The major long-term objectives of this study are to elucidate glial function and neuronal-glial interactions in brain in vivo, and establish novel neuroimaging tracers for glial brain tumors. Glia, a major heterogeneous class of brain cells, are involved in critical aspects of brain structure and function and injury repair. In spite of numerous previous studies, the roles of glial cells in vivo in health and disease are not well understood. Autoradiographic studies are particularly useful for in vivo studies to examine glial function because they can take into account the complex architecture and cell-cell interactions in mature, fully-developed brain. Because acetate is preferentially transported into astrocytes compared to neurons, preliminary studies for this project used radiolabeled acetate to assess metabolic responses of glia to sensory stimulation of neurons and chemical disruption of ion homeostasis. Local acetate metabolism increased by 8-40 percent in response to brain activation, whereas a decrement (7 percent) was observed after acute denervation to eliminate neuronal input; estimates of the rate of acetate utilization suggest that acetate might be a significant fuel for brain. These results indicate that acetate is a useful glial reporter molecule (i.e., a compound metabolized mainly in glia at variable rates) that can be used to assess neuronal-glial interactions in brain in vivo, and test the overall hypothesis that the local rate of acetate utilization by glia varies in proportion to functional activity.
The specific aims of this project are (1) determine the acetate utilization rate in rat brain in vivo by both direct biochemical assays of product formation and by autoradiography; (2) determine the rates of acetate transport into different brain cell types and relationships among acetate, glucose, and oxygen utilization in cultured brain cells; (3) establish glial responses to graded changes in neuronal activity induced by various sensory (e.g., visual, auditory, and whisker) stimuli to normal rats, and assess neuronal-glial interactions; and (4) determine responses of glia to pathophysiological conditions (e.g., puncture wound) that induce reactive astrocytes; (5) establish the use of labeled acetate to localize and monitor growth of glial tumors in rat brain and determine specificity of glial tumor labeling by acetate in human tumor pathological specimens. The proposed studies will lead to a better understanding of glial metabolism in brain, establish fundamental relationships between glial and neuronal activity in brain under normal and pathophysiological conditions, and the develop the use of labeled acetate for human positron emission tomographic (PET) studies of glial function and dysfunction, particularly neuroimaging of brain tumors.
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