Preterm birth results in significant cognitive disability at school age. MRI studies and pair neuropsychological testing of very low birth weight infants at school age demonstrate both significant cognitive handicap as well as correlative morphologic changes. 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 cues, with consequential long-term changes in corticogenesis in the developing brain. The development of a clinically relevant model of preterm birth requires selection of an animal model faithful to the developmental stage of the infants studied, documentation that the injury studied produces neuropathologic change and correlation of that injury with behavioral outcome. An overarching goal of this Program Project, as exemplified in the four investigational projects, is to understand the molecular basis of this complex pathology. In Core A, we describe our protocol for generating our animal model, based on a period of sublethal neonatal hypoxia. The goal of Core B, the Animal Assessment Core, is to provide a sophisticated and uniform infrastructure for the analysis of our animal model and the impact of experimental manipulations carried out in each of the projects. Core B will also add additional data independent of the projects that will allow a more complete understanding of the model and its relevance to premature birth. Specific competencies provided by this core include i) quantitative measurements of brain morphology; ii) serial MRI assessments of behavior (functional MRI), cortical volume (volumetric imaging) and white matter development (diffusion tensor imaging); iii) behavioral and cognitive testing of the model animals; and iv) microarray analysis of transcriptional events in selected brain regions. Statistical services will also be provided by provided by Core B. The data provided by the core, together with the data provided directly by each of the Projects, will be analyzed by a comprehensive ensemble of biostatistical tools. By the uniform assessment of animals, Core B will synergize the interactions between projects, and facilitate the most comprehensive utilization of the available data.
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