Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders

项目摘要 早期暴露于社会劣势，特别是在子宫内的家庭和邻里经济劣势， 在生命的前3年，是一个强大的和潜在的可改变的环境风险决定因素， 儿童精神病理学正在进行的早期生活逆境和生物嵌入（eLABE）研究启动 在2017年，旨在阐明这一风险轨迹的机制，并指导预防干预措施。到目前为止， eLABE检测到产前社会劣势与结构和功能之间存在密切联系 出生时的大脑发育，这是通过母体细胞因子的升高和 肠道微生物组这些新生儿神经发育变异与以下指标的升高有关： 2岁时的精神病理学风险。此外，减少照顾者养育介导的某些方面，这 关系，与支持性治疗减轻儿童精神病理学风险。我们的核心假设是亲- 暴露于产前和生命早期社会的儿童的炎症免疫和肠道微生物组特征明显 不利因素诱导神经元效应，对大脑结构和功能发育产生负面影响， 精神病理学风险增加。此次更新建议在现有数据的基础上继续遵循 我们的377名儿童的独特和特征鲜明的样本，我们为他们收集了丰富的，无与伦比的 资料库，包括社会不利处境的综合衡量标准（在子宫内和1岁、2岁和3岁）， 炎症、肠道微生物组和大脑发育（结构、微结构和 出生时以及2岁和3岁时的功能性MRI）。在eLABE的下一阶段，我们建议按照此示例执行以下操作： 入学（6岁）和童年中期（8岁），增加了对社会不利条件的评估， 发育/行为，炎症标志物，多模式MRI，照顾者和社会支持措施， 两个时间点和6岁时肠道微生物组的一个额外波。我们将利用这些数据来测试特定的 关于开始明显出现在幼儿期的精神障碍的机械途径的假设， 学龄，并将利用新的大脑指标，更直接地检查神经炎症的作用， 在这条风险路径上的可塑性。我们也会检视照顾者、家人、同侪和学校支持的影响 包括它们作为可能的复原力因素的作用，并探讨是否存在敏感的 这些影响的时期。结果将提供第一个系统和密集的前瞻性检查， 社会劣势与慢性全身性炎症、肠道微生物组的关系，以及它们与 与临床精神障碍风险相关的大脑发育和行为。关键的是，通过针对性地， 炎症和肠道微生物组作为关键机制途径，这些数据也将具有巨大的 临床和转化潜力，因为它们研究了潜在的风险介质并提供了可改变的靶点 来预防精神疾病。

PROJECT SUMMARY Early exposure to social disadvantage, specifically family and neighborhood financial disadvantage in utero and through the first 3 years of life, is a powerful and potentially modifiable environmental determinant of risk for childhood psychopathology. The ongoing Early Life Adversity and Biological Embedding (eLABE) study launched in 2017 has aimed to elucidate mechanisms of this risk trajectory and guide preventive interventions. To date, eLABE has detected powerful associations between prenatal social disadvantage and structural and functional brain development at birth which are mediated through elevations in maternal cytokines and alterations in the gut microbiome. These neonatal neurodevelopmental variations have been linked to elevations in markers of psychopathology risk at age 2 years. Further, decreased caregiver nurturance mediated some aspects of this relationship, with supportive caregiving mitigating child psychopathology risk. Our central hypothesis is that pro- inflammatory immune and gut microbiome profiles evident in children exposed to prenatal and early life social disadvantage induce neuronal effects that negatively impact structural and functional brain development leading to increased risk for psychopathology. This renewal proposes to build upon the existing data to continue following our unique and well-characterized sample of 377 children for whom we have assembled a rich, unparalleled repository including comprehensive measures of social disadvantage (in utero and ages 1, 2, and 3 years) with early life measures of inflammation, the gut microbiome, and brain development (structural, microstructural, and functional MRI at birth and ages 2 and 3). In the next phase of eLABE, we propose to follow this sample into school entry (age 6) and middle childhood (age 8), adding assessments of social disadvantage, developmental/behavioral, inflammatory marker, multimodal MRI, and caregiver and social support measures at both timepoints and one additional wave of the gut microbiome at age 6. We will utilize these data to test specific hypotheses about mechanistic pathways to mental disorders that begin to clearly emerge in early childhood and school age, and will utilize novel brain metrics to more directly examine the roles of neuroinflammation and plasticity in this risk pathway. We will also examine the effects of caregiver and family, peer, and school supports on this risk trajectory, including their role as possible resilience factors, and explore whether there are sensitive periods for these effects. The results will provide the first systematic and intensive prospective examination of the relationship of social disadvantage to chronic systemic inflammation, the gut microbiome, and their links to brain development and behavior related to risk for clinical mental disorders. Critically, by targeting caregiving, inflammation, and the gut microbiome as key mechanistic pathways, these data will also have tremendous clinical and translational potential as they investigate potential mediators of risk and provide modifiable targets for prevention of mental disorders.