Astrocyte activation in vivo during graded photic stimulation

Astrocytes have important roles in control of extracellular environment, de novo synthesis of neurotransmitters, and regulation of neurotransmission and blood flow. All of these functions require energy, suggesting that astrocytic metabolism should rise and fall with changes in neuronal activity and that brain imaging can be used to visualize and quantify astrocytic activation in vivo. A unilateral photic stimulation paradigm was used to test the hypothesis that graded sensory stimuli cause progressive increases in the uptake coefficient of [2‐14C]acetate, a substrate preferentially oxidized by astrocytes. The acetate uptake coefficient fell in deafferented visual structures and it rose in intact tissue during photic stimulation of conscious rats; the increase was highest in structures with monosynaptic input from the eye and was much smaller in magnitude than the change in glucose utilization (CMRglc) by all cells. The acetate uptake coefficient was not proportional to stimulus rate and did not correlate with CMRglc in resting or activated structures. Simulation studies support the conclusions that acetate uptake coefficients represent mainly metabolism and respond to changes in metabolism rate, with a lower response at high rates. A model portraying regulation of acetate oxidation illustrates complex relationships among functional activation, cation levels, and astrocytic metabolism.

[1]  Liang Peng,et al.  Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  W. Nicklas,et al.  COMPARTMENTATION OF CITRIC ACID CYCLE METABOLISM IN BRAIN: EFFECT OF AMINOOXYACETIC ACID, OUABAIN AND Ca2+ ON THE LABELLING OF GLUTAMATE, GLUTAMINE, ASPARTATE AND GABA BY [1‐14C]ACETATE, [U‐14C]GLUTAMATE AND [U‐14C] ASPARTATE 1 , 1970, Journal of neurochemistry.

[3]  A. Nehlig,et al.  Selective Uptake of [14C]2-Deoxyglucose by Neurons and Astrocytes: High-Resolution Microautoradiographic Imaging by Cellular 14C-Trajectography Combined with Immunohistochemistry , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  Webster Lt Studies of the acetyl coenzyme A synthetase reaction. II. Crystalline acetyl coenzyme A synthetase. , 1965 .

[5]  T. Takano,et al.  Astrocyte-mediated control of cerebral blood flow , 2006, Nature Neuroscience.

[6]  Effects of physostigmine on local cerebral glucose utilization in the central components of the rat visual system , 1993, Neuroscience Letters.

[7]  G. Dienel,et al.  Astrocyte activation in working brain: Energy supplied by minor substrates , 2006, Neurochemistry International.

[8]  L. T. Webster Studies of the acetyl coenzyme A synthetase reaction. V. The requirement for monovalent and divalent cations in partial reactions involving enzyme-bound acetyl adenylate. , 1967, The Journal of biological chemistry.

[9]  Webster Lt STUDIES OF THE ACETYL COENZYME A SYNTHETASE REACTION. I. ISOLATION AND CHARACTERIZATION OF ENZYME-BOUND ACETYL ADENYLATE. , 1963 .

[10]  B. Driscoll,et al.  Carbon Dioxide Fixation in Neuronal and Astroglial Cells in Culture , 1992, Journal of neurochemistry.

[11]  P J Magistretti,et al.  K+ at concentrations reached in the extracellular space during neuronal activity promotes a Ca2+-dependent glycogen hydrolysis in mouse cerebral cortex , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  G. Dienel,et al.  Distribution of mitochondrial enzymes between the perikaryal and synaptic fractions of immature and adult rat brain. , 1977, Biochimica et biophysica acta.

[13]  C. Crone,et al.  THE PERMEABILITY OF CAPILLARIES IN VARIOUS ORGANS AS DETERMINED BY USE OF THE 'INDICATOR DIFFUSION' METHOD. , 1963, Acta physiologica Scandinavica.

[14]  S. Berl,et al.  The turnover of glutamate, glutamine, aspartate and GABA labeled with [1-14C]acetate in caudate nucleus, thalamus and motor cortex (cat). , 1969, Brain research.

[15]  G. Tyce,et al.  Metabolism of Acetate to Amino Acids in Brains of Rats After Complete Hepatectomy , 1981, Journal of neurochemistry.

