Maternal stress and the gut microblome:impact on neurodevelopment

项目总结 早年的生活干扰，如压力，与发育中的大脑的长期后果有关， 增加随后出现神经精神障碍的风险，这些障碍在陈述中表现出性别偏见，包括 精神分裂症、抑郁症和自闭症谱系障碍。尽管在理解上取得了进展 母体环境在正常和病理性脑发育中的机械作用，许多问题仍然存在 关于怀孕期间的压力如何导致后代压力失调的发展，这是一种普遍存在的 神经精神疾病的症状。最近的研究表明，母体肠道微生物群落 在怀孕期间进行动态改造，以维持对发育中的胎儿的持续营养供应 并让母亲们为哺乳的精力充沛的需求做好准备。在我们建立的早期小鼠模型中 产前应激(EPS)，我们的初步研究表明，暴露于EPS的新生儿表现出性别特异性 与能量平衡和动态平衡有关的代谢特征的改变，根据最近的研究，可能 提示母体微生物介导的养分利用率的变化可能是代谢物改变的原因 暴露的后代的特征。综上所述，这些结果让我们得出了这样的假设：大脑 孕期应激对母体肠道微生物群和营养的影响改变了发育 可用性。利用尖端的组学技术，我们的目标是确定母体之间的新联系 压力、母体肠道微生物群和新陈代谢，以及特定性别的大脑发育。的第一个目标 研究将检查怀孕期间的压力是否会扰乱母亲的肠道微生物区系和营养状况 对胎儿大脑发育至关重要。这一目标将利用母体肠道微生物区系的时间序列简档， 联合使用母体外周代谢物和营养可利用性以及胎儿脑代谢物分布 元基因组学和代谢组学评估，以及整合这些数据集的计算工具。 因为产前应激重新编程对发育中的大脑的影响可能要到晚些时候才会显现 发展，第二个目标将检查压力对母体肠道微生物区系的持久影响 出生后脑部发育的营养成分和可利用性。这一目标将利用 母体肠道微生物区系和子代下丘脑代谢物分布的时间序列分析 结合了元基因组学和代谢组学评估，以及整合了这些的计算工具 数据集。最终目标将确定母体肠道微生物群对大脑发育的因果关系。 在压力暴露窗口期间用益生菌定植后，然后检查对 抢救母体肠道微生物区系组成、母体营养可获得性和特定性别的脑代谢物 组成。综上所述，这些研究将为了解大脑 发育是通过压力对母体肠道微生物群和营养供应的影响而改变的 对于正常的神经发育来说是必要的。

PROJECT SUMMARY Early life perturbations, such as stress, are associated with long-term consequences on the developing brain, increasing subsequent risk of neuropsychiatric disorders that exhibit a sex bias in presentation, including schizophrenia, depression, and autism spectrum disorders. Despite advances in understanding the mechanistic roles of the maternal milieu in normal and pathological brain development, many question remain about how stress during pregnancy result in the development of offspring stress dysregulation, a pervasive symptom in neuropsychiatric disease. Recent studies indicate that maternal gut microbial communities are dynamically remodeled during pregnancy to maintain a continuous supply of nutrients to the developing fetus and prepare the mothers for the energetic demands of lactation. In our established mouse model of early prenatal stress (EPS), our preliminary studies show that newborns exposed to EPS exhibit sex-specific alterations in metabolic profiles related to energy balance and homeostasis, and, based on recent studies, may suggest that maternal changes in microbial-mediated nutrient availability may account for altered metabolite profiles in exposed offspring. Taken together, these results have led us to the hypothesis that brain development is altered by the impact of stress during pregnancy on the maternal gut microbiome and nutrient availability. Using cutting-edge `omics technologies, we aim to identify novel connections between maternal stress, the maternal gut microbiome and metabolism, and sex-specific brain development. The first aim of study will examine whether stress during pregnancy disrupts maternal gut microbiota and nutrient profiles critical for fetal brain development. This aim will utilize time-series profiling of the maternal gut microbiota, maternal peripheral metabolite and nutrient availability, and fetal brain metabolite profiles using combined metagenomics and metabolomics assessment, in addition to computational tools that integrate these datasets. As the effect of prenatal stress reprogramming on the developing brain may not emerge until later in development, the second aim will examine the lasting effect of stress on the maternal gut microbiota composition and nutrient availability on the brain development during the postnatal period. This aim will utilize time-series profiling of maternal gut microbiota, and metabolite profiles of the offspring hypothalamus using combined metagenomics and metabolomics assessment, in addition to computational tools that integrate these datasets. The final aim will determine causality of the maternal gut microbiome on brain development. Following colonization with probiotics during the window of stress exposure, then examine the impact on rescuing maternal gut microbiota composition, maternal nutrient availability, and sex-specific brain metabolite composition. Together, these studies will provide valuable insights into the mechanisms by which brain development is altered through the effect of stress on the maternal gut microbiome and nutrient availability necessary for normal neurodevelopment.