This NIAID-supported project uses a nonhuman primate model to investigate the adverse effects of maternal infection with influenza virus during pregnancy on infant brain development and behavior postpartum. In addition to being a potential cause of morbidity and mortality during gestation, concern has grown about the potential for long-term neurobehavioral consequences in flu-exposed offspring, even when maternal symptoms are seemingly mild and benign. The effects of controlled infections with A/Sydney/5/97 [H3N2] in mid- and late- pregnancy are being examined prospectively in a large cohort of rhesus monkeys. High resolution Magnetic Resonance Imaging (MRI) is employed to examine global and regional brain development at one year of age. White matter integrity is evaluated with Diffusion Tensor Imaging (DTI). This competitive revision in response to NOT-OD-10-032 will expand and strengthen the aims of the parent award through the addition of a genetic analysis, with a focus on the contribution of variation in the serotonin-transporter gene-linked polymorphic region (5-HTTLPR). The notice announced the Availability of Recovery Act Funds for Competitive Revision Applications (RO1, RO3, R15, R21, R21/R33 and R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet). The specific goal of this one-time supplement is to add an assessment of genetic risk to the research already being conducted in the parent project. Individual variation in serotonergic function conferred by 5HTTLPR allelic variation has been associated with the neural circuitry underlying emotion regulation and a risk for larger behavioral effects of adverse rearing conditions. While there has been extensive research on the 5-HTTLPR polymorphism in humans and other animals already, the focus has been primarily on the role of serotonin in the brain, largely ignoring its equally important functions in the periphery, especially related to the vasculature, cell trafficking, and inflammation. Serotonin receptors and transporter proteins are also present in the placenta. Our new research aim will establish whether this functional polymorphism and length variation in 5-HTTLPR is associated with maternal and fetal vulnerability, and the brain and behavioral phenotype emergent postnatally. We will distinguish whether allelic variants in the gravid female act independently or in conjunction with the fetal genotype to create a diathesis and greater impact of prenatal infection. The emphasis of the new aim is on this polymorphism in the promoter region of the serotonin transporter gene, but as a part of the supplement effort, we will extract and archive DNA for all study animals, to leverage the unique primate resource as a basis for additional genetic analyses in the future. Primate studies of prenatal influenza virus infection are critical at this juncture to bridge the findings in rodent models and the concerns raised by retrospective analyses of humans from flu-exposed pregnancies, which have implicated prenatal insults as critical events in the etiology of several neurodevelopmental and psychiatric disorders.
Physical and psychological challenges to maternal wellbeing during pregnancy can adversely affect fetal brain development and increase the likelihood of several neurodevelopmental and psychiatric disorders. In particular, there is currently considerable concern about maternal infection with influenza virus during pregnancy, especially with multiple strains in circulation, including the more virulent H1N1. We are proposing to determine the added risk posed for mothers and infants by specific variation in the serotonin transporter gene-linked polymorphic region (5HTTLPR), which has been associated with increased vulnerability and pathology after a number of different environmental exposures. This application to expand and strengthen our research aims is in response to NOT-OD-10-032 announcing the Availability of Recovery Act Funds for Competitive Revision Applications (RO1, RO3, R15, R21, R21/R33 and R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet).
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