Neonatal brain injury results in lifelong disabilities for surviving infants with motor sensory disabilities often most prominent. Using the Rice- Vannucci model for neonatal hypoxic-ischemic (H/I) brain injury, we have shown the injury to the ventral basal thalamus is delayed in onset (24 hours) compared to forebrain injury and exhibits prominent structural features of apoptosis. Because injury to the ventral basal thalamus occurs in most models of neonatal brain injury and likely results in abnormalities in sensory-motor integration, injury to the ventral basal thalamus may contribute to the motor and sensory handicaps. Suffered by children with cerebral palsy. In preliminary studies, we find biochemical evidence that cell death in the ventral basal thalamus occurs by a programmed cell death mechanism. Cytochrome oxidase histochemistry indicates that mitochondria indicates that mitochondria accumulate and exhibit increased cytochrome oxidase activity in the first 24 hours after H/I injury. Cytochrome oxidase sub-unit 1 protein expression in the ventral basal thalamus is also increased at 3-6 hours after neonatal hypoxia- ischemia. These abnormalities in mitochondrial cytochrome oxidase histochemistry and protein expression in the ventral basal thalamus significantly precede the appearance the appearance of neurodegeneration and apoptotic profiles at 24 hours. The finding of cleavage of caspase-3 into its active forms by 24 hours further supports the idea that these biochemical changes in mitochondria are associated with apoptosis in the ventral basal thalamus following H/I injury. Lastly, in preliminary studies the mitochondrial associated pro-apoptosis protein, BAS is up-regulated between 3 and 24 hours following hypoxia-ischemia in the ventral basal thalamus. Based on these preliminary data, we hypothesize that delayed neurodegeneration in the ventral basal thalamus is apoptosis and occurs as the result of alterations in mitochondrial associated apoptosis proteins. Because delayed neurodegeneration in the ventral basal thalamus may offer a reasonable opportunity for neuronal rescue, we must understand the precise mechanism of delayed cell death following neonatal H/I brain injury. To accomplish this goal, the aims of this proposal will 1) demonstrate that delayed neurodegeneration in ventral basal thalamus after neonatal hypoxia-ischemia is programmed cell death, 2) demonstrate increased expression of the pro-apoptosis proteins, BAX and BAK, and changes in pro and anti-apoptosis bcl-2 family protein interactions in the ventral basal thalamus following neonatal hypoxia- ischemia, and 3) demonstrate neuroprotection in BAX deficient mice following neonatal H/I.