Fetal Programming of Early Development

描述（由申请人提供）：本申请的重点是在怀孕期间暴露在压力下的儿童的发育后果。妊娠灵长类动物胎盘应激的主要信号之一是促肾上腺皮质激素释放激素（CRH）肽。这种肽在胎儿下丘脑-垂体-肾上腺（HPA）轴的成熟中起关键作用，并同步胎儿生长和成熟的事件。胎盘CRH是响应所有主要的生物信号的压力在母体和胎儿室。妊娠期间胎盘CRH生成正常模式的应激相关改变对儿童发育有重要影响。广泛的研究支持胎盘CRH是与出生结局一致相关的应激指数的结论，然而胎盘CRH尚未用于预测神经发育结局。对胎盘CRH的关注利用了胎儿经验的直接指标，避免了母体压力导致连贯一致的母体生理特征传递给胎儿的假设。我们建议评估600名儿童（年龄在6-0岁至7-11岁之间），我们对他们有广泛的产前压力暴露史和出生表型，测量(a)情绪调节；(b)认知;(c)脑结构解剖（使用结构磁共振成像（MRI））；(d) HPA应力轴的调节。产前CRH对情绪调节的影响（目的1）将通过检查CRH水平与父母测量和自我报告气质之间的关系来评估。早期暴露于CRH对认知的编程效应（目的2）将通过检查胎盘CRH水平与智力标准化测量和注意力、记忆和执行功能新测量的表现之间的关系来评估。产前暴露于CRH对海马体、杏仁核和前额皮质体积（Aim 3）的影响将在80名孕晚期CRH水平上下五分位数的儿童中进行评估。产前CRH对HPA反应性的影响（目的4）将通过评估静息和轻度应激后的唾液皮质醇来评估。这些针对儿童的研究首次检验了产前CRH对人类发育的作用。

DESCRIPTION (provided by applicant): The focus of this application is on the developmental consequences for children exposed to stress during gestation. One of the major placental stress signals in pregnant primates is the peptide corticotrophin-releasing hormone (CRH). This peptide plays a key role in the maturation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and it synchronizes events that underlie fetal growth and maturation. Placental CRH is responsive to all the major biological signals of stress in the maternal and fetal compartments. Stress-related alterations in the normal pattern of placental CRH production during pregnancy have major implications for childhood development. Extensive research supports the conclusion that placental CRH is the stress index consistently associated with birth outcomes, however placental CRH has not been used to predict neurodevelopmental outcomes. The focus on placental CRH capitalizes on a direct index of fetal experience and avoids the assumption that maternal stress results in a coherent and consistent maternal physiological profile that is transmitted to the fetus. We propose to assess 600 children (between the ages of 6-0 and 7-11 years) for whom we have extensive histories of prenatal stress exposure and birth phenotypes with measures of (a) emotional regulation; (b) cognition; (c) anatomy of brain structures (using structural magnetic resonance imaging (MRI); and (d) regulation of the HPA stress axis. Influences of prenatal CRH on emotional regulation (Aim 1) will be evaluated by examining the relation between levels of CRH with measures of parent and self-report of temperament. Programming effects of early exposure to CRH on cognition (Aim 2) will be evaluated by examining the relation between levels of placental CRH and performance on standardized measures of intelligence and novel measures of attention, memory and executive function. The effects of prenatal exposure to CRH on the volume of the hippocampus, amygdala and prefrontal cortex (Aim 3) will be evaluated in a subgroup of 80 children in the upper and lower quintile of third trimester CRH level. Prenatal influences of CRH on HPA reactivity (Aim 4) will be evaluated by assessing salivary cortisol at rest and after mild stress. These studies in children are the first to examine the role of prenatal CRH on human development.