The mechanisms by which ischemia leads to neuronal injury within certain """"""""selectively vulnerable"""""""" regions of the central nervous system remain incompletely understood. Within the past few years, a fresh perspective has been cast on this problem by studies implicating neuronal activity in the pathogenesis of ischemic brain injury. In this proposal, we seek to establish the importance of altered levels of neuronal activity in modulating ischemic injury within selectively vulnerable brain regions. We shall employ well-characterized models of reversible focal and global ischemia in the rat to investigate paradigms which entail the modulation of local levels of functional and metabolic activity within the brain.
Our specific aims are to assess the role played by postischemic uncoupling of local glucose utilization and blood flow in contributing to ischemic injury; to determine whether stimulation of local brain metabolism by functional activation of the vibrissal-barrel-field somatosensory pathway in the peri-ischemic period affects the susceptibility of the barrel-field region of neocortex to ischemia; and to discern whether neuronal death in vulnerable areas is influenced by modifications of the local neurotransmitter environment or by pharmacological modulation of local levels of metabolic activity. A related aim represents, in effect, the converse of the above: namely, to use the degree of local metabolic responsivity to a standardized somatosensory activation stimulus as a sensitive regional index of residual functional impairment following transient ischemia. We shall employ a recently validated double-label autoradiographic method to asess the quantitative topography of local brain glucose metabolism, blood flow, and the metabolism/blood flow couple, and shall correlate these observations with the results of regional energy metabolite and neurotransmitter assay, and light-level and ultrastructural morphology. It is intended that these studies will provide impetus to the development of novel prophylactic or therapeutic strategies to protect the brain during ischemia.
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