The regulation of pH is critical for the normal operation of the brain, as numerous channels and enzymes are sensitive to small shifts in hydrogen ion concentration. Acid base status can be particularly important in brain injury, where it can play a determinant role in the manifestation of brain damage and the recovery of function. Normal and pathological electrical activity have been shown to cause large changes in pH, of sufficient magnitude to influence brain physiology. These extracellular and intracellular pH shifts arise from specialized mechanisms in both neurons and glia, and therefore display marked regional heterogeneity, and stereotyped developmental patterns. During brain ischemia, these acid base fluxes can become extremely large, and may therefore influence the processes which lead to secondary tissue injury. The objective of this study is to elucidate the mechanisms which govern the dynamic behavior of pH in mature and developing brain, and to determine the functional relevance of the acid-base shifts under normal and ischemic conditions. The broad aim will be addressed by studying pH dynamics at the systems, regional and cellular levels. Accordingly, experiments will be conducted using anesthetized rats, brain slices, and isolated single cells. Pathophysiological studies on whole animals will be performed during focal ischemia, with emphasis on the infarct rim, a region known to undergo severe electrophysiological disturbances. Unprecedented resolution of acid base status will be provided by new microelectrode techniques, allowing the first real-time determination of pH, bicarbonate, and carbon dioxide in the extracellular space of the brain. These studies will provide new insights into the functional and developmental role pH, and will add critical detail to our understanding of how hydrogen ions affect outcome and recovery, following, stroke, perinatal hypoxia, and cardiac arrest.
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