The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Douglas L. Rothman - One of the best experts on this subject based on the ideXlab platform.
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Development of a Model to Test Whether Glycogenolysis Can Support Astrocytic Energy Demands of Na+, K+-ATPase and Glutamate-Glutamine Cycling, Sparing an Equivalent Amount of Glucose for Neurons
Advances in neurobiology, 2019Co-Authors: Douglas L. Rothman, Gerald A. DienelAbstract:Recent studies of glycogen in brain have suggested a much more important role in brain energy metabolism and function than previously recognized, including findings of much higher than previously recognized concentrations, consumption at substantial rates compared with utilization of blood-borne glucose, and involvement in ion pumping and in neurotransmission and memory. However, it remains unclear how glycogenolysis is coupled to neuronal activity and provides support for neuronal as well as astroglial function. At present, quantitative aspects of glycogenolysis in brain functions are very difficult to assess due to its metabolic lability, heterogeneous distributions within and among cells, and extreme sensitivity to physiological stimuli. To begin to address this problem, the present study develops a model based on pathway fluxes, mass balance, and literature relevant to functions and turnover of pathways that intersect with glycogen mobilization. A series of equations is developed to describe the stoichiometric relationships between net glycogen consumption that is predominantly in astrocytes with the rate of the Glutamate-Glutamine Cycle, rates of astrocytic and neuronal glycolytic and oxidative metabolism, and the energetics of sodium/potassium pumping in astrocytes and neurons during brain activation. Literature supporting the assumptions of the model is discussed in detail. The overall conclusion is that astrocyte glycogen metabolism is primarily coupled to neuronal function via fueling glycolytically pumping of Na+ and K+ and sparing glucose for neuronal oxidation, as opposed to previous proposals of coupling neurotransmission via glutamate transport, lactate shuttling, and neuronal oxidation of lactate.
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Is there In Vivo Evidence for Amino Acid Shuttles Carrying Ammonia from Neurons to Astrocytes
Neurochemical Research, 2012Co-Authors: Douglas L. Rothman, Paul K Maciejewski, Henk M. De Feyter, Kevin L. BeharAbstract:The high in vivo flux of the glutamate/glutamine Cycle puts a strong demand on the return of ammonia released by phosphate activated glutaminase from the neurons to the astrocytes in order to maintain nitrogen balance. In this paper we review several amino acid shuttles that have been proposed for balancing the nitrogen flows between neurons and astrocytes in the glutamate/glutamine Cycle. All of these Cycles depend on the directionality of glutamate dehydrogenase, catalyzing reductive glutamate synthesis (forward reaction) in the neuron in order to capture the ammonia released by phosphate activated glutaminase, while catalyzing oxidative deamination of glutamate (reverse reaction) in the astrocytes to release ammonia for glutamine synthesis. Reanalysis of results from in vivo experiments using 13N and 15N labeled ammonia and 15N leucine in rats suggests that the maximum flux of the alanine/lactate or branched chain amino acid/branched chain amino acid transaminase shuttles between neurons and astrocytes are approximately 3–5 times lower than would be required to account for the ammonia transfer from neurons to astrocytes needed for glutamine synthesis (amide nitrogen) to sustain the glutamate/glutamine Cycle. However, in the rat brain both the total ammonia fixation rate by glutamate dehydrogenase and the total branched chain amino acid transaminase activity are sufficient to support a branched chain amino acid/branched chain keto acid shuttle, as proposed by Hutson and coworkers, which would support the de novo synthesis of glutamine in the astrocyte to replace the ~20 % of neurotransmitter glutamate that is oxidized. A higher fraction of the nitrogen needs of total glutamate neurotransmitter cycling could be supported by hybrid Cycles in which glutamate and tricarboxylic acid Cycle intermediates act as a nitrogen shuttle. A limitation of all in vivo studies in animals conducted to date is that none have shown transfer of nitrogen for glutamine amide synthesis, either as free ammonia or via an amino acid from the neurons to the astrocytes. Future work will be needed, perhaps using methods for selectively labeling nitrogen in neurons, to conclusively establish the rate of amino acid nitrogen shuttles in vivo and their coupling to the glutamate/glutamine Cycle.
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Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy.
