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Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake
Open accessAbstract
SUMMARY Proper brain function requires a substantial energy supply, up to 20% of whole body energy in humans, and brain activation produces large dynamic variations in energy demand. While local increases in cerebral blood flow are well known, the cellular responses to energy demand are controversial. During brain excitation, glycolysis of glucose to lactate temporarily exceeds the rate of mitochondrial fuel oxidation; although the increased energy demand occurs mainly within neurons, some have suggested this glycolysis occurs mainly in astrocytes, which then shuttle lactate to neurons as their primary fuel. Using metabolic biosensors in acute hippocampal slices and brains of awake mice, we find that neuronal metabolic responses to stimulation do not depend on astrocytic stimulation by glutamate release, nor do they require neuronal uptake of lactate; instead they reflect increased direct glucose consumption by neurons. Neuronal glycolysis temporarily outstrips oxidative metabolism, and provides a rapid response to increased energy demand.
Overview
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Written from the paper’s full text.
TL;DR
Using genetically encoded metabolic biosensors in acute hippocampal slices and awake mouse cortex, this paper finds that neuronal stimulation raises cytosolic NADH:NAD+ via increased neuronal glycolysis, not via astrocyte-derived lactate uptake. The results contradict a stimulation-dependent astrocyte-neuron lactate shuttle and support direct neuronal glucose consumption as a rapid metabolic response.
Key findings
- Synaptic stimulation of dentate granule neurons produced a ~2-fold rise in cytosolic NADH:NAD+ (Peredox lifetime 1.73 ± 0.01 ns at baseline to 1.88 ± 0.01 ns stimulated; mean ± SEM, n=166 neurons), lasting about 3 minutes and correlating with Ca2+ responses.
- Blocking postsynaptic glutamate receptors abolished the neuronal NADH transient, and antidromic stimulation still produced similar transients, indicating glutamate stimulation of astrocytes is neither sufficient nor necessary.
- MCT inhibition with AR-C155858 reduced the neuronal response to exogenous lactate to 27% ± 2% of control (n=36 neurons) but did not abolish—and actually increased—the stimulation-induced NADH transient (95% CI 1.23- to 1.34-fold larger). LDH inhibition reduced exogenous lactate responses by 78% ± 3% but increased stimulation-induced NADH transients by 37% ± 5% (n=54 neurons).
- In awake mice, whisker stimulation produced ~4–5 minute NADH transients in responsive S1-BF neurons, with a smaller typical increase (~33% over resting); MCT inhibition reduced exogenous lactate responses by 85.3% ± 6.3% (n=59 neurons in 6 animals) but did not diminish whisker-stimulation NADH transients.
- Neuronal intracellular glucose showed stimulation-induced dips that became larger with partial glucose transport inhibition and were reduced by MCT inhibition; glycolysis inhibition with iodoacetic acid greatly reduced NADH transients.
Methods
- Acute mouse hippocampal slices and awake, unanesthetized mice with cranial windows; C57BL/6NCrl mice, including postnatal day 1 viral injections for hippocampal sensors and adult mice for cortical imaging.
- Two-photon fluorescence lifetime imaging of genetically encoded biosensors: Peredox for cytosolic NADH:NAD+, RCaMP1h for Ca2+, SweetieTS for glucose, Laconic for lactate, and pHRed for pH.
- Stimulation via electrical synaptic or antidromic stimulation in slices and 10-second 5 Hz whisker stimulation in vivo; pharmacology included NBQX/D-AP5, AR-C155858, GSK-2837808A, iodoacetic acid, cytochalasin B, and aminooxyacetate.
Limitations
- The paper states that because experiments used optical signals from neuronal cell bodies, it cannot exclude ANLS activity at synaptic terminals; it also cannot exclude some contribution of mitochondrial NADH shuttles to the NADH transients.
- The paper states that the relative contributions of glycolysis and oxidative phosphorylation to immediate neuronal energy demands remain unknown.
- The text notes technical caveats: Laconic has shallow lactate dependence and pH sensitivity, producing uncertainty in absolute lactate concentrations; AOA’s small effect could partly reflect alanine transaminase inhibition; and in vivo drug delivery through the permeable window required higher concentrations and longer times than in slices.
