Maternal Inflammation Alters Fetal Brain Development via Tumor necrosis Factor-al

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DESCRIPTION (provided by applicant): Maternal illness during pregnancy has been associated with a variety of neurodevelopmental problems in the child, including autism, schizophrenia, cerebral palsy and developmental delay. Animal models show that maternal inflammation, even in the absence of infection of the fetus, is sufficient to cause abnormalities in brain development. We are using a model of maternal inflammation during early gestation in which a single injection of lipopolysaccharide (LPS) into pregnant mice causes an abrupt disruption of neurogenesis in the fetal brain. The timing of challenge and spectrum of behavioral effects in adulthood are most similar to autism or schizophrenia in humans. Our overall goal in this proposal is to understand how the inflammatory cytokine tumor necrosis factor-a (TNF-a) affects fetal brain development. Maternal cytokines and chemokines may be transmitted into the fetus and directly alter neurogenesis, or could induce secondary cytokine production in the fetus and result in defects in neurodevelopment. Additionally, we have observed disruptions in placental function which could lead to restriction of blood and oxygen supply to the fetus, and thereby impact neurodevelopment. Our preliminary data indicates that TNF-a is a major mediator of effects of maternal inflammation in both the fetal brain and placenta. We will use mice genetically deficient in TNF-a to determine if TNF-a is necessary for effects on LPS on fetal brain development and placental function. We will also treat wild type mice with a bolus of TNF-a to determine if it is sufficient for effects on fetal brain development and placental function. We will use three primary outcomes: 1) rates of neurogenesis and survival in the fetal brain using thymidine analogs to label dividing cells; 2) cognitive function in the offspring using various tasks in the Morris water maze; 3) analysis of placental structure and function by histology and measurements of blood flow. These studies will provide mechanistic insight into the process by which maternal illness disturbs neurodevelopment in the fetus and implicates a single gene which could be clinically targeted to protect fetal brain development during acute maternal illness. PUBLIC HEALTH RELEVANCE: Maternal illness has been associated with a number of problems in brain development in the child, including autism and schizophrenia. We have developed a mouse model in which illness in the pregnant mother has significant effects on the number and timing of neurons being born in the fetal brain. We are examining the mechanisms by which fetal brain development is altered in this model, focusing on the role of a single molecule (TNF-a), which could be clinically targeted to prevent developmental diseases.