Functional activation stimulates CMRglc more than CMRO2 and raises lactate levels in brain. This has been interpreted as evidence that brain work is supported mainly by energy derived from anaerobic glycolysis. To determine if lactate production accounts for the "excess" glucose consumption, cerebral arteriovenous differences were measured in conscious rats before, during, and 15 minutes after sensory stimulation; the brains were rapidly frozen in situ immediately after completion of blood sampling and assayed for metabolite levels. The molar O2/glucose uptake ratio fell from 6.1+/-1.1 (mean+/-SD) before stimulation to 5.0+/-1.1 during activation (P<0.01); lactate efflux from brain to blood was detectable at rest but not during stimulation. By 15 minutes after activation, O2 and lactate arteriovenous differences normalized, whereas that for glucose fell, causing the O2/glucose ratio to rise above preactivation levels to 7.7+/-2.6 (P<0.01). Brain glucose levels remained stable through all stages of activity. Brain lactate levels nearly doubled during stimulation but normalized within 15 minutes of recovery. Brain glycogen content fell during activation and declined further during recovery. These results indicate that brain glucose metabolism is not in a steady state during and shortly after activation. Furthermore, efflux from and increased content of lactate in the brain tissue accounted for less than 54% of the "excess" glucose used during stimulation, indicating that a shift to anaerobic glycolysis does not fully explain the disproportionately greater increases in CMRglc above that of CMRO2 in functionally activated brain. These results also suggest that the apparent dissociation between glucose utilization and O2 consumption during functional activation reflects only a temporal displacement; during activation, glycolysis increases more than oxidative metabolism, leading to accumulation of products in intermediary metabolic pools that are subsequently consumed and oxidized during recovery.
Glucose is the primary, obligatory fuel for brain, and glucose metabolism-based assays have, therefore, been a cornerstone of non-invasive imaging and spectroscopic studies of brain function and disease for decades. In the late 1960s, metabolic studies using labeled tracers were initiated to identify brain fuel, define compartmentation of utilization of minor substrates by neurons and astrocytes, assess astrocyte-neuron metabolic interactions, and calculate glucose utilization rates. Enormous progress has been made in understanding function-metabolism relationships but the cellular contributions to brain energy metabolism and brain images are not yet clear. Under resting conditions, nearly all of the glucose is oxidized and the metabolic ratio of oxygen to glucose utilization is close to the theoretical maximum of 6 (i.e., 6O 2 + 1 glucose fi 6CO 2 + 6H 2 0), but during brain activation this metabolic ratio generally, but not always, falls even though oxygen delivery is adequate (reviewed by Cruz 2004, 2008). The basis for the preferential rise in non-oxidative metabolism of glucose during activation is not understood, and increased lactate production that exceeds its oxidation is inferred.The cellular origin and fate of lactate and the contribution of lactate to brain energetics in normal, activated brain are important, unresolved issues. In vivo experiments to define roles of endogenously-generated lactate are technically difficult, and the lack of consensus in the field is reflected by the diversity of the following current metabolic models. (i) Lactate generated by astrocytes during excitatory glutamatergic neurotransmission is hypothesized to be shuttled to neurons as a major fuel ( AbstractBrain is a highly-oxidative organ, but during activation, glycolytic flux is preferentially up-regulated even though oxygen supply is adequate. The biochemical and cellular basis of metabolic changes during brain activation and the fate of lactate produced within brain are important, unresolved issues central to understanding brain function, brain images, and spectroscopic data. Because in vivo brain imaging studies reveal rapid efflux of labeled glucose metabolites during activation, lactate trafficking among astrocytes and between astrocytes and neurons was examined after devising specific, real-time, sensitive enzymatic fluorescent assays to measure lactate and glucose levels in single cells in adult rat brain slices. Astrocytes have a 2-to 4-fold faster and higher capacity for lactate uptake from extracellular fluid and for lactate dispersal via the astrocytic syncytium compared to neuronal lactate uptake from extracellular fluid or shuttling of lactate to neurons from neighboring astrocytes. Astrocytes can also supply glucose to neurons as well as glucose can be taken up by neurons from extracellular fluid. Astrocytic networks can provide neuronal fuel and quickly remove lactate from activated glycolytic domains, and the lactate can be dispersed widely throughout the syncytium to endfeet along the vasculature for...