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25 Own interpretation · 22 Not checked yet · 21 Own result · 8 Own method · 2 No basis given
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In the paper
“Stimulation-induced transients in NADHCYT were not unique to the in vitro hippocampal slice preparation, but were also observed in a more natural in vivo situation, in the brains of awake, unanesthetized mice.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Similar neuronal cytosolic NADH transients occur in vivo with normal sensory stimulation
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“As for the in vitro case, the size of the NADHCYT transients was well-correlated with the Ca2+ response even for small responses (Figure 7C).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Similar neuronal cytosolic NADH transients occur in vivo with normal sensory stimulation
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“Indeed, we found that application of MCT inhibitor to the slice did inhibit the stimulation-induced dips reported by the glucose sensor (Fig 5C, D).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Cytosolic NADH transients reflect increased neuronal glycolysis upon stimulation
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“Recording from many neurons, we observed a wide range of both Ca2+ and NADHCYT responses, but the two were well-correlated even for the smallest responses (Fig. 1D)”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Stimulation produces transient increases of cytosolic NADH:NAD+ in individual neurons
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“There was only a small reduction (~10%) in the transients in the presence of AOA, relative to the slight increase in parallel controls with pyruvate (Fig. 6C, Suppl. Fig. S6).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Transients in cytosolic NADH do not simply reflect mitochondrial NAD(P)H transients
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“The increase in cytosolic NADH:NAD+ ratio (hereafter referred to as NADHCYT) was quite substantial, with 60 stimuli typically producing a change from a baseline ratio of ~1:1000 up to a stimulated ratio of ~1:500, a ~2-fold change (corresponding to a Peredox LT of 1.73 ± 0.01 ns at baseline and 1.88 ± 0.01 ns when stimulated; mean ± SEM, n=166 neurons).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Stimulation produces transient increases of cytosolic NADH:NAD+ in individual neurons
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In the paper
“In the presence of the MCT inhibitor, the NADHCYT response to direct application of exogenous lactate was much smaller (27% ± 2% of the original response, mean ± SEM, n=36 neurons), as expected if lactate uptake is mostly blocked.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Lactate import does not contribute to neuronal NADHCYT transients
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“Upon brief synaptic stimulation of the DGNs by electrical stimulation in the molecular layer of the dentate gyrus (60 brief pulses), there was a prominent and reliable elevation of the cytosolic NADH:NAD+ ratio for a period of about 3 minutes (Figure 1A–C).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Stimulation produces transient increases of cytosolic NADH:NAD+ in individual neurons
plaindirectn = 166- Asserted: passes — The authors put it forward as true.
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“Next we applied the MCT inhibitor AR-C155858 (2 μM), and observed a small decline in the resting NADHCYT”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Lactate import does not contribute to neuronal NADHCYT transients
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“With application of the MCT inhibitor, there was no significant change in these neuronal intracellular [lactate] transients (Fig. 3G)”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Lactate import does not contribute to neuronal NADHCYT transients
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- Probably not a substantial claim. 15
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“The opposite was seen: blockade of the postsynaptic response (as judged from the disappearance of the postsynaptic Ca2+ transient, and the disappearance of the EPSP from an extracellular electrode; Fig 2A, B and Suppl. Fig. S3) was accompanied by disappearance of the NADHCYT transient (Fig 2B, C).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Astrocyte stimulation by glutamate is neither sufficient nor necessary for neuronal NADH transients
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“Practically all of these responsive neurons exhibited an approximately 4–5 minute long elevation in NADHCYT (Figure 7A, B), while neighboring non-responsive neurons showed no significant change.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Similar neuronal cytosolic NADH transients occur in vivo with normal sensory stimulation
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“Application of the MCT inhibitor AR-C155858 (at 50 μM rather than the 2 μM used for slice) effectively reduced the size of the lactate-induced increase (by 85.3% ± 6.3%, mean ± SEM, n=59 neurons in 6 animals; Fig. 7D). Nevertheless, neuronal NADHCYT transients induced by whisker stimulation were not diminished by the MCT inhibitor (Fig. 7E, F).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Similar neuronal cytosolic NADH transients occur in vivo with normal sensory stimulation
plaindirectn = 59- Asserted: passes — The authors put it forward as true.
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“We observed small transient drops (dips) in neuronal intracellular [glucose] upon synaptic stimulation that had a very similar time course to the NADHCYT transients (Fig. 5A).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Cytosolic NADH transients reflect increased neuronal glycolysis upon stimulation
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“As expected, application of the LDH inhibitor reduced the NADHCYT response to direct application of exogenous lactate (by 78% ± 3% of the original response, mean ± SEM, n=54 neurons; Fig. 3E).”
- Also stated in: § Lactate import does not contribute to neuronal NADHCYT transients · plain
“Instead, the stimulation-induced NADHCYT responses were larger (by 37% ± 5%; n=54 neurons; Fig. 3F), as expected for production of NADH within the neuron when LDH-dependent recycling to NAD+ is inhibited.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Lactate import does not contribute to neuronal NADHCYT transients
plaindirectn = 54- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The LDH inhibitor GSK-2837808A specifically inhibits lactate dehydrogenase.
