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Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior

Molecular Psychiatry volume 13, pages 1028–1042 (2008)Cite this article

Abstract

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

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Acknowledgements

We thank Claudia Kühne, Katja Mayer, Tanja Orschmann, Daniela Kohl and Jessica Koepke for excellent technical assistance, Johanna Stalla for performing CRH RIAs, Ursula Habersetzer for endocrinological measurements, Maik Engeholm for vector construction and Peter Weber for his photographic expertise. We thank Ralf Kühn, Susanne Bourier and Sawoula Michailidou for blastocyst injection and generation of chimeric mice. We thank P Soriano and P Mombaerts for gifts of plasmids pROSA26-1 and ETLpA-/LTNL, respectively. D Refojo is supported by the European Molecular Biology Organization Fellowship Programme. This work was partially supported by the Bundesministerium für Bildung und Forschung within the framework of the NGFN2 (01GS0481) and by the Fonds der Chemischen Industrie.

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  1. A Lu

    Present address: 6Current address: Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.,

  2. A Lu and M A Steiner: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany

    A Lu, M A Steiner, A M Vogl, S M Walser, M Ableitner, D Refojo, G K Stalla, F Holsboer, C T Wotjak, W Wurst & J M Deussing

  2. Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria

    N Whittle & N Singewald

  3. Department of Biology, Center for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, ON, Canada

    M Ekker

  4. Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, CA, USA

    J L Rubenstein

  5. Institute for Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    W Wurst

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Lu, A., Steiner, M., Whittle, N. et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol Psychiatry 13, 1028–1042 (2008). https://doi.org/10.1038/mp.2008.51

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