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
Max Planck Institute of Psychiatry (C.L., C.K., J.H., C.D., A.A, P.W., J.A., C.Q., K.V.W., S.H.S., L.C., R.W-A., J.B., R.L., F.H., M.U., F.H., E.B.B., M.V.S.), 80804 Munich, Germany; Lundbeck Research USA (K.A.J.), Paramus, New Jersey 07652; and Johannes Gutenberg University Medical Center (M.B.M.), 55131 Mainz, Germany.
Endocrinology. 2014 Jul;155(7):2500-10. doi: 10.1210/en.2013-1986. Epub 2014 Apr 28.
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.
慢性应激是精神疾病的一个风险因素，但不一定会对心理健康产生一致的长期影响，这表明存在诸如遗传易感性等调节因素。在此，我们探讨小鼠促肾上腺皮质激素释放激素受体1（Crhr1）基因座的自然遗传变异是否会调节青春期慢性社会应激（ACSS）对远交系CD1小鼠长期应激激素失调的影响，这有助于更好地理解目前报道的人类早期创伤与CRHR1之间的基因×环境相互作用。我们在小鼠Crhr1基因座中鉴定出2种主要的单倍型变体，它们可调节ACSS对基础下丘脑-垂体-肾上腺轴活性的长期影响。这种效应可能是由更高水平的CRHR1介导的，因为在风险单倍型携带者中Crhr1 mRNA表达和CRHR1结合增强。此外，一种CRHR1受体拮抗剂可使这些长期效应恢复正常。对CD1小鼠Crhr1基因座进行深度测序发现了大量连锁单核苷酸多态性，其中一些位于重要的调控区域，类似于与调节基因×应激暴露相互作用相关的人类CRHR1变体的位置。我们的数据支持，在这种动物模型中所描述的基因×应激暴露相互作用是基于Crhr1基因中自然发生的与增强的CRHR1介导信号相关的遗传变异。我们的结果表明，CRHR1基因具有特定遗传易感性且暴露于慢性应激的患者可能会从选择性拮抗CRHR1过度活性的治疗中受益。
