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
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.”
After scrutinizing hundreds of videotapes of mice scampering, grooming,
eating, and sleeping, Richard Chemelli, a pediatric research fellow in
Yanagisawas 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
, led to the hypothesis that the missing
orexin somehow alters the mouses 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,
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
"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
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."