Journal of Cerebral Blood Flow and Metabolism, 2009Co-Authors: Fawzi Boumezbeur, Kevin L. Behar, Graeme F. Mason, Gerald I. Shulman, Douglas L. Rothman, Robin A. De Graaf, Gary W. Cline, Kitt Falk PetersenAbstract:A decline in brain function is a characteristic feature of healthy aging; however, little is known about the biologic basis of this phenomenon. To determine whether there are alterations in brain mitochondrial metabolism associated with healthy aging, we combined 13C/1H magnetic resonance spectroscopy with infusions of [1-13C]glucose and [2-13C]acetate to quantitatively characterize rates of neuronal and astroglial tricarboxylic acid Cycles, as well as neuroglial glutamate–glutamine cycling, in healthy elderly and young volunteers. Compared with young subjects, neuronal mitochondrial metabolism and glutamate–glutamine Cycle flux was ~30% lower in elderly subjects. The reduction in individual subjects correlated strongly with reductions in N-acetylaspartate and glutamate concentrations consistent with chronic reductions in brain mitochondrial function. In elderly subjects infused with [2-13C]acetate labeling of glutamine, C4 and C3 differed from that of the young subjects, indicating age-related changes in glial mitochondrial metabolism. Taken together, these studies show that healthy aging is associated with reduced neuronal mitochondrial metabolism and altered glial mitochondrial metabolism, which may in part be responsible for declines in brain function.
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Determination of the Glutamate—Glutamine Cycling Flux Using Two-Compartment Dynamic Metabolic Modeling is Sensitive to Astroglial Dilution
Journal of Cerebral Blood Flow and Metabolism, 2008Co-Authors: Jun Shen, Kevin L. Behar, Douglas L. Rothman, Su XuAbstract:Over the last decade 13C magnetic resonance spectroscopy (13C MRS) combined with the infusion of [1-13C]glucose has been used to measure the cerebral rate of the glutamate–glutamine Cycle (Vcyc). However, the effect of the astroglial label dilution pathways on the accuracy and precision of the 13C MRS measurement of Vcyc has not been evaluated or realized. In this report, we use the numerical Monte Carlo method to study the effect of astroglial dilution on the reliability of extracting Vcyc using the neuronal–astroglial two-compartment metabolic model and [1-13C]glucose infusion. The results show that omission of the astroglial dilution flux leads to a large loss in the sensitivity of the glutamine turnover curve to Vcyc. When the measured isotopic dilution of cerebral glutamine is accounted for in the analysis, the value of Vcyc can be precisely and accurately determined.
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Proposed Cycles for functional glutamate trafficking in synaptic neurotransmission.
Neurochemistry international, 2007Co-Authors: Paul K Maciejewski, Douglas L. RothmanAbstract:To date, the Glutamate-Glutamine Cycle has been the dominant paradigm for understanding the coordinated, compartmentalized activities of phosphate-activated glutaminase (PAG) and glutamine synthetase (GS) in support of functional glutamate trafficking in vivo. However, studies in cell cultures have repeatedly challenged the notion that functional glutamate trafficking is accomplished via the Glutamate-Glutamine Cycle alone. The present study introduces and elaborates alternative Cycles for functional glutamate trafficking that integrate glucose metabolism, glutamate anabolism, transport, and catabolism, and trafficking of TCA Cycle intermediates from astrocytes to presynaptic neurons. Detailed stoichiometry for each of these alternative Cycles is established by strict application of the principle of conservation of atomic species to cytosolic and mitochondrial compartments in both presynaptic neurons and astrocytes. In contrast to the Glutamate-Glutamine Cycle, which requires ATP, but not necessarily oxidative metabolism, to function, Cycles for functional glutamate trafficking based on intercellular transport of TCA Cycle intermediates require oxidative processes to function. These proposed alternative Cycles are energetically more efficient than, and incorporate an inherent mechanism for transporting nitrogen from presynaptic neurons to astrocytes in support of the coordinated activities of PAG and GS that is absent in, the Glutamate-Glutamine Cycle. In light of these newly elaborated alternative Cycles, it is premature to presuppose that functional glutamate trafficking in synaptic neurotransmission in vivo is sustained by the Glutamate-Glutamine Cycle alone.
Yan Zhou - One of the best experts on this subject based on the ideXlab platform.
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Involvement of the glutamate/glutamine Cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice
BMC Complementary and Alternative Medicine, 2017Co-Authors: Xiu-fang Ding, Xin Xin Wang, Long-ji Sun, Hai-yan Jiao, Yue Hua Li, Jia-xu Chen, Yan ZhouAbstract:BackgroundXiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960–1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine Cycle and glutamate transporters.MethodsMice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine Cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1–2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated.ResultsAfter CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS.ConclusionThe studies indicated that XYS may have therapeutic actions on depression-like behaviors induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine Cycle and glutamate transporter GLT-1 in the hippocampus.
