PHYSIOLOGICAL REVIEWCellular consequences of sleep deprivation in the brain☆
Section snippets
A cellular function for sleep?
All animal species studied so far sleep1 and sleep may have multiple functions, which may differ in different species.2 It is quite possible, however, that sleep also has a core function that is conserved from invertebrates to mammals. If this is the case, that function is most likely a cellular one, because flies and humans share most pathways for intercellular and intracellular signaling, from membrane receptors and ion channels to nuclear transcription factors, but differ significantly in
Transcriptomics and targeted approaches
Table 1 lists the studies that used transcriptomics approaches to identify state-dependent genes, i.e. genes whose transcript (mRNA) levels vary as a function of sleep, wakefulness, and/or sleep deprivation. Most state-dependent genes have been identified using microarrays, which allow the analysis of thousands of transcripts in a single experiment. Early studies, however, used subtractive hybridization and mRNA differential display, other methods that allow an extensive and unbiased analysis
Technical considerations
The transcriptomics analysis of behavioral states is a work in progress. As evident in Table 1, for any given species and any brain region there is often just one paper published, and the results need to be replicated and extended before firm conclusions can be drawn. Array experiments, in which thousands of probes are designed to work in a single hybridization experiment, are prone to a large number of both false negatives and false positives. Little can be done to avoid false negatives,
Mitochondrial genes and brain energy metabolism
Figure 1 (upper left) shows the 3 categories of genes that have been found in several species to be upregulated during waking and short-term sleep deprivation relative to sleep.
The first group includes genes involved in energy metabolism. After 3 h of spontaneous wakefulness or sleep deprivation transcript levels of mitochondrial genes encoded by the mitochondrial genome—subunit I of cytochrome c oxidase (CO), subunit 2 of NADH, and 12S rRNA—are increased in several cortical and subcortical
Chaperones, heat shock proteins, and the unfolded protein response
A second group of genes consistently upregulated during wakefulness and down-regulated during sleep includes heat shock proteins, chaperones, and, in general, genes involved in the response to cellular stress. Cellular stress has been defined as the cell's reaction to any adverse environmental condition that perturbs cellular homeostasis, with potential macromolecular damage, i.e. damage to proteins, DNA, RNA, and lipids. Most stress response proteins identified so far include molecular
Brain cell degeneration and sleep deprivation
In addition to a slowing down of protein synthesis, discussed above, one of the mechanisms through which cells respond to stress is growth arrest. Several recent studies have shown that total sleep deprivation for 24,70 4871 or 72–96 h72, 73 reduces cell proliferation in the dentate gyrus. Control experiments ruled out that the main effect was due to an increase in corticosterone levels, or to the forced locomotor activity associated with the sleep deprivation procedure. Sleep restriction for 8
Activity-dependent synaptic plasticity and waking
A third group of genes consistently upregulated during wakefulness and down-regulated during sleep include transcripts sensitive to membrane depolarization and synaptic activity. In the rat cerebral cortex, they include RGS2, Homer/Vesl, tissue-type plasminogen activator, casein kinase 2, cyclooxygenase 2, cpg2, and connexin 30.33 Moreover, several genes involved in activity-dependent neural plasticity and long-term potentiation, such as Arc, BDNF, Homer/Vesl and NGFI-A, have been consistently
Gene expression changes in different brain regions
Forty percent of the genes upregulated by 8 h of spontaneous waking or sleep deprivation in the rat cerebral cortex are also wakefulness-related in the cerebellum, and 50% of the cortical sleep-related genes are also sleep related in the cerebellum.33 None of the transcripts whose expression increases during sleep in the cortex increases instead during waking in the cerebellum, or vice versa. The significant overlap between state-dependent transcripts in these 2 brain regions is intriguing
Long-term sleep deprivation
We have recently concluded a gene expression profiling in the cerebral cortex of long-term sleep deprived rats (Cirelli et al., in preparation). We used the disk-over-water method (DOW;93) to enforce total sleep deprivation for 7–10 days and, as expected, we found that total sleep was reduced by 80–90% in the sleep deprived rats, and by 25–40% in their yoked controls. After screening more than 15,000 cortical transcripts we found that the largest group of genes upregulated after prolonged sleep
Genes upregulated during spontaneous sleep
Genes are also specifically upregulated during sleep, and Fig. 1 shows the sleep-related transcripts identified so far in the rat cerebral cortex.33 Unfortunately, so far only one study in mammals was designed to identify genes upregulated after several (8) hours of sleep relative to both spontaneous waking and sleep deprivation, to rule out effects of stress and of circadian time. Another study in flies used the same experimental conditions used in rats, but for technical reasons the entire
Genes upregulated during recovery sleep after sleep deprivation
Two studies in mice measured the expression of several immediate early genes and chaperones after 6 h of sleep deprivation, and after 6 h of sleep deprivation followed by 4 h of recovery sleep.56, 82 The cortical expression of fra2 (an immediate early gene), BiP, and Grp94 (a chaperone) increased in animals allowed to sleep relative to the time-matched cage controls. The expression of Grp94 also seemed to increase after recovery sleep relative to sleep deprivation. In rats, the cortical expression
Conclusions
The brain responds to changes in behavioral states with rapid and extensive changes in gene expression. A few hours of spontaneous wakefulness or sleep deprivation affect the expression of hundreds of genes in the cerebral cortex and in other brain regions. Three categories of genes are consistently upregulated by short periods of waking and down-regulated during sleep. They include genes involved in energy metabolism, in the cellular stress response, and in memory formation and long-term
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This work was supported by NIMH and NIGMS.