Abstract
The body's ability to adapt to stressors is essential for survival. Failure of stress adaptation may lead to the development of stress-related disorders. The traditionally known adaptation system in vertebrates, is the hypothalamo-pituitary-adrenal (HPA-) axis, in which corticotropin-releasing factor (CRF) plays a central role. The discovery of the CRF-related peptide,
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urocortin 1 (Ucn1), acting through CRF receptors, raises the question how CRF-related peptides, collaborate in stress adaptation. This question underlies this thesis research. We focused on the dynamics of CRF, Ucn1 and their receptors CRF1 and CRF2. In Chapter 2 we show that the CRF overexpressing (CRF-OE) mouse has increased amounts of CRF peptide and mRNA in the CNS only. This over-expression is associated with increased levels of bioactive CRF in the hypothalamus, increased body temperature and heart rate, as compared to wild-type (WT) mice. In Chapter 3 by using this transgenic mouse it is shown that CRF controls differentially the two CRF receptors, as to degree of mRNA expression and expression site in the brain: CRF over-production leads to a reduced number of CRF1 mRNA expressing neurons and to an increased number of neurons expressing CRF2 mRNA in specific brain areas . In Chapter 4 we support our hypothesis that CRF receptors, beside mediating actions of CRF-related peptides within the brain, also mediate such actions at the level of the spinal cord. The presence of both CRF receptor mRNAs is demonstrated throughout the spinal cord. In Chapters 5, 6 and 7 support has been gathered for the presumed role of the EW in stress adaptation. In Chapter 5 it is shown that chronic CRF excess down-regulates the Edinger-Westphal (EW)-Ucn1 expression. Furhtermore, the EW-Ucn1 neurons, in the CRF-OE mice respond, like the HPA axis to an acute challenge by increased Fos and Ucn1 mRNA expression. These results indicate that the HPA-axis and the EW work in concert in response to acute challenges but have opposite actions during chronic stress. We further investigated the EW during chronic activation of the HPA-axis, and show in Chapter 6 that, in contrast to the HPA-axis, the EW does not habituate to a chronic homotypic ether challenge and shows a down-regulation of Ucn1 mRNA levels vs. acutely stressed animals. Finally in Chapter 7 studies are described indicating that chronic-stress-induced activation of the adrenals might lead to inhibition of the EW-Ucn1 system, most likely through a direct action of corticosterone on EW-Ucn1 neurons. Notion supported by demonstrating that glucocorticoid receptors coexist with Ucn1 in EW-neurons, and that chronic corticosterone treatment reduces the number of EW-Ucn1 mRNA and peptide containing neurons. In Chapter 8 the results obtained in the thesis are put into a broader perspective, leading to the conclusion that CRF-OE mouse model is a suitable tool for investigating the role of chronically elevated CRF in the control of stress adaptation. Furthermore we propose that Ucn1-EW is involved in stress adaptation, and propose a series of studies to further elucidate the roles of CRF and Ucn1 in stress adaptation.
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