To evaluate the response of astrocytes in the auditory pathway to increased neuronal signaling elicited by acoustic stimulation, conscious rats were presented with a unilateral broadband click stimulus and functional activation was assessed by quantitative autoradiography using three tracers to pulse label different metabolic pools in brain: [2-14C]acetate labels the 'small' (astrocytic) glutamate pool, [1-14C]hydroxybutyrate labels the 'large' glutamate pool, and [14C]deoxyglucose, reflects overall glucose utilization (CMR(glc)) in all brain cells. CMR(glc) rose during brain activation, and increased activity of the oxidative pathway in working astrocytes during acoustic stimulation was registered with [2-14C]acetate. In contrast, the stimulation-induced increase in metabolic activity was not reflected by greater trapping of products of [1-14C]hydroxybutyrate. The [2-14C]acetate uptake coefficient in the inferior colliculus and lateral lemniscus during acoustic stimulation was 15% and 18% (p < 0.01) higher in the activated compared to contralateral hemisphere, whereas CMR(glc) in these structures rose by 66% (p < 0.01) and 42% (p < 0.05), respectively. Calculated rates of brain utilization of blood-borne acetate (CMR(acetate)) are about 15-25% of total CMR(glc) in non-stimulated tissue and 10-20% of CMR(glc) in acoustically activated structures; they range from 28 to 115% of estimated rates of glucose oxidation in astrocytes. The rise in acetate utilization during acoustic stimulation is modest compared to total CMR(glc), but astrocytic oxidative metabolism of 'minor' substrates present in blood can make a significant contribution to the overall energetics of astrocytes and astrocyte-neuron interactions in working brain.
Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific b-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas breceptor blockade 're-balances' the stoichiometry of oxygenglucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential nonoxidative glucose utilization and glycogen turnover during brain activation. Keywords: aerobic glycolysis, astrocyte, epinephrine, glycogen, lactate, norepinephrine. J. Neurochem. (2016) 138, 14-52.This review first describes characteristics of aerobic glycolysis, and then identifies metabolic pathways that contribute to its becoming manifest with increases in their rates. Lactate release is recognized as a major, but not the only, factor in causing greater utilization of glucose than oxygen during brain activation. Astrocytes have a high impact on the phenomenon because of glycogen turnover, lactate dispersal through gap junctions, and lactate discharge from the brain. Aerobic glycolysis is prevented by propranolol, a non-specific b-adrenoceptor antagonist, implicating adrenergic signaling in regulation of the cellular activities that contribute to aerobic glycolysis. Analysis of studies in diverse fields ranging from metabolic assays of brain activation to memory consolidation led to a model describing adrenergic regulation of aerobic glycolysis. The model posits that stress-related Abbreviations used: AGC, aspartate-gl...
Glycogen is degraded during brain activation but its role and contribution to functional energetics in normal activated brain have not been established. In the present study, glycogen utilization in brain of normal conscious rats during sensory stimulation was assessed by three approaches, change in concentration, release of 14 C from pre-labeled glycogen and compensatory increase in utilization of blood glucose (CMR glc ) evoked by treatment with a glycogen phosphorylase inhibitor. Glycogen level fell in cortex, 14 C release increased in three structures and inhibitor treatment caused regionally selective compensatory increases in CMR glc over and above the activation-induced rise in vehicle-treated rats. The compensatory rise in CMR glc was highest in sensory-parietal cortex where it corresponded to about half of the stimulus-induced rise in CMR glc in vehicle-treated rats; this response did not correlate with metabolic rate, stimulus-induced rise in CMR glc or sequential station in sensory pathway. Thus, glycogen is an active fuel for specific structures in normal activated brain, not simply an emergency fuel depot and flux-generated pyruvate greatly exceeded net accumulation of lactate or net consumption of glycogen during activation. The metabolic fate of glycogen is unknown, but adding glycogen to the fuel consumed during activation would contribute to a fall in CMR O2 / CMR glc ratio. Keywords: brain activation, brain imaging, energetics, glucose utilization, glycogenolysis, sensory stimulation. The importance of quantifying metabolic fluxes induced by brain activation at a cellular level is emphasized by positron emission tomographic, magnetic resonance spectroscopic (MRS) and optical (infrared or fluorescence) studies of brain function in health and disease that rely on measurement of signals generated from endogenous or exogenous tracers metabolized by energy-producing pathways. Astrocytes are increasingly recognized as having essential roles in both signaling and energetics during brain activation, including modulation of neurotransmission via gliotransmitters, synthesis and cycling of amino acid neurotransmitters, regulation of extracellular glutamate and K + levels and blood flow
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