Fetal exposure to maternal stress and inflammation: Effects on neurodevelopment

描述(由申请者提供)：该项目旨在调查孕期母体压力、孕期母体炎症和胎儿缺氧(胎儿缺氧)如何影响后代青春期抑郁症状的风险。第二个目标是绘制这些产前风险因素如何导致一系列事件的轨迹，导致儿童时期情绪、认知和行为结果的发展轨迹改变，以及青春期随后的抑郁。这项拟议的项目基于一项大型出生队列研究，即儿童健康与发展研究(CHDS)，该研究在1959-1966年间对怀孕期间的妇女进行了前瞻性跟踪，并获得了有关母亲在怀孕和分娩期间的经历、健康危险行为和医疗并发症的详细信息。这些信息包括母亲对过去一年中关于担忧或担忧的开放式问题的反应，以及对怀孕的感受。从母亲怀孕期间收集了多个血清样本，并在-20摄氏度下存档。孩子们在5岁、9岁和15岁时接受了认知、行为和心理评估。这项研究将包括750名母亲及其子女，她们在每个时间点都有完整的数据。将对妊娠早期和中期的产前血清进行血清学分析，以测量孕期母亲应激的生物标志物(即皮质醇)、母体炎症蛋白水平、称为细胞因子的细胞因子(IL-1和TNF-β的可溶性受体以及细胞因子IL-8和IL-6)以及胎儿缺氧的标志物(血管内皮生长因子)。此外，预期收集的分娩和分娩信息将用于额外的胎儿缺氧测量。此外，本研究将根据对上述开放式问题的回答，对与压力相关的主题进行定性编码，并对每个受试者的邻里层面的语境因素进行地理编码。具体目的如下：1)调查胎儿暴露于母亲应激和应激激素对青少年后代抑郁风险的贡献；2)调查怀孕期间胎儿暴露于母亲应激和随后的青春期抑郁之间是否存在中间的儿童情绪和行为表型，以及认知轨迹的改变；3)调查胎儿暴露于母亲压力水平升高是否会增加其他产前和围产期并发症，或与其他围产期并发症相互作用，从而增加神经发育后遗症和青少年精神病理的风险。这项拟议的研究在回答有关产前风险因素如何在抑郁症的神经发育过程中发挥作用的关键问题上具有独特的地位。本研究有可能影响早期干预和预防策略的制定，以及确定青春期后续困难的早期危险标记。 公共卫生相关性：拟议的项目旨在调查孕期应激的母体心理社会和神经内分泌指标、孕期母体炎症和胎儿缺氧(缺氧)对青少年后代抑郁的神经发育过程的影响。

DESCRIPTION (provided by applicant): The proposed project aims to investigate how maternal stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen to the fetus) influence the risk of symptoms of depression during adolescence in offspring. A secondary aim is to map trajectories of how these prenatal risk factors result in a cascade of events, leading to altered developmental trajectories in emotional, cognitive, and behavioral outcomes during childhood and subsequent depression during adolescence. The proposed project is based on a large birth cohort study, the Child Health and Development Study (CHDS), that followed women prospectively throughout their pregnancies from 1959-1966 and acquired detailed information on the mothers' experiences, health-risk behaviors, and medical complications during pregnancy and delivery. This information included maternal responses to open-ended questions about concerns or worries within the past year and feelings about the pregnancy. Multiple sera samples were collected from mothers throughout their pregnancies and archived at -20oC. Offspring were administered cognitive, behavioral, and psychological assessments at ages 5, 9, and 15. The present study will include 750 mothers and their offspring who have complete data at each time point. Serological analyses will be conducted on archived prenatal sera from the first and second trimesters of pregnancy in order to measure biomarkers of maternal stress during pregnancy (i.e. cortisol), maternal levels of inflammatory proteins, termed cytokines, (the soluble receptors for IL-1¿ and TNF-¿ and the cytokines IL-8 and IL-6), and markers of fetal hypoxia (VEGF). Further, prospectively collected labor and delivery information will be used for additional measures of fetal hypoxia. In addition, the present study will qualitatively code stress-related themes from narratives acquired in response to the aforementioned open- ended questions and geocode neighborhood-level contextual factors for each subject. The specific aims are as follows: 1) to investigate the contributions of fetal exposure to maternal stress and stress hormones to risk of depression in adolescent offspring, 2) to investigate whether there are intermediate childhood emotional and behavioral phenotypes, as well as altered cognitive trajectories between fetal exposure to maternal stress during pregnancy and subsequent depression in adolescence, and 3) to investigate whether fetal exposure to elevated levels of maternal stress adds to or interacts with other pre- and perinatal complications to increase risk for neurodevelopmental sequelae and adolescent psychopathology. The proposed study is uniquely positioned to answer key questions about how prenatal risk factors operate within the neurodevelopmental course of depression. The present study has the potential to influence the development of early intervention and prevention strategies, as well as to identify early risk markers for subsequent difficulties in adolescence. PUBLIC HEALTH RELEVANCE: The proposed project aims to investigate how maternal psychosocial and neuroendocrine indicators of stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen) contribute to the neurodevelopmental course of depression in adolescent offspring.