School of Psychological Sciences and the Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel.
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Transl Psychiatry. 2021 Feb 5;11(1):113. doi: 10.1038/s41398-021-01220-1.
Pre-reproductive stress (PRS) to adolescent female rats alters anxiogenic behavior in first (F1)- and second-generation (F2) offspring and increases mRNA expression of corticotropin-releasing factor receptor type 1 (Crhr1) in oocytes and in neonate offspring brain. Here, we ask whether the expression of Crhr1 and Crhr1-targeting microRNA is altered in brain, blood, and oocytes of exposed females and in the brain of their neonate and adult F1 and F2 offspring. In addition, we inquire whether maternal post-stress drug treatment reverses PRS-induced abnormalities in offspring. We find that PRS induces a selective increase in Crhr1-targeting mir-34a and mir-34c in blood and oocytes, while non-Crhr1 microRNA molecules remain unaltered. PRS induces similar microRNA changes in prefrontal cortex of F1 and F2 neonates. In adult animals, cortical Crhr1, but not mir-34, expression is affected by both maternal and direct stress exposure. Post-PRS fluoxetine (FLX) treatment increases pup mortality, and both FLX and the Crhr1 antagonist NBI 27914 reverse some of the effects of PRS and also have independent effects on F1 behavior and gene expression. PRS also alters behavior as well as gene and miRNA expression patterns in paternally derived F2 offspring, producing effects that are different from those previously found in maternally derived F2 offspring. These findings extend current knowledge on inter- and trans-generational transfer of stress effects, point to microRNA changes in stress-exposed oocytes as a potential mechanism, and highlight the consequences of post-stress pharmacological interventions in adolescence.
产前应激（PRS）对青春期雌性大鼠的影响会改变第一代（F1）和第二代（F2）后代的焦虑行为，并增加卵母细胞和新生后代大脑中促肾上腺皮质释放因子受体 1（Crhr1）的 mRNA 表达。在这里，我们想知道暴露于 PRS 的雌性体内的 Crhr1 和 Crhr1 靶向 microRNA 的表达是否会发生改变，以及其卵母细胞和新生儿以及成年 F1 和 F2 后代的大脑中是否会发生改变。此外，我们还想了解母体应激后药物治疗是否可以逆转 PRS 诱导的后代异常。我们发现，PRS 会选择性地增加血液和卵母细胞中 Crhr1 靶向的 mir-34a 和 mir-34c，而其他非 Crhr1 microRNA 分子则保持不变。PRS 还会在 F1 和 F2 新生儿的前额叶皮层中引起类似的 microRNA 变化。在成年动物中，皮质 Crhr1 而非 mir-34 的表达受母体和直接应激暴露的影响。PRS 后氟西汀（FLX）治疗会增加幼崽死亡率，FLX 和 Crhr1 拮抗剂 NBI 27914 均可逆转 PRS 的部分影响，并且对 F1 的行为和基因表达也有独立的影响。PRS 还会改变父系衍生的 F2 后代的行为以及基因和 microRNA 表达模式，产生与先前在母系衍生的 F2 后代中发现的不同的影响。这些发现扩展了关于应激效应的跨代传递的现有知识，指出应激暴露的卵母细胞中的 microRNA 变化可能是一种潜在的机制，并强调了青春期应激后药物干预的后果。
