Intrauterine inflammation affects offspring cognitive function

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DESCRIPTION (provided by applicant): Maternal infection during pregnancy is common and can cause adverse neurodevelopmental outcomes in the fetus, such as intellectual disability and deficits in executive function. Importantly, maternal infection during pregnancy is virtually impossible to prevent as detection occurs only after infection, when damage to the fetus may have occurred. Therefore, strategies and therapeutics must be developed to promote and support healthy brain development in the offspring subsequent to exposure to maternal infection. These types of interventions must first be developed in an animal model. The primary barriers to progress in this area are two-fold; (1) the animal model must be translationally relevant and (2) evaluation of higher cognitive function in a mouse is challenging. The most widely used model of prenatal maternal infection involves the use of systemic administration of bacterial (lipopolysaccharide, LPS) or viral (poly I:C) mimetics. However, the validity of these animal models to the most common clinical scenarios during human pregnancy has not been demonstrated. In contrast to the systemic models, an in utero or local model more aptly mirrors intrauterine infection and/or chorioamnionitis (inflammation of the fetal membranes). Intrauterine inflammation is common, present in 6% of term births, and results in over 240,000 affected births per year. To that end, we have developed a mouse model of intrauterine inflammation (intrauterine LPS administration) that leads to offspring born at term with postnatal brain injury, characterized by aberrant dendritic arboritization of fetal neurons. Importantly, this mouse model serves to most aptly mimic the most common human clinical scenario by which a fetus would be exposed to prenatal inflammation. In adulthood, exposed offspring demonstrate significant gene expression changes in neuronal and glial pathways, most notably in the prefrontal cortex. In two aims, we will examine executive function and anxiety and depression-related behaviors in exposed offspring, as well as evaluate dopaminergic dysfunction as a potential mechanism. This collaborative team includes Dr. Elovitz, a physician-scientist whose experience at the bedside led directly to the development of a translationally relevant mouse model of intrauterine infection and Dr. Reyes, a neuroscientist with experience in developmental programming, neuroimmunology and assessment of higher cognitive function in the mouse. !