Information processing in working brain involves astrocyte-neuron and astrocyte-astrocyte signaling and requires a continuous supply of energy. Increased glucose utilization is an essential aspect of brain cell activation, and the linkage between cellular and metabolic activity provides a means to study normal brain function and neurological disease by noninvasive metabolic imaging procedures. The cellular contributions to the energy budget of working brain are not known, and recent findings of disproportionate increases in glucose compared to oxygen utilization plus substantial glycogenolysis in normal, activated brain suggest increased lactate formation. However, lactate presumably formed from blood-borne glucose and astrocytic glycogenolysis cannot be fully accounted for by (1) a local increase in oxygen utilization to match those of glucose and glycogen or (2) lactate accumulation in activated tissue. These and other findings in our lab lead to our overall hypothesis that most lactate produced during brain activation in conscious rats is quickly released from activated structures to blood, and astrocytic gap junctions are an important route for metabolite trafficking. The 'lactate release' hypothesis will be tested in the auditory and other sensory pathways by combining different approaches (biochemical, autoradiographic, microdialysis, fluorescence microscopic) in three specific aims. (1) Identification of metabolites released into extracellular fluid and venous blood of conscious rats will be used to test the hypothesis that lactate is quickly cleared from activated tissue; these results will support or refute the astrocyte-to-neuron lactate shuttle concept. (2) Evaluation of metabolite movement through gap junctions in cultured astrocytes with a new, innovative procedure to assay trafficking of unlabeled metabolites will be used to test the hypothesis that (a) rapid trafficking into the astrocytic syncitium of lactate and energy metabolites is critical for nutrient supply and product clearance, and (b) this trafficking is disrupted by diabetic conditions. (3) Establishing the fate of glycogen during activating conditions in brain of conscious rats and in astrocytes will be used to test the hypothesis that lactate released by glycogenolysis is quickly eliminated, and gap junctions help disperse glycogen-derived lactate. Our long-term goal is to understand astrocyte-neuron interactions in brain activation, and results of our studies will have a high impact on current concepts of contributions of astrocytes to energetics and nutrition in activated brain.

R01NS036728

1999-03-01

2008-11-30