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Dinuzzo M.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi | Dinuzzo M.,University of Rome La Sapienza
Journal of Neurophysiology | Year: 2015

Extensive research over the past decades about the multifaceted roles of brain astrocytes led to the suggestion that the signals observed with functional neuroimaging might primarily reflect astrocytic rather than neuronal activity. The basis for this paradigm-shifting concept was the evidence for an involvement of astrocytes in the control of local cerebral blood flow through intracellular Ca2+ signaling. In this Neuro Forum, I discuss new important experimental findings obtained by Jego et al. (Jego P, Pacheco-Torres J, Araque A, Canals S. J Cereb Blood Flow Metab 34: 1599–1603, 2014) as well as other closely related studies published recently, prompting a dismissal of substantial astrocytic contribution in functional neuroimaging. © 2015 the American Physiological Society. Source


Dinuzzo M.,University of Rome La Sapienza | Mangia S.,University of Minnesota | Maraviglia B.,University of Rome La Sapienza | Giove F.,Fondazione Santa Lucia IRCCS | Giove F.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi
Journal of Cerebral Blood Flow and Metabolism | Year: 2010

In this paper, we combined several mathematical models of cerebral metabolism and nutrient transport to investigate the energetic significance of metabolite trafficking within the brain parenchyma during a 360-secs activation. Glycolytic and oxidative cellular metabolism were homogeneously modeled between neurons and astrocytes, and the stimulation-induced neuronal versus astrocytic Na inflow was set to 3:1. These assumptions resemble physiologic conditions and are supported by current literature. Simulations showed that glucose diffusion to the interstitium through basal lamina dominates the provision of the sugar to both neurons and astrocytes, whereas astrocytic endfeet transfer less than 4% of the total glucose supplied to the tissue. Neuronal access to paracellularly diffused glucose prevails even after halving (doubling) the ratio of neuronal versus astrocytic glycolytic (oxidative) metabolism, as well as after reducing the neuronal versus astrocytic Na+ inflow to a nonphysiologic value of 1:1. Noticeably, displaced glucose equivalents as intercellularly shuttled lactate account for ∼ 6% to 7% of total brain glucose uptake, an amount comparable with the concomitant drainage of the monocarboxylate by the bloodstream. Overall, our results suggest that the control of carbon recruitment for neurons and astrocytes is exerted at the level of glucose uptake rather than that of lactate shuttle. © 2010 ISCBFM All rights reserved. Source


Dinuzzo M.,University of Rome La Sapienza | Mangia S.,University of Minnesota | Maraviglia B.,University of Rome La Sapienza | Giove F.,University of Rome La Sapienza | Giove F.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi
Journal of Cerebral Blood Flow and Metabolism | Year: 2010

In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (∼1.5:1) neuronal versus astrocytic activation-induced Na influx ratio, ∼12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na influx ratio to 190:65 mmol/L (∼3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current thinking paradigm. This might be critical in subcellular domains during functional conditions associated with fast energetic demands. © 2010 ISCBFM All rights reserved. Source


Mangia S.,University of Minnesota | Dinuzzo M.,University of Rome La Sapienza | Giove F.,University of Rome La Sapienza | Giove F.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi | And 3 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

For many years, a tenet of cerebral metabolism held that glucose was the obligate energy substrate of the mammalian brain and that neuronal oxidative metabolism represented the majority of this glucose utilization. In 1994, Pellerin and Magistretti formulated the astrocyte-neuron lactate shuttle (ANLS) hypothesis, in which astrocytes, not neurons, metabolized glucose, with subsequent transport of the glycolytically derived lactate to fuel the energy needs of the neuron during neurotransmission. By considering the concentrations and kinetic characteristics of the nutrient transporter proteins, Simpson et al later supported the opposite view, in which lactate flows from neurons to astrocytes, thus leading to the neuron-astrocyte lactate shuttle (NALS). Most recently, a commentary was published in this journal attempting to discredit the NALS. This challenge has stimulated the present response in which we detail the inaccuracies of the commentary and further model several different possibilities. Although our simulations continue to support the predominance of neuronal glucose utilization during activation and neuronal to astrocytic lactate flow, the most important result is that, regardless of the direction of the flow, the overall contribution of lactate to cerebral glucose metabolism is found to be so small as to make this ongoing debate much ado about nothing. © 2011 ISCBFM All rights reserved. Source


Dinuzzo M.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi | Mangia S.,University of Minnesota | Maraviglia B.,University of Rome La Sapienza | Giove F.,Museo Storico Della Fisica E Centro Of Studi E Ricerche Enrico Fermi | Giove F.,University of Rome La Sapienza
Neurochemistry International | Year: 2013

Recent advances in brain energy metabolism support the notion that glycogen in astrocytes is necessary for the clearance of neuronally-released K + from the extracellular space. However, how the multiple metabolic pathways involved in K+-induced increase in glycogen turnover are regulated is only partly understood. Here we summarize the current knowledge about the mechanisms that control glycogen metabolism during enhanced K + uptake. We also describe the action of the ubiquitous Na +/K+ ATPase for both ion transport and intracellular signaling cascades, and emphasize its importance in understanding the complex relation between glycogenolysis and K+ uptake. © 2013 Elsevier B.V. All rights reserved. Source

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