Abstract
Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-twentieth century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e., indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e., direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provides information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here, we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to sensory stimulation.
Highlights
Cerebral function requires the cooperative interaction between different cell types, namely neurons, astrocytes, microglia and oligodendrocytes, and depends on high metabolic activity supported by continuous supply of oxygen and glucose from the blood (Siesjö, 1978)
Dynamic nuclear polarization (DNP) can be used to increase 13C polarization of 13C-labeled substrates, and offers potentially tremendous signal enhancement and detection of 13C labeling in tissue’s TCA cycle intermediates, such as 2-oxoglutarate in the brain (Mishkovsky et al, 2012), or citrate in the heart (Schroeder et al, 2009; Bastiaansen et al, 2015). While such a technique can probe metabolism in vivo with high sensitivity and a time resolution of 1 s, the acquisition window is limited to approximately a minute (Comment, 2016), since magnetic resonance (MR) acquisition needs to be performed within the time decay of the enhanced nuclear polarization, and detection of downstream compounds depends notably on the turnover rates and on the concentration of labeled metabolites produced within the recording period
Local cerebral blood flow (CBF) response could be immediately regulated by fast (400 ms) feed-forward mechanisms directly related to neuronal activity (e.g., neuronal nitric oxide (NO) production (Buerk et al, 2003), action potential-associated K+ current (Paulson and Newman, 1987), neuronal arachidonic pathway activation Zonta et al, 2003; Metea and Newman, 2006), rather than feedback mechanisms associated with metabolism, that probably occur at longer time scales to match CBF with energy demands
Summary
With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. We review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated.
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