Fetal exposure to maternal stress and inflammation: Effects on neurodevelopment

描述（由申请人提供）：拟开展的项目旨在研究孕期母亲压力、孕期母亲炎症和胎儿缺氧（胎儿缺氧）如何影响后代在青春期出现抑郁症状的风险。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，从而导致儿童时期情绪、认知和行为结果的发展轨迹改变，以及随后的青春期抑郁。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），该研究从1959年至1966年对怀孕期间的妇女进行了前瞻性随访，并获得了关于母亲在怀孕和分娩期间的经历、健康风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的担忧或担忧以及对怀孕的感受的开放式问题的回答。在母亲怀孕期间收集了多种血清样本，并在-20℃存档。后代在5岁、9岁和15岁时进行认知、行为和心理评估。目前的研究将包括750名母亲和她们的后代，她们在每个时间点都有完整的数据。将对妊娠前三个月和妊娠中期存档的产前血清进行血清学分析，以测量妊娠期间母亲压力的生物标志物（即皮质醇），称为细胞因子的炎症蛋白水平（IL-1和TNF-的可溶性受体以及细胞因子IL-8和IL-6），以及胎儿缺氧标志物（VEGF）。此外，前瞻性收集的劳动和分娩信息将用于胎儿缺氧的额外措施。此外，本研究将从回答上述开放式问题的叙述中定性地编码与压力相关的主题，并对每个受试者的社区水平语境因素进行地理编码。具体目标如下：1)研究胎儿暴露于母亲压力和应激激素对青春期后代抑郁风险的影响；2)研究胎儿在怀孕期间暴露于母亲压力与随后的青春期抑郁之间是否存在儿童情绪和行为的中间表型，以及认知轨迹的改变。3)探讨胎儿暴露于高水平的母亲压力是否会增加或与其他产前和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。提出的研究是独特的定位，以回答关于产前风险因素如何在抑郁症的神经发育过程中起作用的关键问题。本研究有可能影响早期干预和预防策略的发展，以及确定青春期后续困难的早期风险标志。

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.