Exposure to early life stress can interfere with neurodevelopmental trajectories to increase the vulnerability for psychiatric disorders later in life. With this respect, epigenetic mechanisms play a key role for the long-lasting changes in brain functions that may elicit and sustain psychopathologic outcomes.

Here, we investigated DNA methylation changes as possible epigenetic mechanism mediating the effect of prenatal stress (PNS), an experimental paradigm associated with behavioral and molecular alterations relevant for psychiatric disorders. We identified 138 genes as being differentially methylated in the prefrontal cortex (PFC) and in the hippocampus (HIP) of male and female adult rats exposed to PNS. Among these genes, miR-30a and Neurod1 emerged as potential players for the negative outcomes associated with PNS exposure. Indeed, in addition to showing consistent methylation differences in both brain regions and in both sexes, and interacting with each other, they are both involved in Axon guidance and Neurotrophin signaling, which are important to neurodevelopmental disorders. We also found a significant reduction in the expression of a panel of genes (CAMK2A, c-JUN, LIMK1, MAP2K1, MAP2K2, PIK3CA and PLCG1) that belong to these two biological pathways and are also validated targets of miR-30a, pointing to a down-regulation of these pathways as a consequence of PNS exposure. Interestingly, we also found that miR-30a levels were significantly upregulated in depressed patients exposed to childhood trauma, as compared to control individuals. Importantly, we also found that a sub-chronic treatment with the atypical antipsychotic drug, lurasidone, during adolescence was able to prevent the up-regulation of miR-30a and normalized the expression of its target genes in response to PNS exposure.

Our results demonstrate that miR-30a undergoes epigenetic changes following early life stress exposure and suggest that this miRNA could play a key role in producing broad and long-lasting alterations in neuroplasticity-related pathways, contributing to the etiology of psychiatric disorders.

暴露于早期生活压力会干扰神经发育轨迹，从而增加生命后期患精神疾病的脆弱性。在这方面，表观遗传机制对可能引发和维持精神病理学结果的大脑功能的长期变化起着关键作用。

在这里，我们研究了 DNA 甲基化变化作为介导产前压力 (PNS) 影响的可能表观遗传机制，这是一种与精神疾病相关的行为和分子改变相关的实验范式。我们确定了 138 个基因在暴露于 PNS 的雄性和雌性成年大鼠的前额叶皮层 (PFC) 和海马 (HIP) 中被差异甲基化。在这些基因中，miR-30a 和 Neurod1 成为与 PNS 暴露相关的负面结果的潜在参与者。事实上，除了在两个大脑区域和两性中显示出一致的甲基化差异，并相互影响外，它们都参与轴突引导和神经营养因子信号传导，这对神经发育障碍很重要。我们还发现一组基因（CAMK2A、c-JUN、LIMK1、MAP2K1、MAP2K2、PIK3CA 和 PLCG1）的表达显着降低，这些基因属于这两种生物学途径，也是 miR-30a 的验证靶标，指向由于 PNS 暴露，这些途径的下调。有趣的是，我们还发现，与对照组相比，遭受童年创伤的抑郁症患者的 miR-30a 水平显着上调。重要的是，我们还发现，在青春期使用非典型抗精神病药物 lurasidone 进行亚慢性治疗能够阻止 miR-30a 的上调，并使其靶基因的表达正常化以响应 PNS 暴露。

我们的研究结果表明 miR-30a 在早期生活压力暴露后会发生表观遗传变化，并表明这种 miRNA 可能在神经可塑性相关通路产生广泛而持久的改变中发挥关键作用，从而导致精神疾病的病因。