Maternal flu infection and brain development in primates

描述(由申请者提供)：该项目将使用非人类灵长类动物模型来调查母体流感感染对婴儿行为和产后大脑功能的影响，基于许多研究表明怀孕条件会显著影响胎儿发育。除了是发病率和死亡率的原因外，人们越来越担心，即使母亲的症状看起来是良性的，怀孕期间的流感感染可能会导致后代的长期变化。对妊娠中期和晚期感染A/悉尼/5/97[H3N2]的受控流感感染的效果将在108只恒河猴的大队列中进行前瞻性评估。在比较了孕期和感染的严重程度之后，第三个实验将确定在怀孕前三个月接种疫苗对改善对婴儿的有害影响的保护作用。所有婴儿的表型和健康状况将通过标准化的神经行为和神经内分泌测试来表征。高分辨率磁共振成像(MRI)技术将被用来检查8个月和12个月大的全球和区域大脑发育。白质完整性和髓鞘化率将用弥散张量成像(DTI)评估。这些目标将利用威斯康星大学哈洛灵长类实验室和韦斯曼3-Telsa磁共振设施的独特资源以及北卡罗来纳大学的J.Gilmore博士和G.Gerig博士的分析专业知识来实现。总体而言，这些研究将检验核心假设，即感染和免疫激活可以改变胎儿发育的自然进程，表现为新生儿的神经运动反应异常，并仍然影响敏感的神经过程和1岁婴儿的行为能力。一个重要的焦点是海马体的潜在脆弱性及其与下丘脑-垂体-肾上腺轴的调节设定点的关系。灵长类动物对产前流感感染的研究在这个关键时刻对于在啮齿动物模型中的发现和对人类样本的回顾分析提出的关注之间架起了桥梁。

DESCRIPTION (provided by applicant): This project will use a nonhuman primate model to investigate the impact of maternal influenza infection on infant behavior and brain functioning postpartum, building upon many studies showing that pregnancy conditions can significantly affect fetal development. In addition to being a cause of morbidity and mortality, concern has grown that flu infections during pregnancy may induce long-term changes in offspring even when maternal symptoms are seemingly benign. The effect of controlled flu infections with A/Sydney/5/97 [H3N2] in mid- and late- pregnancy will be prospectively assessed in a large cohort of 108 rhesus monkeys. After comparing gestational timing and severity of infection, a third experiment will determine the protective benefits of vaccination in the first trimester for ameliorating the deleterious effects on the baby. The phenotype and wellbeing of all infants will be characterized with standardized neurobehavioral and neuroendocrine tests. High resolution Magnetic Resonance Imaging (MRI) techniques will be employed to examine global and regional brain development at 8 and 12 months of age. White matter integrity and rate of myelinization will evaluated with Diffusion Tensor Imaging (DTI). These aims will be accomplished using the unique resources of the Harlow Primate Laboratory and Waisman 3-Telsa MR facility at the University of Wisconsin and the analytic expertise of Drs. J. Gilmore and G. Gerig at the University of North Carolina. Overall, the studies will test the central hypothesis that infection and immune activation can alter the natural progression of fetal development, be evinced by abnormal neuromotor responses in the neonate and still affect sensitive neural processes and the behavioral competence of the 1 year old infant. An important focus is the potential vulnerability of the hippocampus and its relationship to the regulatory set points of the hypothalamic-pituitary-adrenal axis. Primate studies of prenatal flu infection are critical at this juncture to bridge the findings in rodent models and concerns raised by retrospective analyses of human samples.