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Involvement of the glutamate/glutamine Cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice
BMC Complementary and Alternative Medicine, 2017Co-Authors: Xiu-fang Ding, Xin Xin Wang, Hai-yan Jiao, Yue Hua Li, Jia-xu Chen, Yan ZhouAbstract:Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960–1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine Cycle and glutamate transporters. Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine Cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1–2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated. After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS. The studies indicated that XYS may have therapeutic actions on depression -like behavior s induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine Cycle and glutamate transporter GLT-1 in the hippocampus.
Jun Shen - One of the best experts on this subject based on the ideXlab platform.
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Chapter 2.4 – Glutamate
Magnetic Resonance Spectroscopy, 2014Co-Authors: Jun ShenAbstract:Glutamate is the principal excitatory neurotransmitter in the central nervous system as well as a key metabolite linking carbon and nitrogen metabolism. Its high concentration and rapid turnover in brain tissues make it accessible to both proton and 13C magnetic resonance spectroscopy measurements. The dual roles of glutamate in neurotransmission and metabolism are intricately related. Major enzyme reactions involving glutamate and the glutamate–glutamine Cycle are described. The regulation of glutamate concentration and the interpretation of changes in total glutamate concentration measured by proton magnetic resonance spectroscopy are discussed in the context of glutamate metabolism.
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Modeling the glutamate–glutamine neurotransmitter Cycle
Frontiers in Neuroenergetics, 2013Co-Authors: Jun ShenAbstract:Glutamate is the principal excitatory neurotransmitter in brain. Although it is rapidly synthesized from glucose in neural tissues the biochemical processes for replenishing the neurotransmitter glutamate after glutamate release involve the Glutamate-Glutamine Cycle. Numerous in vivo 13C magnetic resonance spectroscopy experiments since 1994 by different laboratories have consistently concluded: i) the Glutamate-Glutamine Cycle is a major metabolic pathway with a flux rate substantially greater than those suggested by early studies of cell cultures and brain slices; ii) the Glutamate-Glutamine Cycle is coupled to a large portion of the total energy demand of brain function. The dual roles of glutamate as the principal neurotransmitter in the CNS and as a key metabolite linking carbon and nitrogen metabolism make it possible to probe glutamate neurotransmitter cycling using magnetic resonance spectroscopy by measuring the labeling kinetics of glutamate and glutamine. At the same time, comparing to non-amino acid neurotransmitters, the added complexity makes it more challenging to quantitatively separate neurotransmission events from metabolism. Over the past few years our understanding of the neuronal-astroglial two compartment metabolic model of the Glutamate-Glutamine Cycle has been greatly advanced. In particular, the importance of isotopic dilution of glutamine in determining the Glutamate-Glutamine cycling rate using [1-13C] or [1,6-13C2]glucose has been demonstrated and reproduced by different laboratories. In this article, recent developments in the two-compartment modeling of the Glutamate-Glutamine Cycle are reviewed. In particular, the effects of isotopic dilution of glutamine on various labeling strategies for determining the Glutamate-Glutamine cycling rate are analyzed. Experimental strategies for measuring the Glutamate-Glutamine cycling flux that are insensitive to isotopic dilution of glutamine are also suggested.
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Determination of the Glutamate—Glutamine Cycling Flux Using Two-Compartment Dynamic Metabolic Modeling is Sensitive to Astroglial Dilution
Journal of Cerebral Blood Flow and Metabolism, 2008Co-Authors: Jun Shen, Kevin L. Behar, Douglas L. Rothman, Su XuAbstract:Over the last decade 13C magnetic resonance spectroscopy (13C MRS) combined with the infusion of [1-13C]glucose has been used to measure the cerebral rate of the glutamate–glutamine Cycle (Vcyc). However, the effect of the astroglial label dilution pathways on the accuracy and precision of the 13C MRS measurement of Vcyc has not been evaluated or realized. In this report, we use the numerical Monte Carlo method to study the effect of astroglial dilution on the reliability of extracting Vcyc using the neuronal–astroglial two-compartment metabolic model and [1-13C]glucose infusion. The results show that omission of the astroglial dilution flux leads to a large loss in the sensitivity of the glutamine turnover curve to Vcyc. When the measured isotopic dilution of cerebral glutamine is accounted for in the analysis, the value of Vcyc can be precisely and accurately determined.
