Female preconception stress programming of offspring neurodevelopment

母亲一生暴露在压力、感染、营养不良和高龄等扰动下， 与子代疾病风险增加有关，包括与神经精神疾病密切相关 精神错乱。虽然怀孕期间母亲的侮辱会直接影响胎儿的发育，但其机制是通过 哪些终生经历可以改变生殖细胞编程并影响后代神经发育 为人所知。令人惊讶的是，几乎没有动物模型被开发来检查编程机制 先入为主的干扰。在这个建议中，我们利用我们的母体怀孕前应激的小鼠模型 (MPS)，其中女性而不是男性的后代具有较高的应激敏感度，以检查性别- 促进神经发育编程的特定机制。基于我们激动人心的出版和 初步数据，我们假设MPS使卵母细胞中存储的相互作用的mRNAs发生变化 在胚泡和胎盘发育期间，编程发育中的下丘脑的性别特异性变化。 我们的假设将在这一提议中得到检验，并在三个不同的机制水平上进行检验：卵母细胞、 胎盘和下丘脑。胎盘中的性别差异可能会产生性别特异性的反式- 胎盘向发育中的大脑发出信号，从性染色体开始。我们的研究和其他人 确定在女性胎盘中高水平表达的X连锁基因。通过全基因组 在母亲应激后的筛查中，我们发现X连锁基因OGT是编程性行为的原因-- 特定应力表型。胎盘OGT准备对环境的变化做出反应 对发育中的胚胎很重要，最终作为下丘脑的性别特异性调节 发展。因此，我们的提案将侧重于界定有助于《方案纲要》方案编制的机制 检查：1)卵母细胞：确定因先入为主而发生的持久的分子变化 受精时存在的压力及其繁殖雌性后代表型的必要性，2) 胎盘：确定女性中涉及的母体先孕应激的性别特异性机制 子代的表型侧重于胎盘的贡献，以及3)下丘脑：确定性别特异性 母亲孕前应激后下丘脑程序的变化及其作为一种 女性神经精神疾病风险的潜在因素。

Maternal lifetime exposures to perturbations such as stress, infection, malnutrition, and advanced age have been linked with an increased risk for offspring disease, including a strong association with neuropsychiatric disorders. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. Surprisingly few animal models have been developed to examine programming mechanisms of preconception perturbations. In this proposal, we utilize our mouse model of maternal preconception stress (MPS) in which female, but not male, offspring present with elevated stress sensitivity, to examine the sex- specific mechanisms contributing to neurodevelopmental programming. Based on our exciting published and preliminary data, we hypothesize that MPS imparts changes in oocyte stored maternal mRNAs that interact during blastocyst and placental development to program sex-specific changes in the developing hypothalamus. Our hypothesis will be tested in this proposal and examined at 3 distinct mechanistic levels: the oocyte, the placenta, and the hypothalamus. Sex differences in the placenta are likely to produce sex-specific trans- placental signals to the developing brain and begin with sex chromosomes. Our studies and others have identified X-linked genes that are expressed at higher levels in the female placenta. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causal in programming a sex- specific stress phenotype. Placental OGT is poised to respond to changes in the environment that are important to the developing embryo, ultimately serving as a sex-specific regulator of hypothalamic development. Therefore, our proposal will focus on defining mechanisms contributing to MPS programming examining the: 1) oocyte: To identify the lasting molecular changes that occur in response to preconception stress that are present at fertilization and their necessity for reproducing the female offspring phenotype, 2) placenta: To determine the maternal preconception stress sex-specific mechanisms involved in the female offspring phenotype focusing on the placental contribution, and 3) hypothalamus: To determine the sex-specific hypothalamic programming changes following maternal preconception stress and the role this plays as an underlying factor in female neuropsychiatric disease risk.