|Support Cells, Not Neurons, Lull the Brain
Brain cells called astrocytes help to cause the urge to sleep
that comes with prolonged wakefulness, according to a study in
mice, funded by the National Institutes of Health. The cells release
adenosine, a chemical known to have sleep-inducing effects that
are inhibited by caffeine.
"Millions of Americans suffer from disorders that prevent a full
night's sleep, and others—from pilots to combat soldiers – have
jobs where sleepiness is a hazard. This research could lead to
better drugs for inducing sleep when it is needed, and for staving
off sleep when it is dangerous," says Merrill Mitler, Ph.D., a
program director with the NIH's National Institute of Neurological
Disorders and Stroke (NINDS).
The study appears Jan. 29, 2009 in Neuron, and was funded by NINDS,
the National Institute of Mental Health (NIMH) and the National
Institute on Aging (NIA), all part of NIH. It is the result of
a collaboration among Michael Halassa, M.D., and Philip Haydon,
Ph.D., at Tufts University School of Medicine in Boston and Marcos
Frank, Ph.D., and Ted Abel, Ph.D. at the University of Pennsylvania
School of Medicine in Philadelphia.
Although the exact purpose of sleep is unknown, everyone seems
to need it, and some research suggests that it strengthens memories
by adjusting the connections between neurons. As the waking hours
tick by, all animals experience an increasing urge to sleep, known
as sleep pressure. If sleep is delayed, a deep, long sleep usually
follows as the body's means of compensating.
Prior studies pointed to adenosine as a trigger for sleep pressure.
The chemical accumulates in the brain during waking hours, eventually
helping to stimulate the unique patterns of brain activity that
occur during sleep.
Dr. Halassa says that the results of the new study show that "adenosine
from astrocytes clearly regulates sleep pressure." He notes that
this is the first time a non-neuronal cell within the brain has
been shown to influence behavior. Unlike neurons, astrocytes do
not fire electrical spikes, and they are often described as support
In experiments on mice, Dr. Halassa and his colleagues used a
genetic switch, called the dnSNARE transgene, to block the release
of adenosine and other chemicals from astrocytes. The researchers
then deprived the mice of sleep for short periods, and evaluated
them with behavioral tests and with electroencephalography (EEG),
a means of recording brain activity.
Mice subjected to the genetic blockade exhibited less sleep pressure
than control mice. Following sleep deprivation, they did not need
as much compensatory sleep, and during the early phases of sleep,
they had patterns of brain activity consistent with low sleep pressure.
When they were evaluated with a memory test, they performed as
if their sleep had been undisturbed.
The researchers observed similar results when they used certain
compounds to block the effects of adenosine on neurons. Neurons
have several types of cell-surface receptors that enable them to
respond to adenosine, but only pharmacological blockade of the
A1 type of receptor was effective. That result shows that adenosine
acts through the A1 receptor to produce sleep pressure.
Taken together, the results hint at the possibility of new drugs
that could increase or decrease sleep pressure as necessary. The
best available sleep aids tend to be effective at inducing sleep,
but not effective at keeping it steady throughout the night. Meanwhile,
the most commonly used stimulant, caffeine, acts on multiple types
of adenosine receptors, and can affect sleep patterns even when
it is consumed in the morning. Drugs that target astrocytes or
the A1 receptors on neurons might be more effective at fine-tuning
the urge to sleep, the study authors say.
The dnSNARE mice also will prove useful for answering some long-standing
questions about sleep, experts say. For instance, since the dnSNARE
mice are resistant to sleep deprivation, they might help explain
why some people need less sleep than others. Further studies of
the dnSNARE mice could help reveal why people need sleep at all.
This research "puts astrocytes at the heart of why we sleep," says
is the nation’s primary supporter of biomedical research on the
brain and nervous system. The mission of NIMH (www.nimh.nih.gov)
is to transform the understanding and treatment of mental illnesses
through basic and clinical research, paving the way for prevention,
recovery and cure.
NIA (www.nia.nih.gov) leads
the federal government effort in research on the biomedical, social
and behavioral aspects of aging.
For more information about sleep, see the NINDS publication, Brain
Basics: Understanding Sleep at http://www.ninds.nih.gov/disorders/brain_basics/understanding_sleep.htm.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Halassa MM, Florian C, Fellin T, Munoz JR, Lee S-Y, Abel
T, Haydon P and Frank MG. "Astrocytic modulation of sleep homeostasis
and cognitive consequences of sleep loss." Neuron, January