A polymorphism in the Crhr1 gene determines stress vulnerability in male mice.

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.