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Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress

Nature Neuroscience volume 6, pages 1100–1107 (2003)Cite this article

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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Figure 1: Generation of mice deficient for Crhr1 in the limbic system.
Figure 2: Verification of the region-specific Crhr1 knockout.
Figure 3: Reduced anxiety-related behavior in Crhr1loxP/loxPCamk2a-cre conditional mutants (males, age 3–5 months).
Figure 4: Plasma ACTH levels under basal conditions and following different durations of restraint stress.
Figure 5: Plasma corticosterone levels under basal conditions and following different durations of restraint stress.
Figure 6: Expression of mineralocorticoid receptor (MR; a–d) and Crh (e–h) under basal conditions and after stress in Crhr1loxP/loxP controls and conditional Crhr1loxP/loxPCamk2a-cre mutants.

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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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  1. Marianne B Müller and Stephan Zimmermann: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich, 80804, Germany

    Marianne B Müller, Stephan Zimmermann, Inge Sillaber, Thomas P Hagemeyer, Jan M Deussing, Peter Timpl, Michael S D Kormann, Susanne K Droste, Johannes M H M Reul, Florian Holsboer & Wolfgang Wurst

  2. Institute of Developmental Genetics, GSF Forschungszentrum, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany

    Ralf Kühn & Wolfgang Wurst

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Supplementary information

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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