Long term consequences of white matter damage by perinatal hyperoxia PI: Vittorio Gallo, PhD PROJECT SUMMARY Survivors of premature birth frequently develop cerebral palsy and cognitive impairment. The primary pathological hallmark is white matter (WM) atrophy resulting from loss of myelin and oligodendrocytes. The cellular pathophysiology underlying the delayed development of WM is not fully understood, but possible causes include hypoxia-ischemia and perinatal infection which impact vulnerable neural cells. High tissue oxygen tension or hyperoxia (HO) has also recently been reported to lead to poor neurological outcome. Premature infants express lower levels of antioxidant enzymes than term infants and experience a greater than two-fold change in oxygen tension at delivery. This exposes WM oligodendrocyte progenitors (OP) to hyperoxic injury, and therefore elucidation of mechanisms of WM damage is critical to strategies for improving neurological outcome. The proposed aims will address the overall hypothesis that delayed WM development after neonatal HO leads to persistent abnormalities in myelin sheath formation, axonal conduction and functional behavior. We have established a mouse model of neonatal HO injury, in which exposure of newborn pups to 80% oxygen causes i) initial myelin deficiency in the WM, ii) loss of progenitors and mature oligodendrocyte cells, and iii) subsequent recovery of myelin protein and oligodendrocytes. However, when WM is analyzed by diffusion tensor imaging later in adulthood, significant abnormalities in corpus callosum are detected which indicate long term changes in myelination. In addition, we have found dyscoordinated regulation of myelin protein expression and reduced Contactin-associated protein in the axon after apparent recovery when oligodendrocyte numbers had returned to control levels. Based on these findings, we plan to analyze progression of the HO injury to characterize the time course of myelin loss and recovery, and determine whether axon damage is observed. We will perform immunochemical analysis for multiple myelin and axonal proteins, and electron microscopy to investigate possible ultrastructural changes in myelin integrity and axon-glial interaction after delayed WM development. We will also determine the effect of HO damage on i) physiological function of axons of the corpus callosum by measuring axonal conduction properties such as velocity and compound action potentials, and ii) changes in motor behavior using the motor skills sequence task test. These studies will not only shed light on long-lasting HO-induced structural and functional alterations in WM resulting from delayed myelination, but also identify changes in oligodendrocyte proteins which may underlie the long-term neurological sequelae of premature birth.

Public Health Relevance

Long term consequences of white matter damage by perinatal hyperoxia PI: Gallo, Vittorio, PhD While the survival of preterm infants has benefited from improved neonatal care, the high incidence of neurological disorders arising from premature birth remains a major societal concern. Exposure of neonatal mice to high levels of oxygen (hyperoxia) has now been shown to delay white matter development and to lead to persistent structural defects in the adult brain. We propose to characterize the long term effects of perinatal hyperoxia on white matter integrity, specifically to identify the structural and biochemical changes in white matter which underlie physiological and behavioral abnormalities later in life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Koenig, James I
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Children's Research Institute
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