Non-signalling energy use in the developing rat brain

Energy use in the brain constrains its information processing power, but only about half the brain's energy consumption is directly related to information processing. Evidence for which non-signalling processes consume the rest of the brain's energy has been scarce. For the first time, we investigated the energy use of the brain's main non-signalling tasks with a single method. After blocking each non-signalling process, we measured oxygen level changes in juvenile rat brain slices with an oxygen-sensing microelectrode and calculated changes in oxygen consumption throughout the slice using a modified diffusion equation. We found that the turnover of the actin and microtubule cytoskeleton, followed by lipid synthesis, are significant energy drains, contributing 25%, 22% and 18%, respectively, to the rate of oxygen consumption. In contrast, protein synthesis is energetically inexpensive. We assess how these estimates of energy expenditure relate to brain energy use in vivo, and how they might differ in the mature brain.

[1]  D. Attwell,et al.  Neuroenergetics and the kinetic design of excitatory synapses , 2005, Nature Reviews Neuroscience.

[2]  P. Nair,et al.  Mass transfer, storage, and utilization of O2 in cat cerebral cortex. , 1970, The American journal of physiology.

[3]  S. Laughlin,et al.  Energy limitation as a selective pressure on the evolution of sensory systems , 2008, Journal of Experimental Biology.

[4]  J. Bamburg,et al.  Actin-ATP Hydrolysis Is a Major Energy Drain for Neurons , 2003, The Journal of Neuroscience.

[5]  M. Kirschner,et al.  Dynamic instability of microtubule growth , 1984, Nature.

[6]  R. Margolis.  Role of GTP hydrolysis in microtubule treadmilling and assembly. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Adelbert Ames,et al.  CNS energy metabolism as related to function , 2000, Brain Research Reviews.

[8]  Energy metabolism in the brain. , 2002, International review of neurobiology.

[9]  G. Porcellati,et al.  The synthesis in vivo of choline and ethanolamine phosphoglycerides in different brain areas during aging , 1982, Lipids.

[10]  P. Lennie.  The Cost of Cortical Computation , 2003, Current Biology.

[11]  G. Withers,et al.  Dendrites differ from axons in patterns of microtubule stability and polymerization during development , 2009, Neural Development.

[12]  M. Blue,et al.  The formation and maturation of synapses in the visual cortex of the rat. II. Quantitative analysis , 1983, Journal of neurocytology.

[13]  Terrence J Sejnowski,et al.  Communication in Neuronal Networks , 2003, Science.

[14]  Y. Hayashi,et al.  Visualization of F-actin and G-actin equilibrium using fluorescence resonance energy transfer (FRET) in cultured cells and neurons in slices , 2006, Nature Protocols.

[15]  H. Nakamura,et al.  Neural activity and the levels of high energy phosphates during deprivation of oxygen and/or glucose in hippocampal slices of immature and adult rats , 1995, International Journal of Developmental Neuroscience.

[16]  Markus Schuelke,et al.  Gamma oscillations in the hippocampus require high complex I gene expression and strong functional performance of mitochondria. , 2011, Brain : a journal of neurology.

[17]  A. Wegner,et al.  Head to tail polymerization of actin. , 1976, Journal of molecular biology.

[18]  J Astrup,et al.  Oxygen and glucose consumption related to Na+-K+ transport in canine brain. , 1981, Stroke.

[19]  B. Gustafsson,et al.  Spontaneous Unitary Synaptic Activity in CA1 Pyramidal Neurons during Early Postnatal Development: Constant Contribution of AMPA and NMDA Receptors , 2002, The Journal of Neuroscience.

[20]  S. Laughlin,et al.  An Energy Budget for Signaling in the Grey Matter of the Brain , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  S. Rapoport,et al.  Energy Consumption by Phospholipid Metabolism in Mammalian Brain , 2002, Neurochemical Research.

[22]  A. Rich,et al.  Actin accumulation in developing chick brain and other tissues. , 1976, Developmental biology.

[23]  S. Mccune,et al.  Inhibition of fatty acid synthesis in isolated adipocytes by 5-(tetradecyloxy)-2-furoic acid , 1984, Lipids.

[24]  U Valentin Nägerl,et al.  STED nanoscopy of actin dynamics in synapses deep inside living brain slices. , 2011, Biophysical journal.

[25]  R. Whittam,et al.  The metabolic response of brain slices to agents affecting the sodium pump , 1967, The Journal of physiology.

[26]  M. Cynader,et al.  Anisomycin activates p38 MAP kinase to induce LTD in mouse primary visual cortex , 2006, Brain Research.

[27]  N. Revsbech,et al.  An oxygen microsensor with a guard cathode , 1989 .

[28]  David Attwell,et al.  The Energetics of CNS White Matter , 2012, The Journal of Neuroscience.

[29]  A. Hall,et al.  Rho GTPases and the actin cytoskeleton. , 1998, Science.

[30]  John Q. Trojanowski,et al.  The disordered neuronal cytoskeleton in Alzheimer's disease , 1992, Current Biology.

[31]  Y. Goda,et al.  Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy , 2008, Nature Reviews Neuroscience.

[32]  C. Cooper.  Competitive, Reversible, Physiological? Inhibition of Mitochondrial Cytochrome Oxidase by Nitric Oxide , 2003, IUBMB life.

[33]  M. Carlier,et al.  Control of Actin Dynamics in Cell Motility , 2022 .

[34]  G. Borisy,et al.  Contribution of plus and minus end pathways to microtubule turnover. , 1999, Journal of cell science.

[35]  P. Penzes,et al.  Impaired regulation of synaptic actin cytoskeleton in Alzheimer's disease , 2011, Brain Research Reviews.

[36]  D. B. Tower.  Ouabain and the distribution of calcium and magnesium in cerebral tissues in vitro , 2004, Experimental Brain Research.

[37]  S. Roh,et al.  The Interface between Cytoskeletal Aberrations and Mitochondrial Dysfunction in Alzheimer's Disease and Related Disorders , 2011, Experimental neurobiology.

[38]  N Spruston,et al.  Resting and active properties of pyramidal neurons in subiculum and CA1 of rat hippocampus. , 2000, Journal of neurophysiology.

[39]  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.

[40]  K. Shibuki.  Calcium-dependent and ouabain-resistant oxygen consumption in the rat neurohypophysis , 1989, Brain Research.

[41]  T. A. Ryan,et al.  Activity-Driven Local ATP Synthesis Is Required for Synaptic Function , 2014, Cell.

[42]  Rita Zemankovics,et al.  Maintaining network activity in submerged hippocampal slices: importance of oxygen supply , 2009, The European journal of neuroscience.

[43]  R. Huganir,et al.  C75, a Fatty Acid Synthase Inhibitor, Modulates AMP-activated Protein Kinase to Alter Neuronal Energy Metabolism* , 2004, Journal of Biological Chemistry.

[44]  A. Holzinger.  Jasplakinolide: an actin-specific reagent that promotes actin polymerization. , 2009, Methods in molecular biology.

[45]  Yi Zhang,et al.  Noninvasive and Three-Dimensional Imaging of CMRO2 in Rats at 9.4 T: Reproducibility Test and Normothermia/Hypothermia Comparison Study , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[46]  Michael Hummel,et al.  Supplementary Figure 3 , 2010 .

[47]  M. Zilberter,et al.  Glycolysis and Oxidative Phosphorylation in Neurons and Astrocytes during Network Activity in Hippocampal Slices , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[48]  F. Dudek,et al.  Increased excitatory synaptic activity and local connectivity of hippocampal CA1 pyramidal cells in rats with kainate-induced epilepsy. , 2004, Journal of neurophysiology.

[49]  S. Rapoport,et al.  Energy requirements for two aspects of phospholipid metabolism in mammalian brain. , 1998, The Biochemical journal.

[50]  Peter Jonas,et al.  Patch-clamp recording from mossy fiber terminals in hippocampal slices , 2006, Nature Protocols.

[51]  T. Pollard,et al.  Cellular Motility Driven by Assembly and Disassembly of Actin Filaments , 2003, Cell.

[52]  Thomas D Pollard,et al.  Cellular Motility Driven by Assembly and Disassembly of Actin Filaments , 2003, Cell.

[53]  C. McPherson,et al.  Microglial M1/M2 polarization and metabolic states , 2016, British journal of pharmacology.

[54]  N. Dale,et al.  High‐resolution real‐time recording with microelectrode biosensors reveals novel aspects of adenosine release during hypoxia in rat hippocampal slices , 2003, Journal of neurochemistry.

[55]  J. Condeelis,et al.  Life at the leading edge: the formation of cell protrusions. , 1993, Annual review of cell biology.

[56]  T. Knöpfel,et al.  Involvement of Protein Synthesis and Degradation in Long-Term Potentiation of Schaffer Collateral CA1 Synapses , 2006, The Journal of Neuroscience.

[57]  Pierre J. Magistretti,et al.  Neuroenergetics Original Research Article Deciphering Neuron-glia Compartmentalization in Cortical Energy Metabolism , 2022 .

[58]  J. Trojanowski,et al.  The disordered neuronal cytoskeleton in Alzheimer's disease , 1992, Current Opinion in Neurobiology.

[59]  A. Zachowski,et al.  ATP-dependent aminophospholipid translocation in erythrocyte vesicles: stoichiometry of transport. , 1993, Biochemistry.

[60]  Shin Lin,et al.  Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change , 1981, Nature.

[61]  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.

[62]  J. Diamond,et al.  Effects of unstirred layers on membrane phenomena. , 1984, Physiological reviews.

[63]  H. Beck,et al.  Stable Mossy Fiber Long-Term Potentiation Requires Calcium Influx at the Granule Cell Soma, Protein Synthesis, and Microtubule-Dependent Axonal Transport , 2010, The Journal of Neuroscience.

[64]  Gary E. Gibson,et al.  Brain energetics, integration of molecular and cellular processes , 2007 .

[65]  Yuri Zilberter,et al.  Critical State of Energy Metabolism in Brain Slices: The Principal Role of Oxygen Delivery and Energy Substrates in Shaping Neuronal Activity , 2011, Front. Neuroenerg..

[66]  Venkatesh N. Murthy,et al.  Rapid turnover of actin in dendritic spines and its regulation by activity , 2002, Nature Neuroscience.

[67]  W. Gan,et al.  ATP mediates rapid microglial response to local brain injury in vivo , 2005, Nature Neuroscience.

[68]  P. Crews,et al.  Jasplakinolide Induces Apoptosis in Various Transformed Cell Lines by a Caspase-3-Like Protease-Dependent Pathway , 2000, Clinical Diagnostic Laboratory Immunology.

[69]  C. Walczak,et al.  Mitotic spindle assembly and chromosome segregation: refocusing on microtubule dynamics. , 2004, Molecular cell.

[70]  M. Webb,et al.  The hydrolysis of ATP that accompanies actin polymerization is essentially irreversible , 1988, FEBS letters.

[71]  D. Attwell,et al.  Assessing the physiological concentration and targets of nitric oxide in brain tissue , 2008, The Journal of physiology.

[72]  Hanzhang Lu,et al.  Noninvasive quantification of whole‐brain cerebral metabolic rate of oxygen (CMRO2) by MRI , 2009, Magnetic resonance in medicine.

[73]  P Wadsworth,et al.  Nanomolar concentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro. , 1997, Molecular biology of the cell.

[74]  G. Brown,et al.  Cellular energy utilization and molecular origin of standard metabolic rate in mammals. , 1997, Physiological reviews.

[75]  H. Holzhütter,et al.  Oxygen Consumption Rates during Three Different Neuronal Activity States in the Hippocampal CA3 Network , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[76]  Rosalina Fonseca.  Activity‐dependent actin dynamics are required for the maintenance of long‐term plasticity and for synaptic capture , 2012, The European journal of neuroscience.

[77]  David Attwell,et al.  Non-signalling energy use in the brain , 2015, The Journal of physiology.

[78]  P. Hrdina.  Basic Neurochemistry: Molecular, Cellular and Medical Aspects. , 1996 .

[79]  D. Zipes,et al.  Cytochalasin D as Excitation‐Contraction Uncoupler for Optically Mapping Action Potentials in Wedges of Ventricular Myocardium , 1998, Journal of cardiovascular electrophysiology.

[80]  I. Spector,et al.  Latrunculins--novel marine macrolides that disrupt microfilament organization and affect cell growth: I. Comparison with cytochalasin D. , 1989, Cell motility and the cytoskeleton.

[81]  M. Duchen,et al.  The regulation of neuronal mitochondrial metabolism by calcium , 2015, The Journal of physiology.

[82]  R. Yuste,et al.  Developmental regulation of spine motility in the mammalian central nervous system. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[83]  Compilation of Henry’s law constants , 2015 .

[84]  S. Kety,et al.  THE GENERAL METABOLISM OF THE BRAIN IN VIVO , 1957 .

[85]  J. Pickett-Heaps,et al.  Metabolic inhibitors and mitosis: II. Effects of dinitrophenol/deoxyglucose and nocodazole on the microtubule cytoskeleton , 1986, Protoplasma.

[86]  D. Bartels,et al.  Temperature Dependence of Oxygen Diffusion in H2O and D2O , 1996 .

[87]  D. Attwell,et al.  Synaptic Energy Use and Supply , 2012, Neuron.

[88]  David Attwell,et al.  Oxidative Phosphorylation, Not Glycolysis, Powers Presynaptic and Postsynaptic Mechanisms Underlying Brain Information Processing , 2012, The Journal of Neuroscience.