Maternal stress and the vaginal microbiome: impacts on brain development

描述(申请人提供)：应激途径失调是神经精神疾病中最普遍的症状，但我们对这一系统的发育编程和成熟以及期间的干扰可能是破坏性的敏感期知之甚少。怀孕期间的压力与神经发育障碍的发生率增加密切相关，包括抑郁、焦虑、精神分裂症和自闭症。我们已经建立了一种胎儿期早期应激的小鼠模型，在该模型中，雄性后代表现出更高的应激敏感性。怀孕期间的压力如何有助于重新编程应激途径的机制可能涉及母体和胎儿环境之间的复杂联系。其中一种尚未被研究的相互作用是产前应激对阴道微生物群的影响。由于新生儿的肠道最初是由母亲的阴道微生物群组成的，母亲应激所产生的阴道生态的变化也将同样影响这一微生物种群。因此，新生儿肠道微生物多样性的这种变化可能通过改变重要营养物质的代谢和吸收来影响神经发育过程。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)应激对母体阴道和幼崽肠道微生物组组成的影响，包括使用MiSeq技术对乳酸菌相对水平和β多样性的变化；2)微生物组通过直接操纵微生物组参与神经发育编程的机制，以挽救和概括EPS表型的各个方面和对下丘脑发育的影响；3)表观遗传学机制，即幼鼠肠道微生物组重新编程下丘脑，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.