Neural Activity Triggers Neuronal Oxidative Metabolism Followed by Astrocytic Glycolysis

We have found that two-photon fluorescence imaging of nicotinamide adenine dinucleotide (NADH) provides the sensitivity and spatial three-dimensional resolution to resolve metabolic signatures in processes of astrocytes and neurons deep in highly scattering brain tissue slices. This functional imaging reveals spatiotemporal partitioning of glycolytic and oxidative metabolism between astrocytes and neurons during focal neural activity that establishes a unifying hypothesis for neurometabolic coupling in which early oxidative metabolism in neurons is eventually sustained by late activation of the astrocyte-neuron lactate shuttle. Our model integrates existing views of brain energy metabolism and is in accord with known macroscopic physiological changes in vivo.

[1]  B CHANCE,et al.  Respiratory enzymes in oxidative phosphorylation. III. The steady state. , 1955, The Journal of biological chemistry.

[2]  B CHANCE,et al.  Respiratory enzymes in oxidative phosphorylation. VII. Binding of intramitochondrial reduced pyridine nucleotide. , 1958, The Journal of biological chemistry.

[3]  J. Williamson,et al.  Glycolytic control mechanisms. V. Kinetics of high energy phosphate intermediate changes during electrical discharge and recovery in the main organ of Electrophorus electricus. , 1967, The Journal of biological chemistry.

[4]  F. Jöbsis,et al.  Intracellular redox changes in functioning cerebral cortex. I. Metabolic effects of epileptiform activity. , 1971, Journal of neurophysiology.

[5]  P. Lipton,et al.  Effects of membrane depolarization on nicotinamide nucleotide fluorescence in brain slices. , 1973, The Biochemical journal.

[6]  D K Merrill,et al.  ELECTROCONVULSIVE SEIZURE: AN INVESTIGATION INTO THE VALIDITY OF CALCULATING THE CYTOPLASMIC FREE [NAD+]/[NADH] [H+] RATIO FROM SUBSTRATE CONCENTRATIONS OF BRAIN , 1976, Journal of neurochemistry.

[7]  R. Guynn,et al.  The calculation of the cytoplasmic free [NADP+]/[NADPH] ratio in brain: Effect of electroconvulsive seizure , 1981, Brain Research.

[8]  M. Mintun,et al.  Nonoxidative glucose consumption during focal physiologic neural activity. , 1988, Science.

[9]  M. Wong-Riley Cytochrome oxidase: an endogenous metabolic marker for neuronal activity , 1989, Trends in Neurosciences.

[10]  W. Denk,et al.  Two-photon laser scanning fluorescence microscopy. , 1990, Science.

[11]  R. Shulman,et al.  Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Magistretti,et al.  Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Adams,et al.  High-performance liquid chromatography analysis of oxidized and reduced pyridine dinucleotides in specific brain regions. , 1995, Analytical biochemistry.

[14]  F. Hyder,et al.  Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H[13C]NMR. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Grinvald,et al.  Interactions Between Electrical Activity and Cortical Microcirculation Revealed by Imaging Spectroscopy: Implications for Functional Brain Mapping , 1996, Science.

[16]  D. Piston,et al.  Quantitative Subcellular Imaging of Glucose Metabolism within Intact Pancreatic Islets (*) , 1996, The Journal of Biological Chemistry.

[17]  D. Bers,et al.  Increased work in cardiac trabeculae causes decreased mitochondrial NADH fluorescence followed by slow recovery. , 1996, Biophysical journal.

[18]  G. S. Wilson,et al.  A Temporary Local Energy Pool Coupled to Neuronal Activity: Fluctuations of Extracellular Lactate Levels in Rat Brain Monitored with Rapid‐Response Enzyme‐Based Sensor , 1997, Journal of neurochemistry.

[19]  R. Shulman,et al.  Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R G Shulman,et al.  In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[21]  R. S. Payne,et al.  An Increase in Lactate Output by Brain Tissue Serves to Meet the Energy Needs of Glutamate-Activated Neurons , 1999, The Journal of Neuroscience.

[22]  G. Patterson,et al.  Separation of the glucose-stimulated cytoplasmic and mitochondrial NAD(P)H responses in pancreatic islet beta cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Peter Lipton,et al.  Do active cerebral neurons really use lactate rather than glucose? , 2001, Trends in Neurosciences.

[24]  A. Villringer,et al.  No Evidence for Early Decrease in Blood Oxygenation in Rat Whisker Cortex in Response to Functional Activation , 2001, NeuroImage.

[25]  M. Bianciardi,et al.  The aerobic brain: lactate decrease at the onset of neural activity , 2003, Neuroscience.

[26]  Pierre J Magistretti,et al.  Food for Thought: Challenging the Dogmas , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[27]  R. Freeman,et al.  Single-Neuron Activity and Tissue Oxygenation in the Cerebral Cortex , 2003, Science.

[28]  E. Welker,et al.  Glial Glutamate Transporters Mediate a Functional Metabolic Crosstalk between Neurons and Astrocytes in the Mouse Developing Cortex , 2003, Neuron.

[29]  J. Connor,et al.  NAD(P)H Fluorescence Imaging of Postsynaptic Neuronal Activation in Murine Hippocampal Slices , 2003, The Journal of Neuroscience.