The pathogenesis of ischemic brain injury is poorly understood. I plan to undertake detailed analyses of the cascade of aberrant microphysiological activities that occur during ischemia and recirculation, a process that has important clinical ramifications. Results from experimental stroke rsearch suggest that either lactic acidosis or disruption of cell calcium homeostasis may be fundamentally responsible for ischemic brain injury. However, little direct evidence exists to confirm these postulated roles for lactate and calcium. A highly reproducible model of severe forebrain ischemia developed in this laboratory will be used in this study. Work with this model has shown a selective vulnerability of neurons in space and time. Histological evidence of damage progresses for days. Microelectrodes sensitive to particular ions, gases, or organic chemicals (microsensors) will be used to test the hypothesis that temporally important local changes in ion and metabolite homeostasis may be detected and be causally related to selective vulnerability. We propose to measure and manipulate the hydrogen and calcium homeostasis and related variables in forebrain regions with varying sensitivity to ischemia during and after the interruption of blood flow. This information will be correlated to histological and electrophysiological characterization of the same areas. Existing microsensors for H+, K+, Ca++, Na+, and Cl- will be used in this study. In addition we expect to develop sensors for CO2, O2, lactate, and glucose.
