IBN 97-28171 DIENEL The functions of two major classes of brain cells, neurons and glia, are highly specialized. Neurons carry out the signaling processes, transferring information from one cell to another to control and coordinate the activities of the body. Glial cells surround neurons and have many important functions, including control of the extracellular environment which can modify neuronal activity thereby influencing behavior. Glial functions and glial- neuronal interactions in brain are poorly understood because it is very difficult to assay the activities of specific classes of cells in the living brain. Brain function is often evaluated by metabolic brain imaging procedures using radiolabeled glucose analogs because there is a close correlation between changes in functional activity and local rate of glucose utilization to provide energy for brain work. Functional metabolism is the breakdown of compounds to extract energy for the working cell, and metabolic imaging is based on local trapping of labeled products of the metabolic tracer in the cell where it is metabolized; the quantity of trapped label reflects the magnitude of functional activity. Because glucose is a fuel for all cells, it cannot distinguish between the functional metabolic changes in the different cell types in brain. In the present study, glial- specific "reporter molecules", i.e., labeled compounds known to be metabolized mainly in glial cells, will be used to measure stimulus-induced metabolic changes in glial cells and evaluate working relationships between glia and neurons. Experiments are designed to test the hypothesis that metabolic activity in glial cells increases in proportion to the activity of neurons when neurons are stimulated by graded changes in sensory input, and that compounds made in glial cells are transferred from glia to neurons in increased quantities. Neurons will be activated by changing the magnitude of a visual stimulus (flash rate or intensity of a strobe light) to cause progressive increases in the signaling activity of neurons in the eye as the visual information is processed in the brains of experimental rats; altered neuronal activity is predicted to cause parallel changes in the activity of glial cells in the visual pathway and rates of metabolism of glial reporter molecules. Some compounds made in glial cells are exported to neurons, and the quantity of labeled compounds transferred and incorporated into a neuron-specific marker (a neurotransmitter called GABA) will be measured, thereby permitting assessment of neuronal-glial metabolic interactions in working brain. The results of the proposed experiments will increase our understanding of how glia obtain their energy to carry out their work and how neurons and glia work together to process visual information. Knowledge of the cellular basis of metabolic brain images will also help to form the basis for future development of new brain imaging techniques to visualize and quantify glial cell activity in human brain.