- Also stated in: § Lactate import does not contribute to neuronal NADHCYT transients · plain
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“When we deliberately reduced glucose transport rate chronically, by partial inhibition with cytochalasin B, the baseline [glucose]i was predictably lower, but the stimulation-induced dips in [glucose]i actually became larger (Fig 5A, B), consistent with our hypothesis.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Cytosolic NADH transients reflect increased neuronal glycolysis upon stimulation
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In the paper
“In dentate granule neurons in a hippocampal slice, the typical increase in this ratio is substantial - approximately a 2-fold increase above the resting level. In neurons of barrel cortex observed in vivo, the typical increase is smaller (about a 33% increase over the resting level), but still substantial.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > The NADH biosensor reports metabolic transients specifically in neuronal cytosol
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“IAA treatment diminished the baseline (consistent with a contribution of glycolysis to the resting NADHCYT level), and upon return to the experimental temperature, the stimulation-induced NADHCYT transient was much smaller, despite a slightly larger Ca2+ transient in response to stimulation.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Cytosolic NADH transients reflect increased neuronal glycolysis upon stimulation
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“It is generally agreed that the “resting” brain, under normal metabolic circumstances, consumes glucose and metabolizes it nearly completely to CO2 (Clarke and Sokoloff, 1994; Madsen et al., 1999).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > INTRODUCTION
What the sources say
- Not checked yetcites Clarke and Sokoloff, 1994
- Not checked yetcites Madsen et al., 1999 source
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In the paper
“Because our experiments were all done with optical signals from the cell bodies of neurons, we cannot exclude the possibility of ANLS activity at synaptic terminals”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Astrocyte-to-neuron lactate shuttling may occur at rest, but not during neuronal stimulation
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“Our results support the possibility of an ANLS that functions at rest but not during neuronal stimulation.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Astrocyte-to-neuron lactate shuttling may occur at rest, but not during neuronal stimulation
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In the paper
“The failure of MCT inhibitor to abolish the stimulation-induced transients in vivo supports the conclusion that such metabolic transients are endogenous to the neurons and do not rely on lactate import from the extracellular space or from astrocytes.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Similar neuronal cytosolic NADH transients occur in vivo with normal sensory stimulation
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In the paper
“The physiological coordination of both glycolysis and oxidative metabolism in response to neuronal activity may be choreographed by calcium influx, which, as shown in Figs. 1D and 7C, is tightly correlated to the cytosolic NADH transients.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Transient aerobic glycolysis may provide a rapid first response to energy resupply, followed by the higher capacity response by oxidative phosphorylation
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In the paper
“The fact that the transients are actually larger when the MCTs are inhibited may indicate that neurons normally export lactate when their metabolism is activated by stimulation, as discussed below.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Lactate import does not contribute to neuronal NADHCYT transients
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In the paper
“NADHCYT can rise in response to either increased glycolysis (which converts NAD+ to NADH at the GAPDH step), to increased conversion of lactate to pyruvate, or to decreased activity of mitochondrial NADH shuttles.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > RESULTS > Stimulation produces transient increases of cytosolic NADH:NAD+ in individual neurons
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“Wild-type C57BL/6NCrl mice of both genders were bred in house and used in all acute brain slice and in vivo experiments, and mice were randomly allocated to experimental groups.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Experimental Models and Subject Details
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“Similarly, RCaMP1h expression alone led to some signal in the green optical channel, probably due to an immature fluorophore, in direct experiments approximately 4.4% of the red fluorescence intensity, and having a lifetime of ~0.71 ns; these values were used to correct the baseline in dual expression experiments.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Quantification and Statistical Analyses
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“When imaging from the same cortical region on multiple days, previously imaged neurons were re-identified using the pattern of the surface vasculature as guidance, and then an adjacent volume was selected to ensure that all neurons in the sample were unique.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Method Details
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“Like muscle, the brain has no doubt evolved to meet the large instant-to-instant changes in energy demands with a choreographed regulation of the core metabolic pathways, to ensure not only brain cell health but organismal survival.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Transient aerobic glycolysis may provide a rapid first response to energy resupply, followed by the higher capacity response by oxidative phosphorylation
