or more times per mouse at night.
The finding was completely unexpected based on the HHMI team's
initial studies of the orexins, which were reported in the February 20,
1998, issue of Cell. "The orexin gene is expressed exclusively
in a very deep part of the brain called the lateral hypothalamus,"
Yanagisawa explained. This structure has classically been implicated
with the regulation of feeding behavior, so his group named the
neuropeptide after the Greek word "orexis," meaning "appetite."
Yanagisawa said the biochemical link between orexin and narcolepsy
is still a mystery. "But if you just think about it philosophically, it
makes sense," he added. "When an animal gets hungry, it had better be
alert. It would be bad from an evolutionary standpoint to be sleepy
when it's time to hunt for food."
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