Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

• Published in: Molecular psychiatry Vol. 15; no. 2; pp. 154 - 165
• Main Authors: Kimura, M, Müller-Preuss, P, Lu, A, Wiesner, E, Flachskamm, C, Wurst, W, Holsboer, F, Deussing, J M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2010; Nature Publishing Group
• Subjects: Analysis of Variance; Animals; Behavioral Sciences; Biological Psychology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Complications and side effects; Corticosterone - blood; Corticotropin releasing hormone; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Electrodes; Electroencephalography; Electroencephalography - methods; Electromyography - methods; Eye movements; Fourier Analysis; Fourier transforms; Gene Expression Regulation - genetics; Health aspects; Intermediate Filament Proteins - genetics; Laboratory animals; Major depressive disorder; Medicine; Medicine & Public Health; Methylcellulose - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nervous system; Nestin; Neurosciences; Original; original-article; Pharmacotherapy; Prosencephalon - drug effects; Prosencephalon - metabolism; Psychiatry; Pyrazoles - pharmacology; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; REM sleep; Risk factors; Sleep deprivation; Sleep Deprivation - physiopathology; Sleep disorders; Sleep, REM - drug effects; Sleep, REM - genetics; Time Factors; Triazines - pharmacology; United States; Germany; corticotropin-releasing hormone; sleep deprivation; depression; hypothalamic–pituitary-adrenocortical axis; CRHR1 antagonist; REM sleep
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2009.46

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.