Postmortem and cerebrospinal fluid studies of corticotropin-releasing factor in humans

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.31). 04/1996; 780:96-105. DOI: 10.1111/j.1749-6632.1996.tb15114.x
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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 corticotropin releasing hormone 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 GxE interactions of early trauma and CRHR1 in humans. We identified two 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, as Crhr1 mRNA expression and CRHR1 binding was 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 GxE 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.
    Endocrinology 04/2014; 155(7):en20131986. DOI:10.1210/en.2013-1986 · 4.72 Impact Factor