A Polymorphism in the Crhr1 Gene Determines Stress Vulnerability in Male Mice
| Autor: | Marianne B. Müller, Felix Hausch, Elisabeth B. Binder, Florian Holsboer, Rainer Landgraf, Julia Brenndörfer, L. Czibere, Peter Weber, Mathias V. Schmidt, Carina Quast, Christiana Labermaier, Andre Altmann, Jakob Hartmann, Sebastian H. Scharf, Christian Devigny, Janine Arloth, Manfred Uhr, Klaus V. Wagner, Christine Kohl, Regina Widner-Andrä, Kenneth A. Jones |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Hypothalamo-Hypophyseal System Genotype Gene Expression Pituitary-Adrenal System Locus (genetics) Single-nucleotide polymorphism Regulatory Sequences Nucleic Acid Biology Binding Competitive Polymorphism Single Nucleotide Receptors Corticotropin-Releasing Hormone Mice Endocrinology Gene Frequency Genetic predisposition Animals Humans Genetic Predisposition to Disease Chronic stress CRHR1 Gene Gene In Situ Hybridization Social stress Genetics Behavior Animal Triazines Haplotype Haplotypes Pituitary Gland Pyrazoles Female Gene-Environment Interaction Corticosterone Stress Psychological Signal Transduction |
| Zdroj: | Endocrinology. 155:2500-2510 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2013-1986 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|