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Human brain development and maintenance is orchestrated by complex interactions between genetic and environmental factors. Our research examines how neural stem cells respond to these factors and how these responses influence the integration of newly generated neurons into functional neural circuits.NEURAL STEM CELLS IN BRAIN DEVELOPMENT: Our studies of neurogenesis in the developing brain focus on the influence of maternal health or illness on fetal brain development. In humans, certain illnesses and infections during pregnancy are associated with increased risk of a neurodevelopmental disorder in the child. In mice, even mild maternal illness during early pregnancy can alter stem cell activity in the developing fetal brain. Offspring are born with subtle changes in brain function that affect social behavior and cognition. The effects are most reminiscent of features seen in children with autism or intellectual disability. Diseases such as autism, intellectual disability, and schizophrenia are caused by complex and poorly understood combinations of genetic and environmental factors. Although many genetic risk factors for neurodevelopmental disorders have been identified, few single-gene mutations are alone sufficient to cause the disorder. For example, in autism, genetics alone may account for less than half of all diagnoses and it is thought that environmental factors must also act during gestation or in the infant to alter brain development. In mice, we have found that several weak genetic risk factors act on the same developmental processes that are affected by a maternal illness during pregnancy. Alone, the genetic and immune risks have only mild influences. When gene and immune risks are combined during pregnancy, social behavior and cognition are severely effected in the offspring.Our ongoing research hopes to identify additional combinations of mild genetic and environmental risks that have synergistically negative effects on brain development. Ultimately, our hope is to develop diagnostic tools that identify genetic risks that are alone insignificant but place the developing child at very high risk from an environmental "second hit”. Knowledge of these unanticipated synergies provides the first step in educating both physicians and mothers about risks and measures that may be taken to reduce risk and prevent neurodevelopmental disorders.HUMAN PLURIPOTENT STEM CELLS TO STUDY AND TREAT NEUROLOGICAL DISEASE: Using information gained from studying neural stem cells in development, it has been possible to recreate the conditions of human fetal neurogenesis in the Petri dish. We are now able to use pluripotent stem cells to generate many types of human neurons, including those most affected in autism, schizophrenia, Alzheimer’s disease and Parkinson’s disease. With pluripotent stem cells derived from individuals with autism or schizophrenia, we are studying how genetic risk factors act to alter brain development. With stem cells derived from patients with Parkinson’s disease, we are discovering how genetic risk factors cause neurons to die in later life. In addition to using pluripotent stem cells as a discovery platform for disease mechanisms, we ultimately hope to use stem cell therapies to augment or restore function in conditions where neurons are irreversibly lost due to stroke, injury or age-related degeneration.