Regional aerobic glycolysis in the human brain

105

Rodent 13 C magnetic resonance spectroscopy studies show that glutamatergic signaling requires high oxidative energy in the awake resting state and allowed calibration of functional magnetic resonance imaging (fMRI) signal in terms of energy relative to the resting energy. Here, we derived energy used for glutamatergic signaling in the awake resting human. We analyzed human data of electroencephalography (EEG), positron emission tomography (PET) maps of oxygen (CMR O2 ) and glucose (CMR glc ) utilization, and calibrated fMRI from a variety of experimental conditions. CMR glc and EEG in the visual cortex were tightly coupled over several conditions, showing that the oxidative demand for signaling was four times greater than the demand for nonsignaling events in the awake state. Variations of CMR O2 and CMR glc from gray-matter regions and networks were within ±10% of means, suggesting that most areas required similar energy for ubiquitously high resting activity. Human calibrated fMRI results suggest that changes of fMRI signal in cognitive studies contribute at most ± 10% CMR O2 changes from rest. The PET data of sleep, vegetative state, and anesthesia show metabolic reductions from rest, uniformly 420% across, indicating no region is selectively reduced when consciousness is lost. Future clinical investigations will benefit from using quantitative metabolic measures. Keywords: astrocytes; baseline; field potentials; glutamate; multiunit activity; resting state INTRODUCTIONThe human brain consumes 20% of the body's energy at rest despite being only 2% of total body mass. 1 Normally glucose oxidation is the source of energy production supporting brain function 2 in which gray-matter signaling (i.e., events associated with neuronal firing) is dominated by glutamatergic neurons. 3 Estimates of the fraction of resting brain energy devoted to signaling were originally quite low. 4 But recent experimental studies in rodents and theoretical modeling have converged on the conclusion that majority of the resting energy consumption supports glutamatergic signaling and the energy demand changes linearly with pyramidal neuron firing rates and glutamate neurotransmitter release and reuptake. [5][6][7][8][9] Therefore in rodent models it is possible, to a first order, to show that the resting energy is primarily dedicated to total glutamatergic signaling, and the changes in neuronal signaling relative to a well-defined resting activity level can be used to calibrate changes in energy consumption during functional magnetic resonance imaging (fMRI) experiments. 10,11 In the awake human brain, however, the fraction of resting energy usage devoted to glutamatergic signaling is less well understood. The magnitude of neuronal signaling in the human brain, and by inference the commensurate energy demand, underscores the functional relevance of resting activity and has profound implications for interpreting fMRI experiments in humans. [12][13][14] Given the rapidly increasing use of resting-state fMRI in mapping networks-defined as a...

Section: Disclosure/conflict Of Interestmentioning

confidence: 73%

“…[31][32][33][34][35] The meta-analysis was composed of CMR O2 and CMR glc values from as few as 23 and as many as 46 distinct brain areas in 109 subjects. BioImage Suite (www.…”

Section: Regional Oxidative Demand For Glutamatergic Activity In the mentioning

confidence: 99%

Section: Regional Oxidative Demand For Glutamatergic Activity In the mentioning

confidence: 99%

See 1 more Smart Citation

Glutamatergic Function in the Resting Awake Human Brain is Supported by Uniformly High Oxidative Energy

Hyder

Fulbright

Shulman

et al. 2013

105

“…In a recent whole-brain voxelwise analysis, 6 it was showed that regional cerebral blood flow (rCBF) measured with arterial spin labeling (ASL) significantly correlated with three nodal topological centrality measures (mean functional connectivity strength, local efficiency, and betweenness centrality) in an extensive resting-brain network estimated from blood-oxygen-level-dependent (BOLD) activity correlations. Given that rCBF is, in turn, closely related to basal cerebral metabolism, 7,8 the tight association between local centrality measures and rCBF suggests an underlying metabolic basis for highly connected and/or highly centralized functional hubs. Moreover, these findings were broadly consistent with an earlier voxelwise analysis of fMRI data that had found a highly significant association between amyloid-b deposition in Alzheimer's disease (AD), a metabolically driven process, 9 and the nodal degree centrality.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Energy Metabolism and the Brain’s Functional Network Architecture: An Integrative Review

Lord

Expert

Huckins

et al. 2013

Recent functional magnetic resonance imaging (fMRI) studies have emphasized the contributions of synchronized activity in distributed brain networks to cognitive processes in both health and disease. The brain's 'functional connectivity' is typically estimated from correlations in the activity time series of anatomically remote areas, and postulated to reflect information flow between neuronal populations. Although the topological properties of functional brain networks have been studied extensively, considerably less is known regarding the neurophysiological and biochemical factors underlying the temporal coordination of large neuronal ensembles. In this review, we highlight the critical contributions of high-frequency electrical oscillations in the g-band (30 to 100 Hz) to the emergence of functional brain networks. After describing the neurobiological substrates of g-band dynamics, we specifically discuss the elevated energy requirements of high-frequency neural oscillations, which represent a mechanistic link between the functional connectivity of brain regions and their respective metabolic demands. Experimental evidence is presented for the high oxygen and glucose consumption, and strong mitochondrial performance required to support rhythmic cortical activity in the g-band. Finally, the implications of mitochondrial impairments and deficits in glucose metabolism for cognition and behavior are discussed in the context of neuropsychiatric and neurodegenerative syndromes characterized by large-scale changes in the organization of functional brain networks.

“…The above studies show that the resting brain also releases small amounts of lactate (B3% to 7% of glucose uptake), and that lactate efflux quickly increases by 3-to 4-fold during activation. A recent positron emission tomographic study in a resting young adult human brain revealed regional heterogeneity in the mismatch between local rates of glucose and oxygen utilization (Vaishnavi et al, 2010), suggesting that lactate release from various brain structures probably differs under basal conditions. …”

mentioning

confidence: 99%

Brain Lactate Metabolism: The Discoveries and the Controversies

Dienel

2011

405

434

Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-toblood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. Keywords: astrocyte; brain activation; glucose; lactate shuttling; metabolism; neuron Glucose is the major fuel for the brain, and its metabolism by different pathways has important functions related to energetics, neurotransmission, oxidation-reduction (redox) reactions, and biosynthesis of essential brain components (Figure 1). For many decades, lactate production in the brain was viewed as a consequence of inadequate oxygen delivery, disruption of oxidative metabolism, or mismatch between glycolytic and oxidative rates (Siesjö, 1978), but more recently, the conceptual role of lactate metabolism and function in the normal brain have undergone major changes, shifting from developmental fuel and glycolytic waste product to include its use as a supplemental fuel and signaling molecule. Starting in the 1970s to 1980s studies carried out in different laboratories with diverse experimental interests related to brain function brought attention to upregulation of glycolysis, lactate production, lactate release into the blood, the possibility of lactate shuttling among cell types within the brain, lactate fueling adult brain during exercise, and roles of lactate in the regulation of blood flow; some of these topics are controversial and highly debated. The experimental paradigm and physiologic status of subjects are critical for interpretation of data, and this review first presents a brief historical overview of studies related to brain lactate transport and metabolism, then compares sets of data to provide a perspective and context within which the consistency of simi...