Paternal Transmission Across Generations of the Negative Effects of Social Stress

 描述(由申请人提供)：长期以来，人们一直认为一个人对精神障碍的易感性来自于从父母那里遗传的特定基因等位基因和个人经历。然而，最近的出版物，包括我实验室的那些，提出了另一种易感性成分来自父母的经历的可能性，这种经历的影响通过仍然鲜为人知的非孟德尔机制传递给他们的后代。一个特别引人注目的例子是通过父系血统传播，即使雄性在怀孕期间与母亲没有互动，或者在出生后与后代没有互动。这项赠款提案是由我们最近发表的一项研究推动的，该研究表明，从青春期开始的长期社会不稳定会导致焦虑加剧和社会互动缺陷，特别是在至少三代女性中。值得注意的是，表型是通过父系世系传播的，即使雄性后代没有表现出这些表型。最近的研究表明，精子除了在受精时将DNA输送到卵母细胞外，还会引入miRNAs，推测可能是通过改变特定的早期胚胎基因集来影响胚胎发育。我们未发表的新数据表明，应激诱导的两个精子miRNAs的变化可能是这种现象的中介，因为它们不仅在应激的雄性中发生变化，而且在没有暴露在应激中的F1和F2雄性后代中也发生变化，但会将应激表型传递给雌性后代。此外，我们通过检测在应激父亲的F1和F2后代的海马区中，钙调神经磷酸酶抑制物和已知的焦虑诱导者RCAN1和rcan-1基因表达的启动子NFATc1的水平升高，确定了特定发生在成年女性中的应激诱导行为的潜在介体。这笔赠款的第一个目标将揭示这些精子miRNAs以及新发现的RNAs在将特定的应激诱导行为异常传递给雌性后代方面所扮演的特定角色。此外，它还将测试精子miRNA的变化和将压力表型传递给世代的能力是否会因应激男性暴露在丰富的环境和/或抗抑郁药物中而受到抑制。第二个目标将揭示社会不稳定导致精子RNA的变化如何导致雌性后代基因调节的改变，这是导致雌性后代焦虑增强和社交缺陷的原因。总体而言，这一建议将加深我们对小鼠这种新发现的遗传形式背后的机制的理解，这种遗传形式也可能有助于提高雌性小鼠对应激相关精神疾病的易感性。

 DESCRIPTION (provided by applicant): It has long been assumed that one's susceptibility to psychiatric disorders is derived from inheriting specific gene alleles from one's parents and from one's personal experiences. However, recent publications, including those from my lab, raise the possibility that another component of susceptibility is from one's parents' experiences, the effects of which are transmitted to their offspring through non-Mendelian mechanisms that remain poorly understood. A particularly striking example is transmission through the paternal lineage, even when the males have no interaction with the mother during pregnancy or with offspring after birth. This grant proposal is driven by our recently published study demonstrating that chronic social instability beginning during adolescence causes enhanced anxiety and defective social interactions specifically in females across at least 3 generations. Remarkably, the phenotype is transmitted through the paternal lineage, even though male offspring do not display these phenotypes. Recent studies have shown that in addition to delivering DNA to oocytes upon fertilization, sperm introduce miRNAs that influence embryo development presumably by altering specific sets of early embryonic genes. Our new unpublished data implicate stress-induced changes in two sperm miRNAs as possible mediators of this phenomenon because they change not only in stressed males but also in their F1 and F2 male offspring that were not exposed to stress but transmit stress phenotypes to their female offspring. Moreover, we have identified potential mediators of stressed-induced behaviors that occur specifically in adult females by detecting elevated levels of both RCAN1, an inhibitor of calcineurin and a known inducer of anxiety, and the NFATc1 transcription factor, a promoter of RCAN-1 gene expression, in the hippocampus of both F1 and F2 offspring of stressed fathers. The first aim of this grant will reveal the specific roles played by these sperm miRNAs, as well as newly identified RNAs, in transmitting specific stress-induced behavior abnormalities to females across generations. In addition, it will test whether sperm miRNA changes and the ability to transmit stress phenotypes across generations are blocked by exposure of stressed males to an enriched environment and/or antidepressants. The second aim will reveal how social instability-induced changes in sperm RNAs lead to altered regulation of genes in female offspring that mediate their enhanced anxiety and defective social interactions. Overall, this proposal will deepen our understanding of the mechanisms underlying this newly revealed form of inheritance in mice that may also contribute to the heightened susceptibility of females to stress-associated psychiatric disorders.