Placental programming of infant neurodevelopment in the context of maternal care

为母亲的心理健康和孩子的神经发育结果之间的关系提供生物学解释是围产期医学最大的挑战之一。母亲的压力、焦虑和抑郁都被证明会增加儿童患精神疾病的风险，而糟糕的母亲护理也会产生类似的不利后果。在一个实验模型中，我们已经证明胎盘内分泌功能障碍会导致糟糕的母体护理和不良的后代行为。这些观察结果使我们提出了一种新的假设，即胎盘内分泌功能障碍是孕妇情绪障碍、产妇护理受损和婴儿神经发育不良结果共同出现的基础，在人类怀孕中经常被报道。我们最近发表的研究(心理医学2016)支持胎盘内分泌功能障碍与产前抑郁之间的关系。我们现在有了一个独特而及时的机会来进一步检验我们的假设，该假说是在目前由MRC资助的一项名为Grown in Wales的人类研究队列上进行的，目的是检查胎盘内分泌功能障碍在产妇护理和异常婴儿行为规划中的作用。分析这一队列中的婴儿神经发育和育儿行为将建立在我们目前的MRC研究的基础上，增加价值，并显著丰富我们对胎盘内分泌功能障碍后果的理解。重要的是，在ALSPAC-G2研究中纳入对育儿行为和婴儿结局的类似测量将大大增加拟议工作的更广泛影响。附加值：关于产妇情绪、产妇的生物学特征和生活方式、产妇的血液和唾液、脐带血、胎盘、来自得分最高和最低的母亲的胎盘RNAseq的现有数据、2个月和12个月的产妇跟踪数据、12个月的婴儿评估数据以及从ALSPAC-G2研究获得的数据。目的1.在母婴配对队列中评估婴儿的认知、情绪和行为发育以及母婴护理，这些母婴配对具有良好的产前和产后母亲情绪数据。目的2.建立胎盘内分泌功能障碍和异常印迹是否与a)产妇护理质量和/或b)婴儿神经发育结局相关目标3.确定这些发现在ALSPAC-G2中的更广泛的相关性。目的4.在确定暴露特征结果的情况下，应用因果分析框架来加强因果推断。研究培训：下一代测序、生物信息学、理论、方法论和高级数据分析技能(被认为是英国社会科学中一个重大技能不足的领域)、多元统计和纵向数据分析(通过正规课程和申请者的监督)、用户参与和传播。多学科：发育表观遗传学、婴儿神经发育、流行病学和社会科学。

Providing a biological explanation for the relationship between the mother's mental health and her child's neurodevelopmental outcomes represents one of the greatest challenges of perinatal medicine. Maternal stress, anxiety and depression have all been shown to increase the risk of psychopathology in children while poor maternal care has similarly adverse outcomes. In an experimental model, we have shown that placental endocrine dysfunction programs both poor maternal care and adverse offspring behaviour. These observations lead us to the novel hypothesis that placental endocrine dysfunction underlies the co-occurrence of maternal mood disorders, impaired maternal care and adverse infant neurodevelopmental outcomes frequently reported in human pregnancies. Our recently published research (Psychological Medicine 2016) supports the relationship between placental endocrine dysfunction and prenatal depression. We now have a unique and timely opportunity to further test our hypothesis captilising on a current MRC funded human study cohort called Grown in Wales, to examine the role of placental endocrine dysfunction in the programming of maternal care and abnormal infant behaviour. Analysing infant neurodevelopment and parenting behaviour in this cohort will build on our current MRC study adding value and significantly enriching our understanding of the consequence of placental endocrine dysfunction. Importantly, the inclusion of similar measurements of parenting behaviour and infant outcomes in the ALSPAC-G2 study will substantially increase the wider impact of the proposed work. Added value: Existing data on maternal mood, maternal biological characteristics and lifestyles, maternal blood and saliva, cord blood, placenta, RNAseq of placenta from mothers with highest and lowest scores, follow-on maternal data at 2 and 12 months, infant assessment data at 12 months and access to data from the ALSPAC-G2 study. Aim 1. To assess infant cognitive, emotional and behavioural development alongside maternal care in a cohort of mother-infant pairs with well characterised pre and postnatal maternal mood data. Aim 2. To establish whether placental endocrine dysfunction and aberrant imprinting correlate with a) quality of maternal care and/or b) infant neurodevelopmental outcomes Aim 3. To determine the wider relevance of these findings within ALSPAC-G2. Aim 4. Where exposure-characterstic-outcome is established, apply a causal analysis framework to strengthen causal inference. Research training: Next generation sequencing, bioinformatics, theoretical, methodological and advanced data analytic skills (recognised as an area of significant skills deficiency in UK social science), multivariate statistics and analysis of longitudinal data (through formal courses and supervision by the applicants), user engagement and dissemination. Multidisciplinary: developmental epigenetics, infant neurodevelopment, epidemiology and social science.Supporting Documentation.