Contribution of Pediatric OSA in Memory and Learning

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ABSTRACT This is a comprehensive mentored research training proposal aimed to support the development of an independent physician-scientist. The applicant is an Assistant Professor of Anesthesiology & Pediatrics at Baylor College of Medicine (BCM), and is supported by the outstanding facilities, clinical and fundamental research, and mentorship. The Anesthesiology Department guarantees a 75% protected research time, indicating institutional priority and ample resources to facilitate the applicant's research and success. This proposal includes strong preliminary data obtained in the past two years, that have been partially funded by the applicant's two competitive research awards: The Clayton Award, and funds from the TCH Anesthesiologist-in- Chief. Based on the multidisciplinary and intersectional research, the applicant has identified six highly supportive and established scientist mentors. This proposal also outlines an educational plan that includes coursework, benchwork, and scholarly activities to complete his training and facilitate independence. Pediatric Obstructive Sleep Apnea (OSA), with an incidence of ~7%, has several untoward sequelae, including neurocognitive dysfunction involving behavior, emotional inhibition, and learning and memory, with unknown reversibility potentials. This proposal aims to characterize neurocognitive changes using a comprehensive and translational study approach to develop a novel pre-clinical model of pediatric OSA that faithfully recapitulates the human phenotype. Using a combination of human polysomnographic and young murine oximetry data we quantify the neurocognitive changes in pediatric OSA, and in age-matched neonatal mice. This proposal will test the hypothesis that OSA induces time-dependent reversible changes in postnatal hippocampal neurobiology, leading to decreased learning capacity. Two aims are proposed to test this hypothesis: Aim 1 will determine the temporal effects of intermittent hypoxia (IH) on learning and memory in the early developing brain. Aim 2 will determine the effects of IH on the hippocampus through a) long term synaptic potentiation in hippocampal slices to interrogate synaptic function, b) identify cell types in the dentate gyrus to quantify changes, and c) study the synaptic and cellular components of the rescue phenotype. The significance of these data include: 1) inform surgical decision making based on exposure timing, 2) elucidate synaptic and cellular data underlying OSA-induced hippocampal injury, and 3) feasibility and determinants of neurocognitive reversibility. Completion of this 5-year mentored award allows the applicant to combine perioperative anesthesia practice with an exploration of the molecular mechanisms of OSA-induced hippocampal damage. It paves the road for an independent physician-scientist committed to informing improved health targets in children with OSA.