The understanding of the cellular pathophysiology following experimental traumatic brain injury in adult animals have led to many different hypotheses regarding potential treatments for human head injury. However, the majority of human head injuries occurs in young people, whose brains are still in the process of developing. In addition, given that age is a powerful predictor of outcome following injury, issues regarding the interaction of development and brain injury are of major importance. Although several studies have addressed the interaction between brian injury and development, these studies have focused on surgically-induced lesions which do not produce the biomedically-induced cascade of neurochemical and metabolic changes that are the hallmark of traumatic brain injury. During the previous funding period, we characterized the cascade of extracellular changes in neurotransmitter concentrations and related ionic fluxes in the adult rat brain following fluid percussion (FP) brain injury. Briefly, in regions of the brain that are exposed to this injury-induced ionic flux, cells exhibit a marked increase in glycolysis, which is followed by a pronounced depression lasting for as long as behavioral deficits exist. Our Preliminary Studies in the developing rat pup indicate that FP can be implemented in the developing rat. Measurements of intracranial pressure and mean arterial blood pressure indicate that although the biomechanisms of the insult are similar to that seen in adult animals, the physiological response is quite different. Furthermore, the degree and extent of the metabolic dysfunction, due to changes in the extracellular milieu do not seem as extensive or last as long in young compared to adult rats. Since our Preliminary Results indicate that the developing CNS responds much differently to a closed head injury, the immediate goals of the project are to, (1) characterize the biomechanical and physiological properties of FP brain injury in the developing rat; (2) to determine the extent, duration and the involvement of the NMDA receptor in the injury-induced metabolic dysfunction; and, (3) to determine the degree and extent of the long term changes in behavioral outcome when injury is sustained early in life, addressing potential morphological and physiological alterations which persist. For this continuation proposal, we will utilize the FP model of brain injury in 17 and 28 day old rat pups, comparing results to animals injured as adults. Animals will be studied acutely following FP brain injury to evaluate the extent of cellular pathophysiology as reflected by calcium accumulation and metabolic dysfunction. In addition, animals will be studied in young adulthood to determine the enduring behavioral and physiological consequences of sustaining a traumatic brain injury early in life.
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