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13C magnetic resonance spectroscopy studies of alterations in glutamate neurotransmission
Biological Psychiatry, 2005Co-Authors: Jun ShenAbstract:Over the past a few years, significant progress has been made in refining the in vivo 13 C magnetic resonance spectroscopy technique and in applying it to studying the alterations in the Glutamate-Glutamine cycling flux. Meanwhile, the details of the metabolic modeling are being rigorously debated. Recent evidence against fast α-ketoglutarate-glutamate exchange across the mitochondrial membrane is examined. Previous reports have indicated that glutamate release or 13 C label incorporation into glutamine is attenuated at elevated concentrations of endogenous γ-aminobutyric acid (GABA). A recent study has shown that phenelzine administration reduces the Glutamate-Glutamine cycling flux while raising endogenous GABA levels in vivo. Effects of several metabotropic glutamate receptor agonists and antagonists and brain disorders on the Glutamate-Glutamine Cycle are also summarized.
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Magnetic resonance spectroscopic approaches to studying neuronal: glial interactions.
Biological Psychiatry, 2002Co-Authors: Jun Shen, Douglas L. RothmanAbstract:Abstract In vivo magnetic resonance spectroscopy (MRS) is a noninvasive technique for the measurement of the concentration and synthesis of metabolites in the brain. Application of the state-of-the-art in vivo 13C and 15N MRS techniques to studying the synthesis of glutamate and glutamine has revealed that the glutamate–glutamine Cycle between neurons and glia is a major metabolic flux, with a flux rate of 60%–80% relative to neuronal oxidative glucose metabolism in the resting human cerebral cortex. The MRS studies leading to the quantification of the glutamate–glutamine cycling flux are reviewed here. The advantages and limitations of different strategies are also discussed.
Xiu-fang Ding - One of the best experts on this subject based on the ideXlab platform.
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Involvement of the glutamate/glutamine Cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice
BMC Complementary and Alternative Medicine, 2017Co-Authors: Xiu-fang Ding, Xin Xin Wang, Long-ji Sun, Hai-yan Jiao, Yue Hua Li, Jia-xu Chen, Yan ZhouAbstract:BackgroundXiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960–1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine Cycle and glutamate transporters.MethodsMice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine Cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1–2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated.ResultsAfter CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS.ConclusionThe studies indicated that XYS may have therapeutic actions on depression-like behaviors induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine Cycle and glutamate transporter GLT-1 in the hippocampus.
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Involvement of the glutamate/glutamine Cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice
BMC Complementary and Alternative Medicine, 2017Co-Authors: Xiu-fang Ding, Xin Xin Wang, Hai-yan Jiao, Yue Hua Li, Jia-xu Chen, Yan ZhouAbstract:Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960–1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine Cycle and glutamate transporters. Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine Cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1–2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated. After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS. The studies indicated that XYS may have therapeutic actions on depression -like behavior s induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine Cycle and glutamate transporter GLT-1 in the hippocampus.
Rolf Gruetter - One of the best experts on this subject based on the ideXlab platform.
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Astrocytic and neuronal oxidative metabolism are coupled to the rate of Glutamate-Glutamine Cycle in the tree shrew visual cortex
Glia, 2017Co-Authors: Sarah Sonnay, Jordan Poirot, Nathalie Just, Anne Catherine Clerc, Rolf Gruetter, Gregor Rainer, João M. N. DuarteAbstract:Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine Cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) Cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA Cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA Cycle rates in neurons by 12% ( math formula, p < 0.001) and in astrocytes by 24% ( math formula, p = 0.007). We further observed linear relationships between VNT and both math formula and math formula. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.
