Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep.
Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.
Kimura
M
M
Max Planck Institute of Psychiatry, Munich, Germany. kimura@mpipsykl.mpg.de
Müller-Preuss
P
P
Lu
A
A
Wiesner
E
E
Flachskamm
C
C
Wurst
W
W
Holsboer
F
F
Deussing
J M
JM
D000704:Analysis of Variance; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D005583:Fourier Analysis; D005786:Gene Expression Regulation / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics; D008747:Methylcellulose / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012892:Sleep Deprivation / Q000503:physiopathology; D012895:Sleep, REM / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
C404928:DMP 696; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1; D008747:Methylcellulose; D003346:Corticotropin-Releasing Hormone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; D003345:Corticosterone