Using the rat hippocampus as a model, the proposed research is designed to provide a better understanding of the different functional interrelationships between oxidative glycolytic pathways in the brain. Recent studies implicating glycolysis as a prominent supplier of metabolic energy in """"""""activated"""""""" neural systems, calls into question the assumption that nearly all of the metabolic energy requirements of the brain are provided by oxidative pathways. We will examine the histological relationships between oxidative and glycolytic metabolic activities, using cytochrome oxidase (CO) & lactate dehydrogenase (LDH) histochemistry, respectively. Histochemical sites of energy production will then be related to the distribution of para-nitrophenolphosphatase (p-NPPase) activity, as a marker for the sodium pump, the major consumer (40-60%) of metabolic energy in the brain. This analysis will be carried out at the laminar, cellular and subcellular levels using histochemical and immunohistochemical methods (and verified with EM). First, a comparison of the laminar distributions of CO (Exp.1) and LDH (Expt. 2) activities will be made to determine how these enzymes of energy production are spatially related to the distribution of the major sites of energy consumption (P- NPPase). Second, levels of CO (Expt.3) and LDH (Expt. 4) will be assessed within the perikaryal cytoplasm of major neuronal types, in order to determine if different cell types can be differentiated on the basis of oxidative vs. glycolytic metabolic markers. Third, we will use immunohistochemical methods to determine if there is a differential laminar, cellular, and subcellular distribution of the M4 (anaerobic; Expt. 5), and H4 (aerobic; Expt 6) isozymes of LDH. Two questions addressed will be: """"""""Do neuronal populations have their own distinct internal metabolic organization?"""""""", and """"""""Is there a differential distribution of glycolytic vs. oxidative metabolic pathways in different parts of the same neuron? In Expt. 7, the main source of excitatory synaptic input to the hippocampus will be eliminated by lesion of the entorhinal cortex to determine if decreased excitatory synaptic input is accompanied by changes in CO, LDH or pNPPase. Lastly, Expt. 8 is designed to examine CO, LDH and pNPPase changes following elevations in hippocampal activity induced by ketamine. Knowledge of the subcellular distribution of oxidative and glycolytic enzymes is essential for providing as with a fuller understanding of basic cellular mechanisms that underlie the selective vulnerability or resistance of particular neurons to metabolic insults.

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