Maternal flu infection and brain development in primates

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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 acomplished 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.