[16]  E. Walum,et al.  Sodium‐dependent glutamate uptake as an activator of oxidative metabolism in primary astrocyte cultures from newborn rat , 1995, Glia.

[17]  D. Muir,et al.  Acetate and fluoroacetate as possible markers for glial metabolism in vivo , 1986, Brain Research.

[18]  M. Grégoire,et al.  Glycolysis versus TCA Cycle in the Primate Brain as Measured by Combining 18F-FDG PET and 13C-NMR , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[19]  I. Kapetanovic,et al.  Time‐Related Loss of Glutamine from Hippocampal Slices and Concomitant Changes in Neurotransmitter Amino Acids , 1993, Journal of neurochemistry.

[20]  J. Goldstein,et al.  Molecular Characterization of Human Acetyl-CoA Synthetase, an Enzyme Regulated by Sterol Regulatory Element-binding Proteins* , 2000, The Journal of Biological Chemistry.

[21]  L. T. Webster Studies of the acetyl coenzyme A synthetase reaction. IV. The requirement for monovalent cations. , 1966, The Journal of biological chemistry.

[22]  G. Dienel,et al.  Preferential labeling of glial and meningial brain tumors with [2-(14)C]acetate. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  H. R. Zielke,et al.  Exogenous Glutamate Concentration Regulates the Metabolic Fate of Glutamate in Astrocytes , 1996, Journal of neurochemistry.

[24]  Richard G. W. Anderson,et al.  Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: Implications for the Cori cycle , 1994, Cell.

[25]  R. Gruetter,et al.  Neuroglial Metabolism in the Awake Rat Brain: CO2 Fixation Increases with Brain Activity , 2004, The Journal of Neuroscience.

[26]  A. Schousboe,et al.  Pyruvate Carboxylase Activity in Primary Cultures of Astrocytes and Neurons , 1983, Journal of neurochemistry.

[27]  A. Halestrap,et al.  Transport of lactate and other monocarboxylates across mammalian plasma membranes. , 1993, The American journal of physiology.

[28]  J. E. Cremer Studies on brain-cortex slices. The influence of various inhibitors on the retention of potassium ions and amino acids with glucose or pyruvate as substrate. , 1967, The Biochemical journal.

[29]  H. Bielarczyk,et al.  Effects of Aluminum and Calcium on Acetyl‐CoA Metabolism in Rat Brain Mitochondria , 1998, Journal of neurochemistry.

[30]  P. Marquet,et al.  A quantitative analysis of l‐glutamate‐regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics , 2000, The European journal of neuroscience.

[31]  K. Morikawa,et al.  Kinetic properties and structural characterization of highly purified acetyl-CoA synthetase from bovine heart and tissue distribution of the enzyme in rat tissues. , 1995, The Tohoku journal of experimental medicine.

[32]  G. Dienel,et al.  Nutrition during brain activation: does cell-to-cell lactate shuttling contribute significantly to sweet and sour food for thought? , 2004, Neurochemistry International.

[33]  W. Nicklas,et al.  Tricarboxylic acid-cycle metabolism in brain. Effect of fluoroacetate and fluorocitrate on the labelling of glutamate aspartate, glutamine and γ-amino butyrate , 1970 .

[34]  R. Veech,et al.  Direct enzymic determination of acetate in tissue extracts in the presence of labile acetate esters. , 1974, Analytical biochemistry.

[35]  R. Ackermann,et al.  Evaluation of radiolabeled acetate and fluoroacetate as potential tracers of cerebral oxidative metabolism , 1990, Metabolic Brain Disease.

[36]  M. J. Ernsting,et al.  THE EFFECT OF PSYCHOTROPIC DRUGS ON γ‐AMINOBUTYRIC ACID AND GLUTAMIC ACID IN BRAIN TISSUE , 1960 .

[37]  F. Fonnum,et al.  Trafficking of Amino Acids between Neurons and Glia In Vivo. Effects of Inhibition of Glial Metabolism by Fluoroacetate , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[38]  R. A. Waniewski,et al.  Preferential Utilization of Acetate by Astrocytes Is Attributable to Transport , 1998, The Journal of Neuroscience.

