Small RNA molecules in early embryos, delivered from sperm to zygotes upon fertilization, are required for normal mouse embryonic development. Even modest changes in the levels of sperm‐derived miRNAs appear to influence early embryos and subsequent development. For example, stress‐associated behaviors develop in mice after injection into normal zygotes sets of sperm miRNAs elevated in stressed male mice. Here, we implicate early embryonic miR‐409‐3p in establishing anxiety levels in adult female, but not male mice. First, we found that exposure of male mice to chronic social instability stress, which leads to elevated anxiety in their female offspring across at least three generations through the paternal lineage, elevates sperm miR‐409‐3p levels not only in exposed males, but also in sperm of their F1 and F2 male offspring. Second, we observed that while injection of a mimic of miR‐409‐3p into zygotes from mating control males was incapable of mimicking this effect in offspring derived from them, injection of a specific inhibitor of this miRNA led to the opposite, anxiolytic effect in female, but not male, and offspring. These findings imply that baseline miR‐409‐3p activity in early female embryos is necessary for the expression of normal anxiety levels when they develop into adult females. In addition, elevated embryo miR‐409‐3p activity, possibly as a consequence of stress‐induced elevation of its expression in sperm, may participate in, but may not be sufficient for, the induction of enhanced anxiety.

中文翻译：

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早期胚胎miR-409-3p参与了雌性小鼠焦虑水平的建立。

正常小鼠胚胎发育需要早期胚胎中的小RNA分子（受精后从精子传递到受精卵）。精子来源的miRNA的水平即使发生适度的变化，也会影响早期的胚胎和随后的发育。例如，与正常压力的雄性小鼠相比，正常的受精卵精子miRNAs组注射后，小鼠中出现了与压力相关的行为。在这里，我们暗示了早期胚胎miR-409-3p在成年雌性小鼠而非男性小鼠中建立焦虑水平。首先，我们发现雄性小鼠暴露于慢性社会不稳定压力，导致其父系至少三代后代的雌性后代焦虑加剧，不仅使暴露的雄性小鼠的精子miR-409-3p水平升高，而且在他们的F1和F2雄性后代的精子中。第二，我们观察到，虽然从交配对照雄性的受精卵中注射miR‐409-3p模拟物无法模仿衍生自它们的后代的这种作用，但注射这种miRNA的特异性抑制剂却导致雌性产生相反的抗焦虑作用，但不是男性，也不是后代。这些发现表明，早期成年女性胚胎发育成年雌性时，其基线miR-409-3p活性对于正常焦虑水平的表达是必要的。另外，升高的胚胎miR-409-3p活性可能是压力诱导的精子表达升高的结果，可能参与了焦虑的诱导，但可能不足以引起焦虑。注射这种miRNA的特异性抑制剂会导致雌性（而非雄性）和后代产生相反的抗焦虑作用。这些发现表明，早期成年女性胚胎发育成年雌性时，其基线miR-409-3p活性对于正常焦虑水平的表达是必要的。另外，升高的胚胎miR-409-3p活性可能是压力诱导的精子表达升高的结果，可能参与了焦虑的诱导，但可能不足以引起焦虑。注射这种miRNA的特异性抑制剂会导致雌性（而非雄性）和后代产生相反的抗焦虑作用。这些发现表明，早期成年女性胚胎发育成年雌性时，其基线miR-409-3p活性对于正常焦虑水平的表达是必要的。另外，升高的胚胎miR-409-3p活性可能是压力诱导的精子表达升高的结果，可能参与了焦虑的诱导，但可能不足以引起焦虑。