Preterm birth results in significant cognitive disability at school age. MRI studies paired with neuropsychological testing of very low birth weight infants at school age demonstrate significant cognitive handicap as well as correlative morphologic anomalies. Circulatory disturbances and oxygen deprivation are the two major causes of neurodevelopmental impairments in these children. We hypothesize that the chronic sublethal hypoxia that accompanies preterm birth disrupts the developmentally programmed maturation of the preterm brain. This injury results in the inappropriate phasing of both early and late developmental events, with consequential long-term changes in corticogenesis and behavior. The development of a clinically-relevant model of preterm birth requires selection of an animal model that is: (1) faithful to the developmental stage of the infants studied;(2) documentation that the injury studied produces neuropathologic alterations: and (3) provides evidence of a correlation between injury and behavioral outcome. An overarching goal of this Program Project, as exemplified in the four investigational projects, is to understand the cellular and molecular basis of this complex pathology. The goal of Core B, is to oversee the experimental exposure to hypoxia and enrichment interventions required by all projects. Core B will also add additional data both independently, and cooperatively, on the behavioral capacity of experimental and transgenic mice and on the maturation of connectivity using Diffusion Tensor Imaging (DTI) imaging. Finally, the Core will provide statistical consultation to all projects, and will aid in data analysis using a comprehensive ensemble of biostatistical tools.

Public Health Relevance

Preterm birth is one of the major pediatric public health problems of our time. The goal of this P01 is to identify new means of therapeutic intervention to decrease the neurobehavioral sequelae of preterm birth. This will be approached in four interrelated projects, all using our mouse model exposed to sublethal hypoxia between P3 and P11. Core B will provide for the standardization of hypoxic and enrichment exposures and behavioral assessment for animals of all projects, as well as, statistical consultation and support.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Yale University
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