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A Polymorphism in the Crhr1 Gene Determines Stress Vulnerability in Male Mice

MPG-Autoren
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Labermaier,  Christiana
Max Planck Institute of Psychiatry, Max Planck Society;

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Kohl,  Christine
Max Planck Institute of Psychiatry, Max Planck Society;

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Hartmann,  Jakob
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Devigny,  Christian
Max Planck Institute of Psychiatry, Max Planck Society;

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Altmann,  André
Max Planck Institute of Psychiatry, Max Planck Society;

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Weber,  Peter
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Arloth,  Janine
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Quast,  Carina
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Wagner,  Klaus V.
Max Planck Institute of Psychiatry, Max Planck Society;

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Scharf,  Sebastian H.
Max Planck Institute of Psychiatry, Max Planck Society;

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Czibere,  Ludwig
Max Planck Institute of Psychiatry, Max Planck Society;

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Widner-Andrä,  Regina
Max Planck Institute of Psychiatry, Max Planck Society;

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Brenndörfer,  Julia
Max Planck Institute of Psychiatry, Max Planck Society;

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Landgraf,  Rainer
Max Planck Institute of Psychiatry, Max Planck Society;

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Hausch,  Felix
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Uhr,  Manfred
Max Planck Institute of Psychiatry, Max Planck Society;

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Holsboer,  Florian
Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

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Binder,  Elisabeth B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Schmidt,  Mathias V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Zitation

Labermaier, C., Kohl, C., Hartmann, J., Devigny, C., Altmann, A., Weber, P., et al. (2014). A Polymorphism in the Crhr1 Gene Determines Stress Vulnerability in Male Mice. ENDOCRINOLOGY, 155(7), 2500-2510. doi:10.1210/en.2013-1986.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0024-ACA7-8
Zusammenfassung
Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes x environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene x stress exposure interactions. Our data support that the described gene x stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.