Many functional imaging techniques are based on measuring changes in cerebral blood flow (CBF), either directly (such as radiotracer methods or perfusion MRI) or indirectly, such as blood-oxygen level dependent (BOLD) functional MRI. These changes in CBF are thought to reflect changes in cerebral metabolic activity, specifically cerebral glucose consumption, CMRglc, which in turn is thought to reflect neuronal activity. The hypotheses of this project are: A) That glutamate-glutamine cycling measured from glutamine labeling reflects neurotransmission, which is increased in focal activation (neuronal spike activity). B) That changes in neurotransmission are matched by changes in metabolic rates, such as flux through (neuronal) pyruvate dehydrogenase (CMRO2), glycolysis and malate-aspartate shuttle and that these changes are consistent with BOLD fMRI and perfusion MRI providing a coherent depiction of neurotransmission and its metabolic/hemodynamic correlates. C) Those enzymatic pathways of cerebral glycogen synthesis and breakdown are simultaneously active, such that brain glycogen concentration and cerebral activity levels modulate metabolism. With the following specific aims: 1. To simultaneously measure label incorporation into several distinct carbon positions in cerebral glutamate, glutamine and aspartate during 13C labeled glucose infusions with concomitant measurement of tissue glucose and lactate concentrations and combined with perfusion and BOLD fMRI. 2 To develop 13C NMR detection of brain glycogen concentration and metabolism. Significant phosphorylase and synthase activity as reported for brain tissue is expected to lead to label transfer from plasma glucose to brain glycogen when infusing labeled 13C glucose and thus to an observable 13C NMR signal.
These aims will be achieved in rat brain using localized 1H and 13C NMR spectroscopy in conjunction with 1H fMRI of BOLD and perfusion.
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