PNAS:创伤后应激障碍或与基因有关
生物360 · 2014/09/01
近期发表于《PNAS》的一项针对老鼠的研究指出,多达334种基因可能会导致个体易受创伤后压力影响,即创伤后应激障碍(PTSD)。通过进一步推测表明,73种转录因子控制与创伤脆弱性及恢复力有关的基因表达,其中1/4和糖皮质激素受体信号相关。


大多数人能逐渐从创伤中恢复,但一小部分人会患创伤后应激障碍(PTSD)——对严重创伤(例如战争、车祸、自然灾害)的一种极端反应。科学家一直在寻找该病的生物学基础。近期发表于《PNAS》的一项针对老鼠的研究指出,多达334种基因可能会导致个体易受创伤后压力影响。

研究人员让约100只老鼠暴露在脏乱的猫砂环境中——使其担心捕食者的存在,并在一周后检测创伤对老鼠的影响。约1/4的老鼠被归类为“极端”反应体,即表现出极高水平的焦虑和很容易听到高分贝噪音。另外1/4的老鼠是“最低限度的”反应体,即表现出的焦虑水平和正常环境下的老鼠无异。

为了探究控制创伤敏感性的机制,研究人员用DNA微阵技术扫描了来自血液、杏仁核和海马体(和恐惧和记忆相关的大脑区域)样本中的2.2万个基因。其中86~334个基因呈现出表达水平的变化——这似乎和最大程度或最小程度的响应能力有关。

大多数基因似乎会表现脆弱性或恢复力,但不会同时表达这两种能力。纽约市西奈山伊坎医学院神经内分泌学家Daskalakis说,该结果表明,在基因水平,两种不同的应激反应系统似乎控制个体对PTSD的敏感性。

在该研究的基础上,研究人员进而推测,73种转录因子控制与创伤脆弱性及恢复力有关的基因表达,其中1/4和糖皮质激素受体信号相关。一直以来,科学家怀疑PTSD的发生和糖皮质激素受体信号的错误调节有关,一些研究也表明,异常低水平的受体活动可能是罪魁祸首。

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  • Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes

    Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology and treatment of posttraumatic stress disorder (PTSD). In this study, 7 d after predator-scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., “PTSD-like”) and resilient (i.e., minimally affected) phenotypes on the basis of their performance on a variety of behavioral measures. Genome-wide expression profiling in blood and two limbic brain regions (amygdala and hippocampus), followed by quantitative PCR validation, was performed in these two groups of animals, as well as in an unexposed control group. Differentially expressed genes were identified in blood and brain associated with PSS-exposure and with distinct behavioral profiles postexposure. There was a small but significant between-tissue overlap (4–21%) for the genes associated with exposure-related individual differences, indicating convergent gene expression in both sexes. To uncover convergent signaling pathways across tissue and sex, upstream activated/deactivated transcription factors were first predicted for each tissue and then the respective pathways were identified. Glucocorticoid receptor (GR) signaling was the only convergent pathway associated with individual differences when using the most stringent statistical threshold. Corticosterone treatment 1 h after PSS-exposure prevented anxiety and hyperarousal 7 d later in both sexes, confirming the GR involvement in the PSS behavioral response. In conclusion, genes and pathways associated with extreme differences in the traumatic stress behavioral response can be distinguished from those associated with trauma exposure. Blood-based biomarkers can predict aspects of brain signaling. GR signaling is a convergent signaling pathway, associated with trauma-related individual differences in both sexes.

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