The Body Sleeps, but the Genes Do Not

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The Scientist.com

Volume 18 | Issue 3 | 24 | Feb. 16, 2004

The Body Sleeps, but the Genes Do Not

Everyone does it, but no one knows why; a sleep-gene survey may offer

clues

By Jack Lucentini

In a study that could offer a glimpse into sleep's still poorly

understood functions, researchers have identified genes upregulated

specifically during sleep.1 The findings contain surprises,

investigators say. One is simply that there are many such genes, at

least as many as are turned on while awake, belying the common-sense

view that sleep implies inactivity. Another is that the sleep-related

changes in gene expression extend to the cerebellum, a structure not

previously known to participate in sleep.

Perhaps most tantalizing, the team found that " sleep genes "

largely fall into categories that could serve to test and refine

hypotheses of sleep's functions. Four notable divisions include: genes

involved in synaptic plasticity, which may bolster recent findings that

sleep aids memory consolidation; genes underlying translation,

supporting observations that protein synthesis increases during slumber;

genes regulating membrane and vesicle trafficking; and genes for

synthesizing cholesterol, which may be crucial for synaptogenesis.

" This is the first study that provides molecular support for the

concept that sleep is an active state implicated in synaptic plasticity

and memory, " writes Mircea Steriade of Laval University, Quebec, in an

E-mail.

FISHING IN THE DARK The study, published in Neuron, was " a fishing

expedition, " acknowledges lead author Chiara Cirelli of the University

of Wisconsin, Madison, " prompted by the desperation of not being able to

understand what sleep is for. " The authors used high-density microarrays

to analyze brain-gene expression in awake, sleeping, and sleep-deprived

rats.

Researchers have previously unearthed circadian genes

differentially expressed during day and night. Cirelli's group found

that for some of these, upregulation is attributable to sleep itself.

The team found that of some 15,000 transcripts present in rat cerebral

cortex, about 10% (1,564) were differentially expressed by day or night.

But the group also found that for about half of these (752), the change

was attributable to the waking or sleeping state, independent of time.

The authors focused on the cortex because it creates sleep's

characteristic electrical rhythms, underlies cognitive defects tied to

sleep deprivation, and is at the center of most hypotheses concerning

sleep's functions. They also found that the cerebellum displays largely

the same gene-expression sleep signature as the cerebrum, a key

discovery, says Shaw of Washington University School of Medicine,

St. Louis.

Cerebellar involvement in sleep was hitherto unknown, because the

structure doesn't participate in the sleep-related electrical

oscillations characterizing other brain structures. The finding has

" large phylogenetic implications, " Shaw says. For instance, " The fruit

fly doesn't have a cortex to generate these electrophysiological

signatures. So this shows sleep is really a fundamental biological

process. "

Cirelli and colleagues also checked rat liver and skeletal muscle

for upregulation of the sleep-related genes in the brain but found none.

Increased translational machinery transcripts in the brain suggest that

protein-synthesis increases during sleep.

Other so-called sleep genes found to influence membrane

trafficking at various levels include those for exocytosis,

neurotransmitter release, synaptic vesicle recycling, and tethering and

docking of vesicles to organelles. Still others code for membrane

synthesis, especially myelin and one of its key components, cholesterol.

The authors cite recent evidence that glia-derived cholesterol may be

crucial for synapse formation and maintenance, which could, in turn,

enhance neural plasticity (the brain's ability to change and learn).

" The state of the membrane is going to influence whether a cell responds

to the right signals, " Shaw says, so " I'd be quite surprised if [these

genes] didn't influence learning and memory. "

Jack Lucentini (jekluc@...) is a freelance writer in New York

City.

1. C. Cirelli et al., " Extensive and divergent effects of sleep

and wakefulness on brain gene expression, " Neuron, 41:35-43, Jan. 8,

2004.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org