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

• Published in: Endocrinology (Philadelphia) 2014-07, Vol.155 (7), p.2500-2510
• Main Authors: Labermaier, Christiana, Kohl, Christine, Hartmann, Jakob, Devigny, Christian, Altmann, Andre, Weber, Peter, Arloth, Janine, Quast, Carina, Wagner, Klaus V, Scharf, Sebastian H, Czibere, Ludwig, Widner-Andrä, Regina, Brenndörfer, Julia, Landgraf, Rainer, Hausch, Felix, Jones, Ken A, Müller, Marianne B, Uhr, Manfred, Holsboer, Florian, Binder, Elisabeth B, Schmidt, Mathias V
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Behavior, Animal - drug effects; Binding, Competitive; Corticosterone - blood; Corticotropin-releasing hormone; Exposure; Female; Gene Expression; Gene Frequency; Gene polymorphism; Gene-Environment Interaction; Genetic diversity; Genetic Predisposition to Disease - genetics; Genotype; Haplotypes; Humans; Hyperactivity; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus; In Situ Hybridization; Loci; Long-term effects; Male; Mental disorders; Mice; Nucleotides; Pituitary; Pituitary Gland - metabolism; Pituitary-Adrenal System - metabolism; Polymorphism; Polymorphism, Single Nucleotide; Pyrazoles - pharmacology; Receptors; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - genetics; Receptors, Corticotropin-Releasing Hormone - metabolism; Regulatory sequences; Regulatory Sequences, Nucleic Acid - genetics; Risk factors; Signal Transduction - genetics; Single-nucleotide polymorphism; Social interactions; Stress; Stress, Psychological - genetics; Triazines - pharmacology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-1986

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 × 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 × stress exposure interactions. Our data support that the described gene × 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.