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.
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