[39]  F J Ballard,et al.  Production and utilization of acetate in mammals. , 1974, The Biochemical journal.

[40]  G. Dienel,et al.  A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover , 2007, Journal of neurochemistry.

[41]  H Ronald Zielke,et al.  Activation of astrocytes in brain of conscious rats during acoustic stimulation: acetate utilization in working brain , 2005, Journal of neurochemistry.

[42]  O. H. Lowry,et al.  Distribution in brain and retina of four enzymes of acetyl CoA synthesis in relation to choline acetyl transferase and acetylcholine esterase , 1991, Neurochemical Research.

[43]  J. E. Cremer AMINO ACID METABOLISM IN RAT BRAIN STUDIED WITH 14C‐LABELLED GLUCOSE , 1964, Journal of neurochemistry.

[44]  Albert Gjedde,et al.  Neuronal–Glial Glucose Oxidation and Glutamatergic–GABAergic Function , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[45]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[46]  D. Williamson,et al.  Origins of blood acetate in the rat. , 1977, Biochemical Journal.

[47]  C. J. Berg,et al.  THE INCORPORATION OF DOUBLE‐LABELLED ACETATE INTO GLUTAMATE AND RELATED AMINO ACIDS FROM ADULT MOUSE BRAIN: COMPARTMENTATION OF AMINO ACID METABOLISM IN BRAIN , 1976, Journal of neurochemistry.

[48]  J. Meldolesi,et al.  Astrocytes, from brain glue to communication elements: the revolution continues , 2005, Nature Reviews Neuroscience.

[49]  R. Gebhardt,et al.  Glycogen in astrocytes: possible function as lactate supply for neighboring cells , 1993, Brain Research.

[50]  S. Berl,et al.  Metabolic compartmentation and neurotransmission : relation to brain structure and function , 1975 .

[51]  G. Dienel,et al.  Functional imaging of focal brain activation in conscious rats: Impact of [14C]glucose metabolite spreading and release , 2007, Journal of neuroscience research.

[52]  B. Künnecke,et al.  Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. , 1990, The Journal of biological chemistry.

[53]  J. Hatazawa,et al.  Effect of Astrocytic Energy Metabolism Depressant on 14C-Acetate Uptake in Intact Rat Brain , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[54]  F. Opperdoes,et al.  Pyruvate transport across the plasma membrane of the bloodstream form of Trypanosoma brucei is mediated by a facilitated diffusion carrier. , 1992, Biochemical and biophysical research communications.

[55]  R. Shank,et al.  Pyruvate car☐ylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools , 1985, Brain Research.

[56]  J. E. Cremer,et al.  Selective inhibition of glucose oxidation by triethyltin in rat brain in vivo. , 1970, The Biochemical journal.

[57]  W. Walz Role of astrocytes in the clearance of excess extracellular potassium , 2000, Neurochemistry International.

[58]  K. Morikawa,et al.  Acetyl-CoA Synthetase 2, a Mitochondrial Matrix Enzyme Involved in the Oxidation of Acetate* , 2001, The Journal of Biological Chemistry.

[59]  Joseph C. LaManna,et al.  Regional blood-brain lactate influx , 1993, Brain Research.

[60]  R. C. Collins,et al.  Cerebral Glucose Utilization: Comparison of [14C]Deoxyglucose and [6‐14C]Glucose Quantitative Autoradiography , 1987, Journal of neurochemistry.

[61]  R. Haller,et al.  Energy Contribution of Octanoate to Intact Rat Brain Metabolism Measured by 13C Nuclear Magnetic Resonance Spectroscopy , 2003, The Journal of Neuroscience.

[62]  Mads K Dalsgaard,et al.  Fuelling Cerebral Activity in Exercising Man , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[63]  H. Bachelard,et al.  Cerebral metabolism of acetate and glucose studied by 13C-n.m.r. spectroscopy. A technique for investigating metabolic compartmentation in the brain. , 1990, The Biochemical journal.

[64]  M. Duchen,et al.  Energy metabolism of adult astrocytes in vitro , 1996, Neuroscience.

