Maternal stress and the vaginal microbiome: impacts on brain development

描述（由申请人提供）：应激通路失调是神经精神疾病中最普遍的症状，但我们对该系统的发育编程和成熟以及扰动可能破坏的敏感期知之甚少。怀孕期间的压力与神经发育障碍的发病率增加密切相关，包括抑郁症，焦虑症，精神分裂症和自闭症。我们已经开发了一种小鼠模型的早期产前压力，其中男性后代目前与压力敏感性增加。怀孕期间的压力如何有助于压力途径的重新编程的机制可能涉及母体和胎儿环境之间的复杂联系。一种尚未探索的相互作用是产前压力对阴道微生物组的影响。由于新生儿肠道最初是由母体阴道微生物组构成的，因此母体压力产生的阴道生态变化也会同样影响这种微生物群。因此，新生儿肠道微生物多样性的这种变化可能会通过重要营养物质代谢和吸收的变化影响神经发育过程。因此，我们的建议将利用我们的早期产前应激小鼠模型来检查：1）压力对母体阴道和幼鼠肠道微生物组组成的影响，包括使用MiSeq技术的相对乳酸杆菌水平和β多样性的变化，（二）微生物组参与神经发育编程的机制，通过直接操纵微生物组来拯救和重现EPS表型的各个方面以及对下丘脑发育的影响，以及3）幼犬肠道微生物组重新编程下丘脑的表观遗传机制，重点关注与功能基因集相关的代谢组学结果并检查其上游表观遗传标记。

DESCRIPTION (provided by applicant): Stress pathway dysregulation is the most pervasive symptom in neuropsychiatric disease, yet we understand little as to the developmental programming and maturation of this system and the sensitive periods during which perturbations may be disruptive. Stress during pregnancy has been strongly associated with an increased incidence of neurodevelopmental disorders, including depression, anxiety, schizophrenia, and autism. We have developed a mouse model of early prenatal stress in which male offspring present with increased stress sensitivity. Mechanisms for how stress during pregnancy contributes to reprogramming of stress pathways likely involve complex connections between the maternal and fetal environments. One such interaction that has not been explored is the effect of prenatal stress on the vaginal microbiome. As the neonatal gut is initially populated from the maternal vaginal microbiome, changes in the vaginal ecology produced by maternal stress will similarly affect this microbial population. Hence, such changes in neonatal gut microbial diversity could impact neurodevelopmental processes via changes in vital nutrient metabolism and absorption. Therefore, our proposal will utilize our mouse model of early prenatal stress to examine: 1) the effects of stress on the maternal vaginal and pup gut microbiome composition, including changes in relative Lactobacillus levels and beta diversity using MiSeq technology, 2) mechanisms by which the microbiome is involved in neurodevelopmental programming through direct manipulation of the microbiome to rescue and recapitulate aspects of the EPS phenotype and effects on hypothalamic development, and 3) epigenetic mechanisms by which the pup gut microbiome reprograms the hypothalamus, focusing on metabolomics outcomes linked with functional gene sets and examining their upstream epigenetic marks.