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Romanowski, Christoph (2010): The involvement of central corticotropin-releasing hormone and its receptors in sleep-wake regulation of mice. Dissertation, LMU München: Faculty of Biology
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Abstract

The corticotropin-releasing hormone (CRH) is widely recognised as the major activator of the hypothalamic-pituitary-adrenocortical (HPA) axis, thereby mediating neuroendocrine, autonomic, and behavioural responses to stress. Dysregulation of the release of stress hormones, caused by excessive CRH secretion from the hypothalamus, is frequently observed in patients with affective disorders such as depression. One of the cardinal symptoms of major depression is a severe impairment of sleep (e.g. reduced sleep intensity, disinhibition of rapid eye movement sleep (REMS), and early morning awakenings). Consequently, besides a role of CRH in stress-induced arousal, its additional contribution to spontaneous sleep-wake regulation was suggested in literature. Due to the lack of highly specific CRH receptor antagonists and adequate CRH receptor knockout animal models, the mechanism and pathways by which CRH communicates its arousal function remained indistinct. Up to now it is unclear whether CRH interferes with sleep by a direct central action, or if the activation of the HPA axis and the subsequent release of peripheral stress hormones are mandatory. The present study with conditional CNS-specific CRH receptor type 1 (CRH-R1 CKO) and conventional CRH receptor type 2 knockout mice (CRH-R2 KO), allows assessment of CRH effects on wakefulness and sleep separately from a functional HPA axis together with various levels of CRH receptor system functionality. In addition, challenging sleep homeostasis in these mouse lines by sleep deprivation allows investigating the involvement of CRH and its receptor system in basic sleep-wake regulatory processes. Besides slight dissimilarities between the baseline sleep profiles in the various genotypes, CRH-R1 CKO displayed a markedly different response to intracerebroventricular (i.c.v.) CRH injections. The dose-dependent increases in wakefulness and decreases in non-REM sleep (NREMS), which could be observed in all other mouse lines, were almost totally absent in CRH-R1 CKO. The dose-dependent REMS suppression on the other hand persisted in all, even CRH-R1 CKO, animals. This suggests that the centrally expressed CRH receptor type 1 (CRH-R1) but not the CRH receptor type 2 (CRH-R2), mediates the crucial effects of CRH on wake induction and NREMS suppression. Since REMS inhibition by CRH still occurred in CRH-R1 CKO animals pretreated with a highly specific CRH-R2 antagonist, the clear role of central CRH and both receptors in REMS suppression remains elusive. Sleep deprivation induced significant increases in plasma corticosterone levels in all mouse lines, demonstrating HPA axis activation and suggesting that all mice perceived sleep loss as a stressor. After termination of sleep deprivation, all animals responded with a significant increase of slow wave activity (SWA), an indicator of sleep intensity, followed by a rebound of NREMS. With the exception of CRH-R1 CKO mice, all mice furthermore similarly displayed REMS rebound. Another difference in response to sleep deprivation constitutes the course of SWA in CRH-R1 CKO which was significantly increased over baseline levels for a longer period as compared to all other mouse lines. Accordingly CRH-R1 CKO animals presumably sleep more intensely or efficiently than mice of the other breeding lines. These results suggest that CRH mediates the effects, at least the stressful component, of sleep loss, and moreover that CRH-R1 is essentially involved in sleep homeostasis. This study is the first to show considerable evidence for a crucial involvement of central CRH and CRH-R1 in arousal and the suppression of NREMS. It could further be shown that activation of the HPA axis is not a prerequisite of these effects. Additionally, the action of central CRH, mediated by CRH-R1 seems to influence sleep quality. The role of CRH-R2 has to be regarded as of a minor nature. The impact of CRH on REMS regulation demands further investigation.