Maternal stress and the vaginal microbiome: impacts on brain development

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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.