The last decade has seen a renaissance of interest in how astroglial metabolism supports neuronal function. Magnetic Resonance Spectroscopy (MRS) in combination with stable 13C labeled precursors is the only method which may be used for studying neuronal/glial metabolic relationships non invasively in humans. In our previous funding cycle we used 13C MRS to show that the neuronal/glial glutamate/glutamine cycle is highly active in human cerebral cortex, and is the major pathway of both neuronal glutamate repletion and astroglial glutamine synthesis. In the course of this research we developed a novel labeling strategy for human studies using 2-13C acetate. Acetate is unique as a brain fuel because it is almost exclusively metabolized in astroglial cells, a property which makes it ideal for studying neuronal/glial neurotransmitter cycles. The primary goals of this grant are to further develop the 2-13C acetate/MRS method at 4T, and then use it to answer several pivotal questions on the role of neuronal/glial neurotransmitter cycles in normal brain function.
Our specific aims are in human cerebral cortex to (1) characterize acetate transport and metabolism to allow absolute rates to be determined from acetate tracer studies, (2) study the role of glia in supporting excitatory function by measuring with much higher spatial resolution the neuronal/glial glutamate/glutamine cycle and its coupling to neuronal and glial glucose oxidation (3) study the role of glia in supporting inhibitory function by measuring the GABA/glutamine cycle and GABAergic neuron glucose oxidation and (4) assess the importance of astroglial glutamate oxidation for maintaining proper neuronal function. In addition we will validate these measurements both through comparison with results obtained using a 1-13C glucose tracer, and by assessing test-retest stability of metabolic rates. Although no patient studies are proposed, our goal is for these studies to provide validated methodology and normative values to be used in future studies of neuronal-glial neurotransmitter cycles in development, aging, and disease.
| Herzog, Raimund I; Jiang, Lihong; Herman, Peter et al. (2013) Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. J Clin Invest 123:1988-98 |
| Patel, Anant B; de Graaf, Robin A; Rothman, Douglas L et al. (2010) Evaluation of cerebral acetate transport and metabolic rates in the rat brain in vivo using 1H-[13C]-NMR. J Cereb Blood Flow Metab 30:1200-13 |
| Boumezbeur, Fawzi; Mason, Graeme F; de Graaf, Robin A et al. (2010) Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab 30:211-21 |
| Boumezbeur, Fawzi; Petersen, Kitt F; Cline, Gary W et al. (2010) The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J Neurosci 30:13983-91 |
| Jiang, Lihong; Herzog, Raimund I; Mason, Graeme F et al. (2009) Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo. Diabetes 58:1266-74 |
| Shen, Jun; Rothman, Douglas L; Behar, Kevin L et al. (2009) Determination of the glutamate-glutamine cycling flux using two-compartment dynamic metabolic modeling is sensitive to astroglial dilution. J Cereb Blood Flow Metab 29:108-18 |
| Shulman, Robert G; Hyder, Fahmeed; Rothman, Douglas L (2009) Baseline brain energy supports the state of consciousness. Proc Natl Acad Sci U S A 106:11096-101 |
| Befroy, Douglas E; Falk Petersen, Kitt; Rothman, Douglas L et al. (2009) Assessment of in vivo mitochondrial metabolism by magnetic resonance spectroscopy. Methods Enzymol 457:373-93 |
| van Eijsden, Pieter; Hyder, Fahmeed; Rothman, Douglas L et al. (2009) Neurophysiology of functional imaging. Neuroimage 45:1047-54 |
| Befroy, Douglas E; Petersen, Kitt Falk; Dufour, Sylvie et al. (2008) Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurance-trained individuals. Proc Natl Acad Sci U S A 105:16701-6 |
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