Inter- and transgenerational consequences of early life adversity on oxytocin-receptor gene expression

暴露于一种或多种形式的早期生活逆境（ELA）是发展躯体和行为障碍的主要风险因素，也是各种精神障碍的病因。有证据表明ELA的行为和大脑结构/功能后果可以传递给下一代，然而，ELA代际传递的详细机制仍然知之甚少。在我们的ELA动物模型中，我们将试图揭示ELA暴露、行为功能障碍、催产素受体（OxtR）基因表达变化与脑和卵母细胞中潜在表观遗传修饰之间的因果关系。基于我们先前的发现，本项目的目的是评估i）我们在ELA暴露的F0母体中观察到的OxtR基因表达的变化是否传递到下一代（F1，F2），以及ii）这些变化是否通过DNA甲基化和/或组蛋白修饰进行表观遗传调节。考虑到哺乳动物尤其是人类群体中通过母系的跨代表观遗传，我们还将确定ELA传播路径，即是否通过行为母系特征和/或通过卵母细胞中的表观遗传变化介导传播。由于大多数关于ELA对大脑发育的影响的已知信息来自男性个体的实验研究，鉴于ELA引起的疾病的患病率存在相当大的性别偏见，这有点令人惊讶，本项目的另一个目的是加深我们对ELA的性别特异性影响的认识，并将性别描述为脆弱性或弹性因素。

Exposure to one or multiple forms of early-life adversity (ELA) constitutes a major risk factor for developing somatic and behavioral disorders and in the etiology of a wide range of mental disorders. Evidence is emerging that behavioral and brain structural/functional consequences of ELA can be transmitted to the next generations, however, the detailed mechanisms underlying inter- and transgenerational transmission of ELA are still poorly understood. In our animal model for ELA we will attempt to unveil causal relationships between ELA exposure, behavioral dysfunctions, changes in oxytocin receptor (OxtR) gene expression and underlying epigenetic modifications in brain and oocytes. Based on our previous findings the aim of this project is to assess i) whether changes of OxtR gene expression, which we observed in ELA exposed F0 mothers are transmitted to the next (F1, F2) generations, and ii) if these changes are epigenetically regulated via DNA-methylation and/or histone modofications. Considering transgenerational epigenetic inheritance via the maternal line in mammals and in particular human populations, we will also identify ELA transmission paths, i.e. if transmission is mediated via behavioral maternal traits and/or through epigenetic changes in oocytes.Since most of what is known about the effects of ELA on brain development arises from experimental studies in male individuals, which is somewhat surprising in view of the considerable sex-bias in the prevalence of ELA-induced disorders, another aim of this project is to deepen our knowledge about sex-specific effects of ELA and to characterize sex as vulnerability or resiliency factor.