[65]  L. Sokoloff,et al.  Retina-dependent activation by apomorphine of metabolic activity in the superficial layer of the superior colliculus. , 1980, Science.

[66]  W H Oldendorf,et al.  Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. , 1973, The American journal of physiology.

[67]  A W Toga,et al.  Metabolic response of optic centers to visual stimuli in the albino rat: Anatomical and physiological considerations , 1981, The Journal of comparative neurology.

[68]  V. Grill,et al.  Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance. , 1992, Metabolism: clinical and experimental.

[69]  E. Newman New roles for astrocytes: Regulation of synaptic transmission , 2003, Trends in Neurosciences.

[70]  M. Minchin,et al.  Compartmentation of amino acid metabolism in the rat dorsal root ganglion; a metabolic and autoradiographic study , 1975, Brain Research.

[71]  H. Waelsch,et al.  Compartmentation of glutamate metabolism in brain. Evidence for the existence of two different tricarboxylic acid cycles in brain. , 1969, The Biochemical journal.

[72]  G. Dienel,et al.  Effect of reactive cell density on net [2- 14 C ]acetate uptake into rat brain: labeling of clusters containing GFAP+- and lectin+-immunoreactive cells , 2003, Neurochemistry International.

[73]  G. Dienel,et al.  Astrocytic connexin distributions and rapid, extensive dye transfer via gap junctions in the inferior colliculus: Implications for [14C]glucose metabolite trafficking , 2007, Journal of neuroscience research.

[74]  K. Petersen,et al.  Astroglial Contribution to Brain Energy Metabolism in Humans Revealed by 13C Nuclear Magnetic Resonance Spectroscopy: Elucidation of the Dominant Pathway for Neurotransmitter Glutamate Repletion and Measurement of Astrocytic Oxidative Metabolism , 2002, The Journal of Neuroscience.

[75]  A. Crane,et al.  Analysis of Time Courses of Metabolic Precursors and Products in Heterogeneous Rat Brain Tissue: Limitations of Kinetic Modeling for Predictions of Intracompartmental Concentrations from Total Tissue Activity , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[76]  Leif Hertz,et al.  Astrocytic control of glutamatergic activity: astrocytes as stars of the show , 2004, Trends in Neurosciences.

[77]  L. Sokoloff,et al.  Journal of Cerebral Blood Flow and Metabolism , 2012 .

[78]  W. Nicklas,et al.  COMPARTMENTATION OF CITRIC ACID CYCLE METABOLISM IN BRAIN: LABELLING OF GLUTAMATE, GLUTAMINE, ASPARTATE AND GABA BY SEVERAL RADIOACTIVE TRACER METABOLITES 1 , 1970, Journal of neurochemistry.

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

[80]  S. Berl,et al.  Effects of LI + on the metabolism in brain of glutamate, glutamine, aspartate and GABA from (1- 14 C)acetate in vitro. , 1972, Brain research.

[81]  J. Lai,et al.  Brain metabolism and specific transport at the blood- brain barrier after portocaval anastomosis in the rat , 1979, Brain Research.

[82]  J. H. Quastel,et al.  Transport and metabolism of acetate in rat brain cortex in vitro. , 1966, The Biochemical journal.

[83]  S. Berl,et al.  Metabolic Compartmentation and Neurotransmission , 1975, Springer US.

[84]  L. Hertz,et al.  Effects of barbiturates on energy metabolism by cultured astrocytes and neurons in the presence of normal and elevated concentrations of potassium , 1986, Neuropharmacology.

[85]  C. Juel Symmetry and pH dependency of the lactate/proton carrier in skeletal muscle studied with rat sarcolemmal giant vesicles. , 1996, Biochimica et biophysica acta.

[86]  G. Dienel,et al.  Local uptake of 14C‐labeled acetate and butyrate in rat brain in vivo during spreading cortical depression , 2001, Journal of neuroscience research.

[87]  P M Daniel,et al.  The transport of glucose into the brain of the rat in vivo , 1973, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[88]  G. Dienel,et al.  Behavioral training increases local astrocytic metabolic activity but does not alter outcome of mild transient ischemia , 2003, Brain Research.