A role for cryptochromes in sleep regulation.
BACKGROUND
The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-) lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes.


RESULTS
Under all three conditions, cry1,2-/- mice exhibit the hallmarks of high non-REM sleep (NREMS) drive (i.e., increases in NREMS time, NREMS consolidation, and EEG delta power during NREMS). This unexpected phenotype was associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and albumin d-binding protein (dbp), which are known to be transcriptionally inhibited by CRY1,2. To further examine the relationship between circadian genes and sleep homeostasis, we examined wild type mice and rats following sleep deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp mRNA specifically in the cerebral cortex; these changes subsided with recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase-1epsilon did not change with sleep deprivation.


CONCLUSIONS
These results indicate that mice lacking cryptochromes are not simply a genetic model of circadian arrhythmicity in rodents and functionally implicate cryptochromes in the homeostatic regulation of sleep.
Wisor
Jonathan P
JP
Dept of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. jwisor@stanford.edu
O'Hara
Bruce F
BF
Terao
Akira
A
Selby
Chris P
CP
Kilduff
Thomas S
TS
Sancar
Aziz
A
Edgar
Dale M
DM
Franken
Paul
P
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D047388:Casein Kinases; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D003624:Darkness; D003700:Delta Rhythm; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled; D012890:Sleep / Q000502:physiology*; D012892:Sleep Deprivation / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D047388:Casein Kinases; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011494:Protein Kinases; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; C538965:Cry1 protein, rat; C538967:Cry2 protein, mouse; C538968:Cry2 protein, rat; C485975:DBP protein, rat; C498260:Dbp protein, mouse; C491259:Npas2 protein, mouse; C539023:Per1 protein, mouse; C539024:Per1 protein, rat; C513312:Per2 protein, mouse; C513311:Per2 protein, rat; C512645:Per3 protein, mouse; C512646:Per3 protein, rat; C119828:cry protein, Drosophila; C538944:Clock protein, mouse; C538945:Clock protein, rat