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

项目摘要：早期生活中的心理社会逆境和压力是公认的最强大的 儿童神经发育和心理健康结果不良的环境风险因素。中的减损 发展情绪调节和认知控制以及大脑发育的相关改变， 被证明可以调节逆境对精神病理学发展风险的影响。早期社会心理学 逆境影响了表观遗传和炎症介导的过程，这些过程导致了这些负面影响。 结果，这一过程被称为“压力的生物嵌入”。虽然这一风险轨迹显然与 精神病理学的发病率增加，这一过程的机制，其靶向介质和如何早期 在发展中，它们运作尚待确定。在这里，我们关注的是早期生活逆境对 与精神障碍风险相关的大脑、情绪调节和认知控制结果， 产前和延长至3岁。我们将研究产前和产后逆境/压力的作用，产妇 以及儿童围产期肠道微生物组和早期护理人员对这些关键神经发育结果的支持 利用最先进的神经成像技术我们的统一假设是，这些因素调节系统性 炎症反应，通过这一过程和其他过程诱导神经元效应， 边缘系统和皮层区域的发展，并介导早期逆境对儿童情绪调节的影响， 认知控制和心理健康结果。这些因素将在一个独特的，前瞻性的研究 370名有高心理社会风险的母亲及其子女的确定队列被招募作为一项 已经资助了华盛顿大学的“一角钱三月”项目。该队列将包括长期和 早产儿和幼儿的心理社会逆境和异常肠道的风险增加 早产儿的微生物组。将从妊娠早期到妊娠后期对后代进行深入的前瞻性研究。 年龄3，提供了一个独特的数据集，其中检查产前和产后逆境之间的相互关系， 炎症的生物标志物，肠道微生物组以及发育和心理健康结果。围产儿 儿童早期是研究这些暴露与不良神经发育相关的关键时期， 逆境在子宫里就开始了同样，围产期也是一个关键时期， 微生物影响的发育窗口，当肠道微生物定植具有最持久的影响时。 这项拟议中的研究将这些领域的研究小组合并到一个中心， 儿童神经成像和广泛的微生物组专业知识，并提供了前所未有的机会， 了解逆境对大脑，认知和情感的生物嵌入机制 高风险人群的轨迹。我们还将应用创新的计算方法，使用深度学习， 加深对这些数据的理解。研究结果将提供关键和新颖的见解，为早期预防提供信息。 与最高风险儿童的情感、认知和心理健康结果相关的干预措施。

Project Summary: Early life psychosocial adversity and stress are well-established as the most powerful environmental risk factors for poor neurodevelopmental and mental health outcomes in children. Impairments in developing emotion regulation and cognitive control and associated alterations in brain development have been shown to mediate the effects of adversity on risk for the development of psychopathology. Early psychosocial adversity impacts the epigenetic and inflammation-mediated processes that contribute to these negative outcomes, a process known as “biological embedding of stress.” While this risk trajectory has been clearly linked to increased rates of psychopathology, the mechanisms of this process, its targetable mediators and how early in development they operate are yet to be determined. Here we focus on the effects of early life adversity on brain, emotion regulation and cognitive control outcomes relevant to risk for mental disorders, beginning antenatally and extending to age 3. We will examine the role of pre- and postnatal adversity/stress, the maternal and child perinatal gut microbiome and early caregiver support on these key neurodevelopmental outcomes utilizing state-of-the-art neuroimaging. Our unifying hypothesis is that these factors modulate systemic inflammatory responses, induce neuronal effects through this and other processes that adversely impact brain development in limbic and cortical regions, and mediate the effects of early adversity on child emotion regulation, cognitive control and mental health outcomes. These factors will be studied in a unique, prospectively ascertained cohort of 370 mothers and their offspring at high psychosocial risk being recruited as part of an already funded March of Dimes project at Washington University. The cohort will include both term- and prematurely-born infants and toddlers given the increased risk of psychosocial adversity and aberrant gut microbiome in preterm children. The offspring will be intensively prospectively studied from the 1st trimester to age 3, providing a unique dataset in which to examine the interrelationships among pre- and postnatal adversity, biomarkers of inflammation, the gut microbiome and developmental and mental health outcomes. The perinatal and early childhood periods are critical times to study these exposures as adverse neurodevelopment associated with adversity begins in utero through fetal programming. Likewise, the perinatal period is a critical developmental window for microbial influences, when gut microbial colonization has its most enduring effects. The proposed study merges established research groups in these areas in a center with advanced infant and childhood neuroimaging and extensive microbiome expertise, and offers an unprecedented opportunity to understand the mechanisms of the biological embedding of adversity on brain, cognitive and emotional trajectories in a high-risk cohort. We will also apply innovative computational methods, using Deep Learning, to extend understanding of these data. Findings will provide critical and novel insights to inform early preventive interventions relevant to emotional, cognitive and mental health outcomes for children at greatest risk.