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Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by 13 C Magnetic Resonance Spectroscopy
Neurotoxicity Research, 2017Co-Authors: Freya-merret Girault, Sarah Sonnay, Rolf Gruetter, João M. N. DuarteAbstract:Type 2 diabetes (T2D) is associated with deterioration of brain structure and function. Here, we tested the hypothesis that T2D induces a reorganization of the brain metabolic networks that support brain function. For that, alterations of neuronal and glial energy metabolism were investigated in a T2D model, the Goto-Kakizaki (GK) rat. (13)C magnetic resonance spectroscopy in vivo at 14.1 T was used to detect (13)C labeling incorporation into carbons of glutamate, glutamine, and aspartate in the brain of GK (n = 7) and Wistar (n = 13) rats during intravenous [1,6-(13)C]glucose administration. Labeling of brain glucose and amino acids over time was analyzed with a two-compartment mathematical model of brain energy metabolism to determine the rates of metabolic pathways in neurons and glia. Compared to controls, GK rats displayed lower rates of brain glutamine synthesis (- 32%, P < 0.001) and Glutamate-Glutamine Cycle (- 40%, P < 0.001), and mitochondrial tricarboxylic acid (TCA) Cycle rate in neurons (- 7%, P = 0.036). In contrast, the TCA Cycle rate of astrocytes was larger in GK rats than controls (+ 21%, P = 0.042). We conclude that T2D alters brain energy metabolism and impairs the Glutamate-Glutamine Cycle between neurons and astrocytes, in line with diabetes-induced neurodegeneration and astrogliosis underlying brain dysfunction.
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Rates oxidative metabolism in astrocytes and neurons are coupled to the Glutamate-Glutamine Cycle in the tree shrew visual cortex
Journal of Neurochemistry, 2017Co-Authors: Sarah Sonnay, Jordan Poirot, Nathalie Just, Anne Catherine Clerc, Rolf Gruetter, Gregor Rainer, João M. N. DuarteAbstract:Keywords: CIBM-AIT Reference EPFL-CONF-230551View record in Web of Science Record created on 2017-09-05, modified on 2017-09-08
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Compartmentalised energy metabolism supporting glutamatergic neurotransmission in response to increased activity in the rat cerebral cortex: A 13C MRS study in vivo at 14.1 T
Journal of Cerebral Blood Flow and Metabolism, 2016Co-Authors: Sarah Sonnay, Nathalie Just, J. M. Duarte, Rolf GruetterAbstract:Many tissues exhibit metabolic compartmentation. In the brain, while there is no doubt on the importance of functional compartmentation between neurons and glial cells, there is still debate on the specific regulation of pathways of energy metabolism at different activity levels. Using 13C magnetic resonance spectroscopy (MRS) in vivo, we determined fluxes of energy metabolism in the rat cortex under α-chloralose anaesthesia at rest and during electrical stimulation of the paws. Compared to resting metabolism, the stimulated rat cortex exhibited increased glutamate–glutamine Cycle (+67 nmol/g/min, +95%, P < 0.001) and tricarboxylic (TCA) Cycle rate in both neurons (+62 nmol/g/min, +12%, P < 0.001) and astrocytes (+68 nmol/g/min, +22%, P = 0.072). A minor, non-significant modification of the flux through pyruvate carboxylase was observed during stimulation (+5 nmol/g/min, +8%). Altogether, this increase in metabolism amounted to a 15% (67 nmol/g/min, P < 0.001) increase in CMRglc(ox), i.e. the oxidative fraction of the cerebral metabolic rate of glucose. In conclusion, stimulation of the glutamate–glutamine Cycle under α-chloralose anaesthesia is associated to similar enhancement of neuronal and glial oxidative metabolism.
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Brain energy metabolism measured by (13)C magnetic resonance spectroscopy in vivo upon infusion of [3-(13)C]lactate.
Journal of Neuroscience Research, 2014Co-Authors: João M. N. Duarte, Freya-merret Girault, Rolf GruetterAbstract:The brain uses lactate produced by glycolysis as an energy source. How lactate originated from the blood stream is used to fuel brain metabolism is not clear. The current study measures brain metabolic fluxes and estimates the amount of pyruvate that becomes labeled in glial and neuronal compartments upon infusion of [3-13 C]lactate. For that, labeling incorporation into carbons of glutamate and glutamine was measured by 13 C magnetic resonance spectroscopy at 14.1 T and analyzed with a two-compartment model of brain metabolism to estimate rates of mitochondrial oxidation, glial pyruvate carboxylation, and the Glutamate-Glutamine Cycle as well as pyruvate fractional enrichments. Extracerebral lactate at supraphysiological levels contributes at least two-fold more to replenish the neuronal than the glial pyruvate pools. The rates of mitochondrial oxidation in neurons and glia, pyruvate carboxylase, and Glutamate-Glutamine Cycles were similar to those estimated by administration of 13 C-enriched glucose, the main fuel of brain energy metabolism. These results are in agreement with primary utilization of exogenous lactate in neurons rather than astrocytes.