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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036728-07
Application #
7152915
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Sieber, Beth-Anne
Project Start
1999-03-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2008-11-30
Support Year
7
Fiscal Year
2007
Total Cost
$294,528
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Neurology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Dienel, Gerald A; Cruz, Nancy F (2015) Contributions of glycogen to astrocytic energetics during brain activation. Metab Brain Dis 30:281-98
Ball, Kelly K; Cruz, Nancy F; Mrak, Robert E et al. (2010) Trafficking of glucose, lactate, and amyloid-beta from the inferior colliculus through perivascular routes. J Cereb Blood Flow Metab 30:162-76
Gandhi, Gautam K; Ball, Kelly K; Cruz, Nancy F et al. (2010) Hyperglycaemia and diabetes impair gap junctional communication among astrocytes. ASN Neuro 2:e00030
Gandhi, Gautam K; Cruz, Nancy F; Ball, Kelly K et al. (2009) Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem 111:522-36
Gandhi, Gautam K; Cruz, Nancy F; Ball, Kelly K et al. (2009) Selective astrocytic gap junctional trafficking of molecules involved in the glycolytic pathway: impact on cellular brain imaging. J Neurochem 110:857-69
Dienel, Gerald A; Cruz, Nancy F (2009) Exchange-mediated dilution of brain lactate specific activity: implications for the origin of glutamate dilution and the contributions of glutamine dilution and other pathways. J Neurochem 109 Suppl 1:30-7
Dienel, Gerald A; Cruz, Nancy F (2008) Imaging brain activation: simple pictures of complex biology. Ann N Y Acad Sci 1147:139-70
Cruz, Nancy F; Ball, Kelly K; Dienel, Gerald A (2007) Functional imaging of focal brain activation in conscious rats: impact of [(14)C]glucose metabolite spreading and release. J Neurosci Res 85:3254-66
Hertz, Leif; Peng, Liang; Dienel, Gerald A (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219-49
Dienel, Gerald A; Schmidt, Kathleen C; Cruz, Nancy F (2007) Astrocyte activation in vivo during graded photic stimulation. J Neurochem 103:1506-22

Showing the most recent 10 out of 27 publications