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

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.

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Labermaier, Christiana1, Author           
Kohl, Christine1, Author           
Hartmann, Jakob2, Author           
Devigny, Christian1, Author           
Altmann, André1, Author           
Weber, Peter3, Author           
Arloth, Janine3, Author           
Quast, Carina3, Author           
Wagner, Klaus V.1, Author           
Scharf, Sebastian H.1, Author           
Czibere, Ludwig1, Author           
Widner-Andrä, Regina1, Author           
Brenndörfer, Julia1, Author           
Landgraf, Rainer1, Author           
Hausch, Felix3, Author           
Jones, Ken A.4, Author
Mueller, Marianne B.4, Author
Uhr, Manfred1, Author           
Holsboer, Florian5, Author           
Binder, Elisabeth B.3, Author           
Schmidt, Mathias V.2, Author            more..
Affiliations:
1Max Planck Institute of Psychiatry, Max Planck Society, ou_1607137              
2Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035294              
3Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
4external, ou_persistent22              
5Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              

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 Abstract: 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.

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 Dates: 2014-07
 Publication Status: Issued
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 Identifiers: ISI: 000342343400018
DOI: 10.1210/en.2013-1986
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Title: ENDOCRINOLOGY
Source Genre: Journal
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Pages: - Volume / Issue: 155 (7) Sequence Number: - Start / End Page: 2500 - 2510 Identifier: ISSN: 0013-7227