Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
Biomolecules. 2024 Mar 19;14(3):371. doi: 10.3390/biom14030371.
Exposure to early-life stress (ELS) has been related to an increased susceptibility to psychiatric disorders later in life. Although the molecular mechanisms underlying this association are still under investigation, glucocorticoid signaling has been proposed to be a key mediator. Here, we used two preclinical models, the prenatal stress (PNS) animal model and an in vitro model of hippocampal progenitor cells, to assess the long-term effect of ELS on , , , and , four stress-responsive genes involved in the effects of glucocorticoids. In the hippocampus of male PNS rats sacrificed at different time points during neurodevelopment (PND 21, 40, 62), we found a statistically significant up-regulation of at PND 40 and PND 62 and a significant increase in at PND 62. Interestingly, all four genes were significantly up-regulated in differentiated cells treated with cortisol during cell proliferation. As was consistently modulated by PNS at adolescence (PND 40) and adulthood (PND 62) and by cortisol treatment after cell differentiation, we measured a panel of miRNAs targeting in the same samples where expression levels were available. Interestingly, both miR-20b-5p and miR-29c-3p were significantly reduced in PNS-exposed animals (both at PND40 and 62) and also in the in vitro model after cortisol exposure. Our results highlight the key role of miR-20b-5p and miR-29c-3p in sustaining the long-term effects of ELS on the stress response system, representing a mechanistic link possibly contributing to the enhanced stress-related vulnerability to mental disorders.
早期生活应激（ELS）暴露与生命后期精神障碍易感性增加有关。尽管这种关联的分子机制仍在研究中，但糖皮质激素信号已被提出是关键的中介。在这里，我们使用了两种临床前模型，产前应激（PNS）动物模型和海马祖细胞的体外模型，来评估 ELS 对四种参与糖皮质激素作用的应激反应基因、、、和的长期影响。在神经发育过程中不同时间点处死的雄性 PNS 大鼠的海马中（PND21、40、62），我们发现 在 PND40 和 PND62 时统计学上显著上调， 在 PND62 时显著增加。有趣的是，在细胞增殖过程中用皮质醇处理的分化细胞中，所有四个基因都显著上调。由于 在青春期（PND40）和成年期（PND62）的 PNS 以及细胞分化后的皮质醇处理中持续受到调节，我们在具有 表达水平的相同样本中测量了针对 的一组 miRNA。有趣的是，在 PNS 暴露的动物（PND40 和 62 时）和皮质醇暴露后的体外模型中，miR-20b-5p 和 miR-29c-3p 都显著降低。我们的结果强调了 miR-20b-5p 和 miR-29c-3p 在维持 ELS 对应激反应系统的长期影响中的关键作用，代表了可能有助于增强与应激相关的精神障碍易感性的机制联系。
