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.



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 Paul 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, neuro-transmitter 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@aol.com is a freelance writer in New York City.


Includes measured percentage increase in mRNA levels, and proposed functions.

Albumin D-site binding protein (DBP, 176%): Expression of this transcription factor shows circadian rhythmicity in many tissues; target genes identified only in liver. DBP influences circadian but not homeostatic sleep regulation.

Stearoyl-CoA desaturase (90%): An enzyme involved in synthesizing monounsaturated fatty acids, membrane phos-pholipids, triglycerides, and cholesterol esters.

N-ethylmaleimide sensitive factor (NSF, 77%): Essential for membrane fusion, such as between synaptic vesicles and plasma membrane. At synaptic membranes, NSF maintains levels of AMPA receptors, whose trafficking is involved in plasticity.

Calcineurin (protein phosphatase 2B or PP2B, 64%): A predominant calcium-regulated protein phosphatase in neurons. PP2B modulates gene expression and intracellular calcium stores; favors down-regulation of synaptic transmission.

Myelin-associated glycoprotein (MAG, 62%): Constituent of myelin, the neuronal wrapping made of plasma membranes for glial cells (oligodendro-cytes). MAG influences neuron-oligodendrocyte interactions.

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