Brain injury remains a significant cause of mortality and permanent neurological handicap in infants born prematurely. The peak incidence of white matter damage (WMD) is between 24 and 32 weeks gestation in the human. WMD is the most common form of brain injury in this population and contributes significantly to the incidence of neurologic damage and cerebral palsy (CP). Etiologic factors proposed for WMD include prenatal and postnatal inflammation and cerebral hypoxia/ischemia. The unique brain injury that results is, in part, a consequence of the selective vulnerability of oligodendrocyte precursor cells within this developmental window. Prior to 30 weeks gestation, the oligodendrocyte precursors within the cerebral white matter are predominantly pre-oligodendrocytes (pre-OLs). These pre-OLs are more susceptible to various insults than more mature oligodendrocytes. A loss of oligodendrocyte precursors results in impaired myelination, a reduction in white matter volume, dysfunctional motor tracts, and CP. The investigators propose to develop several mouse models of WMD that combine the various etiologic factors for WMD - inflammation and hypoxia/ischemia. In the mouse, the developmental window for pre-OL predominance in the cerebral white matter lasts through postnatal day 5. The investigators will assess the effects of prenatal and postnatal lipopolysaccharide (IPS) exposure in combination with hypoxia on white matter development during this critical developmental period. Preliminary testing for WMD on all animals will be done on postnatal days 10 to 12 by assessing ventricular size, corpus callosum thickness, and myelin basic protein immunostaining. Models that show evidence of WMD will be assessed in-depth to quantify the number of oligodendrocytes and their precursors in the cerebral white matter following injury. The development of mouse models of WMD will facilitate research defining the pathogenesis of this disorder, and will suggest prevention and treatment strategies for use in the human neonate. ? ?
