The objective of this research is to characterize the effects of perinatal hypoxic/ischemic injury on brain development, with the long-term aims of reducing the morbidity and mortality associated with this type of brain injury. Perinatal hypoxic/ischemic brain injury occurs in both term and preterm infants, and is a major cause of perinatal mortality, neonatal morbidity, and long-term neurologic deficits. The morphological and functional damage of perinatal ischemia is different from that in the adult brain. Possible explanations for these differences include: variation in the etiology of the hypoxia/ischemia, the developmental state of susceptible cells, changes in the distribution of susceptible cells, or differences in the cellular mechanisms of injury. The initial experiments in this proposal will determine the morphologic effects of a focal hypoxic/ischemic injury on the developing brain at a range of ages and severity of injury, using unilateral carotid occlusion and hypoxia in the neonatal rat. The effects of ischemic injury on neurogenesis, cell migration, and neuronal differentiation, will be examined using 3H-thymidine autoradiography and staining with the rapid Golgi method. This model will then be used for study of the effects of perinatal hypoxic/ischemic injury on learning behavior. Subsequent experiments will examine the roles of the glutamate (NMDA) receptor in the physical and behavioral deficits resulting from perinatal hypoxic/ischemic brain injury, first by examining the developmental distribution of this receptor in the immature rat and human brain, then by looking at the effects of NMDA receptor antagonism. No reliable small animal model for global perinatal ischemia is currently in use. Development of a global ischemia model to supplement the above studies will be an important goal during the course of this proposal, as much perinatal ischemic injury occurs or begins prior to birth.
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