Contribution of Pediatric OSA in Memory and Learning

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.

Grant Number: 5K08HL161263-04
NIH Institute/Center: NIH
Principal Investigator: Arvind Chandrakantan