1,720,986 research outputs found
Activity-dependent energy budget for neocortical signaling: Effect of short-term synaptic plasticity on the energy expended by spiking and synaptic activity
No full textThe available estimate of the energy expended for signaling in rat neocortex is refined to examine the separate contribution of spiking and synaptic activity as a function of average neuronal firing rate. By taking into account a phenomenological model of short-term synaptic plasticity, we show that the transition from low to high cortical activity is accompanied by a substantial increase in relative energy consumed by action potentials vs. synaptic potentials. This consideration might be important for a deeper understanding of how information is represented in the cortex and which metabolic pathways are upregulated to sustain cortical activity. (c) 2012 Wiley Periodicals, Inc
Metabolic Pathways and Activity-Dependent Modulation of Glutamate Concentration in the Human Brain
No full textGlutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for gamma-aminobutyric acid, the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies
Regulatory mechanisms for glycogenolysis and K+ uptake in brain astrocytes
No full textRecent 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
Why does the brain (not) have glycogen?
No full textIn the present paper we formulate the hypothesis that brain glycogen is a critical determinant in the modulation of carbohydrate supply at the cellular level. Specifically, we propose that mobilization of astrocytic glycogen after an increase in AMP levels during enhanced neuronal activity controls the concentration of glucose phosphates in astrocytes. This would result in modulation of glucose phosphorylation by hexokinase and upstream cell glucose uptake. This mechanism would favor glucose channeling to activated neurons, supplementing the already rich neuron-astrocyte metabolic and functional partnership with important implications for the energy compounds used to sustain neuronal activity. The hypothesis is based on recent modeling evidence suggesting that rapid glycogen breakdown can profoundly alter the short-term kinetics of glucose delivery to neurons and astrocytes. It is also based on review of the literature relevant to glycogen metabolism during physiological brain activity, with an emphasis on the metabolic pathways identifying both the origin and the fate of this glucose reserve
Glucose metabolism down-regulates the uptake of 6-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-2-deoxyglucose (6-NBDG) mediated by glucose transporter 1 isoform (GLUT1): Theory and simulations using the symmetric four-state carrier model
No full textThe non-metabolizable fluorescent glucose analogue 6-(N-(7-nitrobenz-2-oxa- 1,3-diazol-4-yl)amino)-2-deoxyglucose (6-NBDG) is increasingly used to study cellular transport of glucose. Intracellular accumulation of exogenously applied 6-NBDG is assumed to reflect concurrent gradient-driven glucose uptake by glucose transporters (GLUTs). Here, theoretical considerations are provided that put this assumption into question. In particular, depending on the microscopic parameters of the carrier proteins, theory proves that changes in glucose transport can be accompanied by opposite changes in flow of 6-NBDG. Simulations were carried out applying the symmetric four-state carrier model on the GLUT1 isoform, which is the only isoform whose kinetic parameters are presently available. Results show that cellular 6-NBDG uptake decreases with increasing rate of glucose utilization under core-model conditions, supported by literature, namely where the transporter is assumed to work in regime of slow reorientation of the free-carrier compared with the ligand-carrier complex. To observe an increase of 6-NBDG uptake with increasing rate of glucose utilization, and thus interpret 6-NBDG increase as surrogate of glucose uptake, the transporter must be assumed to operate in regime of slow ligand-carrier binding, a condition that is currently not supported by literature. Our findings suggest that the interpretation of data obtained with NBDG derivatives is presently ambiguous and should be cautious because the underlying transport kinetics are not adequately established. In this study, we used the four-state carrier model for brain GLUT1 to examine whether cellular glucose metabolism can be inferred from the accumulation of the fluorescent glucose analogue 6-NBDG, which is increasingly employed for indirect determination of glucose transport and utilization in neurons and astrocytes. However, our findings show that the relation between 6-NBDG uptake and glucose transport and utilization configures antiport not symport of the two substrates. © 2013 International Society for Neurochemistry
Changes in glucose uptake rather than lactate shuttle take center stage in subserving neuroenergetics: Evidence from mathematical modeling
No full textIn 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
The Role of Astrocytic Glycogen in Supporting the Energetics of Neuronal Activity
No full textEnergy homeostasis in the brain is maintained by oxidative metabolism of glucose, primarily to fulfil the energy demand associated with ionic movements in neurons and astrocytes. In this contribution we review the experimental evidence that grounds a specific role of glycogen metabolism in supporting the functional energetic needs of astrocytes during the removal of extracellular potassium. Based on theoretical considerations, we further discuss the hypothesis that the mobilization of glycogen in astrocytes serves the purpose to enhance the availability of glucose for neuronal glycolytic and oxidative metabolism at the onset of stimulation. Finally, we provide an evolutionary perspective for explaining the selection of glycogen as carbohydrate reserve in the energy-sensing machinery of cell metabolism
Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen-derived lactate shuttling to neurons: evidence from mathematical modeling
No full textIn 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 175:115mmol/L (similar to 1.5:1) neuronal versus astrocytic activation-induced Na(+) influx ratio, similar to 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 190:65mmol/L (similar to 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. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1895-1904; doi:10.1038/jcbfm.2010.151; published online 8 September 201
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