The mechanisms that link increased neuronal activity to increased metabolism are not fully understood. The LONG-TERM GOAL of this project is to uncover the mechanisms that couple brain energy metabolism to neurotransmission at the cellular level. The OBJECTIVE of this application is to measure compartmentalized brain metabolism between neurons and astrocytes, using a new emerging technique, namely in vivo 13C dynamic 13C isotopomer analysis. The HYPOTHESES to be tested are: (a) that the glutamate-glutamine cycle as measured by 13C NMR reflects glutamatergic neurotransmission and is increased during focal activation (increased electrical activity). (b) that changes in the glutamate-glutamine cycle are accompanied by matched changes in other metabolic fluxes, such as neuronal and glial glucose oxidative metabolism, malate-aspartate shuttle and pyruvate carboxylation, during activation. (c) that only a fraction of brain energy production is to used to support glutamatergic neurotransmission.
The SPECIFIC AIMS are: (1) To determine the optimal 13C-labeled substrate or combination of substrates for reliable measurement of compartmentalized metabolic fluxes in the brain in vivo using dynamic 13C isotopomer analysis. (2) To measure compartmentalized metabolic fluxes, including the glutamate-glutamine cycle, in the whole brain at various levels of brain activity using different anesthetics in rat brain. (3) To measure compartmentalized metabolic fluxes following pharmacological inhibition of neuronal-glial metabolism using methionine sulfoximine (inhibitor of glutamine synthase) and fluoroacetate (inhibitor of glial TCA cycle) in rat brain. (4) To measure compartmentalized metabolic fluxes, including the glutamate-glutamine cycle, in activated cortex during visual stimulation in cat and human brain. The RATIONALE for this work is that it will lead to a better understanding of neurotransmission in the context of astrocyte-neuron interactions, and it will validate the possibility of measuring glutamatergic neurotransmission non-invasively in the human brain. This will open exciting prospects for assessing glutamatergic function in a wide range of brain disorders in which a dysfunction of glutamatergic neurotransmission is suspected, at a stage where structural lesions are not yet apparent. ? ? ?
|Tiret, Brice; Shestov, Alexander A; Valette, Julien et al. (2015) Metabolic Modeling of Dynamic (13)C NMR Isotopomer Data in the Brain In Vivo: Fast Screening of Metabolic Models Using Automated Generation of Differential Equations. Neurochem Res 40:2482-92|
|Deelchand, Dinesh Kumar; Nguyen, Tra-My; Zhu, Xiao-Hong et al. (2015) Quantification of in vivo ³¹P NMR brain spectra using LCModel. NMR Biomed 28:633-41|
|Deelchand, Dinesh Kumar; Iltis, Isabelle; Henry, Pierre-Gilles (2014) Improved quantification precision of human brain short echo-time (1) H magnetic resonance spectroscopy at high magnetic field: a simulation study. Magn Reson Med 72:20-5|
|Jeffrey, F Mark; Marin-Valencia, Isaac; Good, Levi B et al. (2013) Modeling of brain metabolism and pyruvate compartmentation using (13)C NMR in vivo: caution required. J Cereb Blood Flow Metab 33:1160-7|
|Shestov, Alexander A; Valette, Julien; Deelchand, Dinesh K et al. (2012) Metabolic modeling of dynamic brain ¹³C NMR multiplet data: concepts and simulations with a two-compartment neuronal-glial model. Neurochem Res 37:2388-401|
|Mochel, Fanny; N'Guyen, Tra-My; Deelchand, Dinesh et al. (2012) Abnormal response to cortical activation in early stages of Huntington disease. Mov Disord 27:907-10|
|Shestov, Alexander A; Emir, Uzay E; Kumar, Anjali et al. (2011) Simultaneous measurement of glucose transport and utilization in the human brain. Am J Physiol Endocrinol Metab 301:E1040-9|
|Ennis, Kathleen; Deelchand, Dinesh Kumar; Tkac, Ivan et al. (2011) Determination of oxidative glucose metabolism in vivo in the young rat brain using localized direct-detected ¹³C NMR spectroscopy. Neurochem Res 36:1962-8|
|van de Ven, Kim C C; de Galan, Bastiaan E; van der Graaf, Marinette et al. (2011) Effect of acute hypoglycemia on human cerebral glucose metabolism measured by ¹³C magnetic resonance spectroscopy. Diabetes 60:1467-73|
|Melø, Torun M; Håberg, Asta K; Risa, Øystein et al. (2011) Tricarboxylic acid cycle activity measured by 13C magnetic resonance spectroscopy in rats subjected to the kaolin model of obstructed hydrocephalus. Neurochem Res 36:1801-8|
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