Corticospinal Tract Development in Intrauterine Growth Restriction

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Project Summary Infants born following intrauterine growth restriction (IUGR) are at risk for the development of cerebral palsy (CP). However, it is not precisely understood how perinatal neurologic injury due to IUGR results in motor dysfunction. Using a novel thromboxane A2 (TXA2) murine model of IUGR, we have previously demonstrated significant downregulation of major myelin genes (MoBP, PLP1, CNPase, MOG) in whole brain, decreased corticospinal tract (CST) volume in the brain, and impaired gait. The most profound injury occurred when IUGR was combined with postnatal hyperoxia exposure, suggesting a “double hit” mechanism. These findings support a model in which transcriptional changes occur after IUGR that alter oligodendrocytes (OL) making them more susceptible to hyperoxia. Our findings lead us to the central hypothesis that IUGR with postnatal hyperoxia results in cell specific changes to the OL transcriptome that lead to pathologic changes to the CST and motor deficits seen in CP. In Aim 1, in vivo genetic and biochemical methods will be employed in this model to determine how IUGR/postnatal hyperoxia change the OL transcriptome. This aim will add further understanding to the underlying causes of white matter (WM) injury after IUGR. As CST is known to be disturbed in spastic CP, the most common type of CP in perinatal brain injury, Aim 2 will evaluate CST development using advanced in vivo imaging techniques to demonstrate how IUGR/postnatal hyperoxia alter development of descending motor tracts in the spinal cord. In Aim 3, altered motor input resulting in distal limb movement abnormalities and increased hyperreflexia/ spasms will be quantified using novel motor tests. The innovative motor testing employed in this aim will provide the means to rigorously quantify motor dysfunction resulting from our injury model and compare it to motor dysfunction seen in CP. This study will impact the field by 1) providing insight into specific changes to the OL transcriptome leading to abnormal myelination and CST development and 2) expanding the understanding of the development of the CP phenotype in IUGR. This study is significant because of its quantitative approach to imaging modalities and motor assessments that can be applied more broadly to other murine models of perinatal brain injury and provide a basis for investigating novel therapeutic interventions in humans. Finally, this study will provide an excellent vehicle for the applicant to develop into an independent investigator. Investigations will be performed in an environment with an established history of successful mentorship of junior faculty to independence. With the support of this application, the applicant will 1) advance her technical skills (RiboTag RNA isolation, next generation sequencing, murine MRI, electromyography and kinematic testing techniques) and 2) learn advanced biostatistics. Future independent studies will focus on the interplay between pathways altered by IUGR/hyperoxia in WM development and potential therapeutic interventions that can be directly tested in the murine models and ultimately neonatal patients.