Abstract
Corticotropin-releasing hormone (CRH) is centrally involved in coordinating responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human affective disorders. To differentiate the CNS pathways involving CRH and CRH receptor 1 (Crhr1) that modulate behavior from those that regulate neuroendocrine function, we generated a conditional knockout mouse line (Crhr1loxP/loxPCamk2a-cre) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures, but not in the pituitary. This leaves the hypothalamic-pituitary-adrenocortical (HPA) system intact. Crhr1loxP/loxPCamk2a-cre mutants showed reduced anxiety, and the basal activity of their HPA system was normal. In contrast to Crhr1 null mutants, conditional mutants were hypersensitive to stress corticotropin and corticosterone levels remained significantly elevated after stress. Our data clearly show that limbic Crhr1 modulates anxiety-related behavior and that this effect is independent of HPA system function. Furthermore, we provide evidence for a new role of limbic Crhr1 in neuroendocrine adaptation to stress.
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Acknowledgements
The authors would like to thank A. Nagy and C. Lobe for providing the Z/AP mouse line, G. Schütz for the antibody against Cre; M.E. Keck and C.T. Wotjak for critical reading of the manuscript, A. Yassouridis for statistical advice, and S. Alam, S. Bourier, C. Ehmann and B. Klaedtke for technical assistance. This work was partly supported by a grant from the Volkswagen Foundation (to F.H. and W.W.) and the Bundesministerium für Bildung und Forschung (BMBF, to W.W.).
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Supplementary Fig. 1.
Plasma ACTH and corticosterone levels in female mice under basal conditions and following stress. '*' denotes statistical significance at α = 0.05. (PDF 17 kb)
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Müller, M., Zimmermann, S., Sillaber, I. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6, 1100–1107 (2003). https://doi.org/10.1038/nn1123
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DOI: https://doi.org/10.1038/nn1123
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