Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction
Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction
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DOI：
10.1038/tp.2016.70
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发表时间：
2016-05-03
影响因子：
6.8
通讯作者：
Soreq, H.
中科院分区：
文献类型：
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作者：
Lin, T.;Simchovitz, A.;Soreq, H.
由于未知的基因组-神经元相互作用，创伤导致创伤后应激症状（PTSS）的可变风险。在这里，我们报道了乙酰胆碱酯酶（AChE）基因单核苷酸多态性（SNP） rs17228616的个体中，杏仁核和腹内侧前额叶皮层（vmPFC）共同增强的情绪反应可能克服PTSS。我们最近的研究表明，在具有rs17228616等位基因的个体中，该SNP阻断了microRNA -608对乙酰胆碱酯酶的抑制，导致脑皮质乙酰胆碱酯酶升高，皮质醇和miRNA-608靶gaba能调节剂CDC42降低，所有这些都与应激相关。为了研究这种SNP是否对PTSS和威胁相关的脑回路有影响，我们将76名经历过慢性军事压力的以色列国防军健康士兵暴露在情绪和中性视觉刺激的功能性磁共振成像任务中。小等位基因个体对情绪刺激的反应可以通过杏仁核过度激活来预测，杏仁核过度激活是创伤后应激障碍的标志，也是创伤后应激障碍（PTSD）的易感因素。尽管如此，小等位基因个体在PTSS水平上没有表现出差异。中介分析表明，小等位基因士兵的杏仁核反应增强促进了vmPFC的增加，这与他们有限的创伤后应激障碍有关。此外，我们在人类杏仁核样本中发现了包括CD44、CDC42和白细胞介素6在内的几种miRNA-608靶点的相关表达水平（N=7）。我们的研究结果表明，miRNA-608/AChE相互作用参与了威胁回路和PTSS，并支持了一个模型，即在小等位基因个体中，更大的vmPFC调节活性补偿了杏仁核过度激活，以中和其PTSS易感性。
Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome-neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility.