Rapid fluctuations in extracellular brain glucose levels induced by natural arousing stimuli and intravenous cocaine: fueling the brain during neural activation.

Glucose, a primary energetic substrate for neural activity, is continuously influenced by two opposing forces that tend to either decrease its extracellular levels due to enhanced utilization in neural cells or increase its levels due to entry from peripheral circulation via enhanced cerebral blood flow. How this balance is maintained under physiological conditions and changed during neural activation remains unclear. To clarify this issue, enzyme-based glucose sensors coupled with high-speed amperometry were used in freely moving rats to evaluate fluctuations in extracellular glucose levels induced by brief audio stimulus, tail pinch (TP), social interaction with another rat (SI), and intravenous cocaine (1 mg/kg). Measurements were performed in nucleus accumbens (NAcc) and substantia nigra pars reticulata (SNr), which drastically differ in neuronal activity. In NAcc, where most cells are powerfully excited after salient stimulation, glucose levels rapidly (latency 2-6 s) increased (30-70 μM or 6-14% over baseline) by all stimuli; the increase differed in magnitude and duration for each stimulus. In SNr, where most cells are transiently inhibited by salient stimuli, TP, SI, and cocaine induced a biphasic glucose response, with the initial decrease (-20-40 μM or 5-10% below baseline) followed by a reboundlike increase. The critical role of neuronal activity in mediating the initial glucose response was confirmed by monitoring glucose currents after local microinjections of glutamate (GLU) or procaine (PRO). While intra-NAcc injection of GLU transiently increased glucose levels in this structure, intra-SNr PRO injection resulted in rapid, transient decreases in SNr glucose. Therefore, extracellular glucose levels in the brain change very rapidly after physiological and pharmacological stimulation, the response is structure specific, and the pattern of neuronal activity appears to be a critical factor determining direction and magnitude of physiological fluctuations in glucose levels.

[1]  B. Siesjö,et al.  Brain energy metabolism , 1978 .

[2]  L. Fellows,et al.  Physiological Stimulation Increases Nonoxidative Glucose Metabolism in the Brain of the Freely Moving Rat , 1993, Journal of neurochemistry.

[3]  R. Wise,et al.  Brain temperature fluctuation: a reflection of functional neural activation , 2002, The European journal of neuroscience.

[4]  W. Schultz.  Activity of pars reticulata neurons of monkey substantia nigra in relation to motor, sensory, and complex events. , 1986, Journal of neurophysiology.

[5]  Yu Ohmura,et al.  Regulation of cerebral blood flow in the hippocampus by neuronal activation through the perforant path: Relationship between hippocampal blood flow and neuronal plasticity , 2011, Brain Research.

[6]  R. Lund,et al.  Light induced EEG desynchronization and behavioral arousal in rats with restored retinocollicular projection by peripheral nerve graft , 1996, Neuroscience Letters.

[7]  P. E. Gold,et al.  Fluctuations in Brain Glucose Concentration during Behavioral Testing: Dissociations between Brain Areas and between Brain and Blood , 2001, Neurobiology of Learning and Memory.

[8]  E. Abercrombie,et al.  Differential Effect of Stress on In Vivo Dopamine Release in Striatum, Nucleus Accumbens, and Medial Frontal Cortex , 1989, Journal of neurochemistry.

[9]  M. Fillenz,et al.  The relation between local cerebral blood flow and extracellular glucose concentration in rat striatum , 1998, Experimental physiology.

[10]  A. Dale,et al.  Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal , 2010, Proceedings of the National Academy of Sciences.

[11]  M. Fillenz,et al.  Evidence for uncoupling of oxygen and glucose utilization during neuronal activation in rat striatum. , 1997, The Journal of physiology.

[12]  R. Wightman,et al.  Dopamine release is heterogeneous within microenvironments of the rat nucleus accumbens , 2007, The European journal of neuroscience.

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

[14]  G. Rebec,et al.  Dopamine‐independent action of cocaine on striatal and accumbal neurons , 2000, The European journal of neuroscience.

[15]  P. E. Gold,et al.  Increases in extracellular fluid glucose levels in the rat hippocampus following an anesthetic dose of pentobarbital or ketamine–xylazine: an in vivo microdialysis study , 2005, Physiology & Behavior.

[16]  B. Ances,et al.  Coupling of Changes in Cerebral Blood Flow with Neural Activity: What Must Initially Dip Must Come Back Up , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[17]  E. Kiyatkin,et al.  Brain temperature change and movement activation induced by intravenous cocaine delivered at various injection speeds in rats , 2005, Psychopharmacology.

[18]  L. Sokoloff.  The brain as a chemical machine. , 1992, Progress in brain research.

[19]  G. Rebec,et al.  Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats. , 1996, Journal of neurophysiology.

[20]  A P Georgopoulos,et al.  Role of basal ganglia in limb movements. , 1984, Human neurobiology.

[21]  G. Rebec.  Dopamine, glutamate, and behavioral correlates of striatal neuronal activity. , 1998, Advances in pharmacology.

[22]  S. T. Kitai,et al.  Electrophysiological and immunocytochemical characterization of GABA and dopamine neurons in the substantia nigra of the rat , 1997, Neuroscience.

[23]  G. S. Wilson,et al.  Rapid Changes in Local Extracellular Rat Brain Glucose Observed with an In Vivo Glucose Sensor , 1997, Journal of neurochemistry.

[24]  M. Fillenz,et al.  Extracellular Brain Glucose Levels Reflect Local Neuronal Activity: A Microdialysis Study in Awake, Freely Moving Rats , 1992, Journal of neurochemistry.

[25]  Egill Rostrup,et al.  Cerebral Blood Flow Response to Functional Activation , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  M. Raichle,et al.  The Effects of Changes in PaCO2 Cerebral Blood Volume, Blood Flow, and Vascular Mean Transit Time , 1974, Stroke.

[27]  L. Fellows,et al.  Rapid changes in extracellular glucose levels and blood flow in the striatum of the freely moving rat , 1993, Brain Research.

[28]  J. Schneider.  Responses of striatal neurons to peripheral sensory stimulation in symptomatic MPTP-exposed cats , 1991, Brain Research.

[29]  A. Gratton,et al.  Electrochemical monitoring of extracellular dopamine in nucleus accumbens of rats lever-pressing for food , 1994, Brain Research.

[30]  M. Raichle,et al.  Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Charpier,et al.  The pars reticulata of the substantia nigra: a window to basal ganglia output. , 2007, Progress in brain research.

[32]  R. Wightman,et al.  Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens , 2012, Journal of neurochemistry.

[33]  K. T. Wakabayashi,et al.  Rapid changes in extracellular glutamate induced by natural arousing stimuli and intravenous cocaine in the nucleus accumbens shell and core. , 2012, Journal of neurophysiology.

[34]  Joseph Wang,et al.  Electrochemical Glucose Biosensors , 2008 .

[35]  D. Spencer,et al.  Striking Differences in Glucose and Lactate Levels between Brain Extracellular Fluid and Plasma in Conscious Human Subjects: Effects of Hyperglycemia and Hypoglycemia , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  E. Kiyatkin,et al.  Dopamine‐dependent and dopamine‐independent actions of cocaine as revealed by brain thermorecording in freely moving rats , 2005, The European journal of neuroscience.

[37]  R. Duelli,et al.  Brain glucose transporters: relationship to local energy demand. , 2001, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[38]  J. Mayhew,et al.  A Model of the Dynamic Relationship between Blood Flow and Volume Changes during Brain Activation , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[39]  N. Jaffrezic‐Renault,et al.  In vivo brain glucose measurements: differential normal pulse voltammetry with enzyme-modified carbon fiber microelectrodes. , 1996, Analytical chemistry.

[40]  L. Felipe Barros,et al.  Why glucose transport in the brain matters for PET , 2005, Trends in Neurosciences.

[41]  P. Wand,et al.  Sensory‐motor processing in substantia nigra pars reticulata in conscious cats. , 1984, The Journal of physiology.

[42]  C. Anthony Hunt,et al.  Glucose transport to the brain: A systems model , 2005, Brain Research Reviews.

[43]  E. Kiyatkin,et al.  Rapid EEG desynchronization and EMG activation induced by intravenous cocaine in freely moving rats: a peripheral, nondopamine neural triggering. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[44]  G. Rebec,et al.  Modulation of striatal neuronal activity by glutamate and GABA: iontophoresis in awake, unrestrained rats , 1999, Brain Research.

[45]  Paul E. Gold,et al.  Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing , 2011, PloS one.

[46]  E. Kiyatkin,et al.  Brain temperature homeostasis: physiological fluctuations and pathological shifts. , 2010, Frontiers in bioscience.

[47]  P. Cagnoni,et al.  Modification of the pharmacokinetics of high-dose cyclophosphamide and cisplatin by antiemetics , 1999, Bone Marrow Transplantation.

[48]  David A. Boas,et al.  Simultaneous recording of task-induced changes in blood oxygenation, volume, and flow using diffuse optical imaging and arterial spin-labeling MRI , 2005, NeuroImage.

[49]  E. Reilly,et al.  Urethane modification of EEG-like activity and acoustically evoked field potentials recorded from deep nuclei. , 1976, Applied neurophysiology.

[50]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[51]  Anders M. Dale,et al.  Cognitive “ Overshoot ” of O 2 Is Required to Maintain Baseline Tissue Oxygenation at Locations Distal to Blood Vessels , 2011 .

[52]  M. Fillenz,et al.  Continuous Monitoring of Extracellular Glucose Concentrations in the Striatum of Freely Moving Rats with an Implanted Glucose Biosensor , 1998, Journal of neurochemistry.

[53]  Linda M Arseneau,et al.  Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. , 2003, Diabetes.

[54]  E. Kiyatkin,et al.  GABA, Not Glutamate, Controls the Activity of Substantia Nigra Reticulata Neurons in Awake, Unrestrained Rats , 2004, The Journal of Neuroscience.

[55]  J. Walters,et al.  Dopamine modulation of the effects of gamma-aminobutyric acid on substantia nigra pars reticulata neurons. , 1983, Science.

[56]  I. Silver,et al.  Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[57]  Afonso C. Silva,et al.  Spatiotemporal Evolution of the Functional Magnetic Resonance Imaging Response to Ultrashort Stimuli , 2011, The Journal of Neuroscience.

[58]  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.

[59]  T. Becker,et al.  Relationship among Brain and Blood Glucose Levels and Spontaneous and Glucoprivic Feeding , 2009, The Journal of Neuroscience.

[60]  E. Kiyatkin,et al.  I.v. cocaine induces rapid, transient excitation of striatal neurons via its action on peripheral neural elements: Single-cell, iontophoretic study in awake and anesthetized rats , 2007, Neuroscience.

[61]  John E. W. Mayhew,et al.  Investigating neural–hemodynamic coupling and the hemodynamic response function in the awake rat , 2006, NeuroImage.

[62]  On-line, continuous measurement of extracellular striatal glucose using microdialysis sampling and electrochemical detection , 1997, Journal of Neuroscience Methods.