Prenatal stress and the development of inhibitory neurons in the forebrain

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DESCRIPTION (provided by applicant: This application presents a career development award that integrates clinical child and adult psychiatry, animal models of developmental neuroscience, and stress neurobiology. The immediate goal is to create a program investigating the developmental mechanisms of the neurobiological effects of prenatal stress, focused on inhibitory neurons. The long term objective is to contribute to the understanding of early developmental events that contribute to severe childhood and adult psychiatric illness, the pathophysiology that underlies disorders such as schizophrenia and Tourette syndrome, and how interventions can modify early developmental changes. The candidate completed a Ph.D. in neuroscience with individual NIH funding and has now been involved in comprehensive training in clinical and research psychiatry for the past 5 years at the Yale Child Study Center (YCSC) and Department of Psychiatry. This award will provide critical support for the continuation of her integrated research in the YCSC Developmental Neurobiology Laboratory and the transition to an independent career in basic developmental neuroscience within the framework of understanding child and adult psychiatric illness. In the research proposal, an animal model of prenatal stress will be used to study the mechanisms of widespread, persistent effects on CNS structure and function. GABAergic systems will be the focus of the research plan, as patients with schizophrenia and other behavioral disorders linked to prenatal stress in humans have abnormal GABAergic neuron populations. Dr. Stevens will complete the first stage of the research plan on the anatomical effects of prenatal stress on inhibitory neurons with the support of this award and the skills she has developed in her postdoctoral work. She will then go on to make assessments of molecular mechanisms of prenatal stress affecting GABAergic populations both during the embryonic time period and during adult development. Functioning of inhibitory neuronal systems will be examined with behavioral and electrophysiological measures. This experimental work also comprises the career development plan for this candidate to obtain the necessary skills for an independent career in basic neuroscience research that can investigate important questions about the neurodevelopment of mental illness. The candidate has recruited an outstanding group of mentors and advisors that will guide the research plan in design, performance of experiments, and analysis of results. For career development, this mentor and advisor team will continue to support the candidate as she develops an independent laboratory program at the YCSC relevant to the neurodevelopment of mental illness and as she pursues additional training in molecular, behavioral, and electrophysiological techniques through coursework, intensive workshops and national conferences. PUBLIC HEALTH RELEVANCE: At a minimum, this work will address important gaps in the knowledge base regarding the neurodevelopmental basis of conditions related to prenatal stress, including schizophrenia. Broader implications include a more sophisticated understanding of the regulation of inhibitory neuron development and systemic and environmental effects on this regulation. Results of this work will inform child, adolescent and adult psychiatric treatment and the treatment of pregnant women with both pharmacologic and psychotherapeutic interventions.