BACKGROUND Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood. METHODS Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. RESULTS From a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F messenger RNA levels in human blood were downregulated in cases with symptoms of comorbid PTSD and depression and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we showed that a genetic variant of PPM1F, rs17759843, was associated with comorbid PTSD and depression and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2 (CAMKII), we examined blood messenger RNA level of CAMK2G in humans and found it to be lower in cases with comorbid PTSD and depression. We also found that PPM1F protein levels and colocalization with CAMK2G were altered in amygdala and mPFC of male mice. Additionally, we found that a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and messenger RNA levels of Ppm1f in amygdala and mPFC in male mice and in mPFC of female mice. CONCLUSIONS Taken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress- and trauma-related manifestation of anxiety and depression across species.

中文翻译：

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PPM1F 基因的表达受压力调节并与焦虑和抑郁相关


背景技术暴露于应激经历（例如创伤后应激障碍（PTSD）和抑郁症）的心理后遗症的分子机制尚不清楚。方法利用动物和人类转录组和基因组研究的综合证据，我们的目的是确定创伤经历后抑郁和焦虑的遗传机制。结果通过对小鼠的全转录组分析，我们发现在固定应激一周后，Ppm1f 基因在杏仁核和内侧前额叶皮层 (mPFC) 中存在差异表达。接下来，我们发现在单独的人类数据集中，在患有 PTSD 和抑郁症共病症状的病例中，人类血液中的 PPM1F 信使 RNA 水平下调，并且在有焦虑症状的病例中一致下调。此外，我们发现 PPM1F 的遗传变异 rs17759843 与共病 PTSD 和抑郁症以及人脑和血液中 PPM1F 的表达相关。鉴于之前报道的 PPM1F 和 CAMK2 (CAMKII) 之间的机制联系，我们检查了人类 CAMK2G 的血液信使 RNA 水平，发现在共病 PTSD 和抑郁症的情况下，该水平较低。我们还发现雄性小鼠的杏仁核和 mPFC 中 PPM1F 蛋白水平以及与 CAMK2G 的共定位发生了改变。此外，我们发现全身剂量的皮质酮可以阻断雌性小鼠因压力引起的抑郁样表型。最后，皮质酮挽救了雄性小鼠杏仁核和 mPFC 以及雌性小鼠 mPFC 中的焦虑样表型和 Ppm1f 信使 RNA 水平。结论 综上所述，我们的数据表明，在跨物种的压力和创伤相关的焦虑和抑郁表现中，存在涉及 PPM1F 和 CAMK2G 的机制途径。