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“Viral expression of Peredox and RCaMP1h permitted recording from different neurons in the same mice on different days (Andermann et al., 2010; O’Connor et al., 2010).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Method Details
What the sources say
- Not checked yetcites Andermann et al., 2010
- Not checked yetcites O’Connor et al., 2010
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In the paper
“PET studies also show that blood flow and glucose consumption are dramatically increased by brain activation, but oxygen consumption barely increases (Fox and Raichle, 1986; Fox et al., 1988).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Transient aerobic glycolysis may provide a rapid first response to energy resupply, followed by the higher capacity response by oxidative phosphorylation
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“Most likely the changes in free [NADH] are already buffered by high levels of cytosolic dehydrogenases that bind NADH (Zhang et al., 2002), and the additional expression of sensor makes only a negligible change in the buffering capacity.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Method Details
What the sources say
- Not checked yetcites Zhang et al., 2002
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“For this reason, we mostly measured the net lifetime change for the transients, relative to baseline (ΔLT).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Quantification and Statistical Analyses
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“However, it is known that in the evolution of skeletal muscle, the muscle fibers with the most dynamic energy requirements -- the fast-twitch fibers -- tend to rely on glycolysis for prompt energy production (Crow and Kushmerick, 1982; Spriet, 1989).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Transient aerobic glycolysis may provide a rapid first response to energy resupply, followed by the higher capacity response by oxidative phosphorylation
What the sources say
- Not checked yetcites Crow and Kushmerick, 1982
- Not checked yetcites Spriet, 1989
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“unlike the commonly used MCT inhibitor α-cyano-4-hydroxycinnamate (4-CIN), which blocks mitochondrial pyruvate uptake with higher affinity than it blocks MCTs (Halestrap and Denton, 1974).”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Method Details
What the sources say
- Not checked yetcites Halestrap and Denton, 1974
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Bleedthrough of green Peredox fluorescence into the red RCaMP optical channel was corrected using the ratio of measured red to green fluorescence observed when only Peredox was expressed (Suppl. Fig. S2), approximately 6.0%.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Quantification and Statistical Analyses
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“of “catch-up” oxidation by many neighboring brain cells (and by the stimulated neurons themselves) as well as some net lactate excretion from the brain (Dienel, 2012; Glenn et al., 2015), particularly when activation is strong and synchronous, as in epilepsy (Collins et al., 1970; During et al., 1994)”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > DISCUSSION > Transient aerobic glycolysis may provide a rapid first response to energy resupply, followed by the higher capacity response by oxidative phosphorylation
What the sources say
- Not checked yetcites Dienel, 2012 source
- Not checked yetcites Glenn et al., 2015
- Not checked yetcites Collins et al., 1970
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Likewise, green glucose sensor fluorescence produced a bleedthrough of ~5.9% to the red channel.”
§ Neuronal stimulation triggers neuronal glycolysis and not lactate uptake > STAR★Methods > Quantification and Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The increased energy demand during brain excitation occurs mainly within neurons.
“although the increased energy demand occurs mainly within neurons, some have suggested this glycolysis occurs mainly in astrocytes”
The paper relies on this without support.
The Peredox biosensor is expressed in the cytosol and not targeted to mitochondria.
“The biosensor is expressed in cytosol and not targeted to mitochondria; it therefore reports cytosolic NADH: NAD+ ratio.”
The paper relies on this without support.
NADH does not pass through mitochondrial membranes.
“The NADHCYT transients reported by Peredox are in principle compartmentally separated from the changes in mitochondrial NADH, and NADH does not pass through the mitochondrial membranes.”
The paper relies on this without support.
The LDH inhibitor GSK-2837808A specifically inhibits lactate dehydrogenase.
“the neuronal NADHCYT transients were elevated rather than abolished upon inhibition of lactate dehydrogenase by the high-affinity inhibitor GSK-2837808A (2 μM; Fig. 3D, F).”
The paper relies on this without support.
Both glycolysis and oxidative metabolism are elevated after stimulation.
“Despite the fact that both glycolysis and oxidative metabolism are elevated after stimulation”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“but previously published data strongly indicate that the increase in lactate and glutamate levels is the consequence of the surge in glycolysis and the ensuing increase of cytosolic NADH:NAD+ ratio taking place during neuronal activation (Díaz-García et al., 2017).”
From Perception is associated with the brain’s metabolic response to sensory stimulation (2022) · cites this paper as Díaz-García et al., 2017
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This is consistent with a recent report that astrocyte-derived lactate is not required for the bioenergetic response to stimulation in neurons (Díaz-García et al., 2017).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Díaz-García et al., 2017
In the citing paper
“However, the use of pure lactate as an alternative fuel, rather than a redox-balanced mixture of lactate and pyruvate, abnormally elevates the low cytosolic NADH redox ratio in neurons (seen in vitro by Hung et al. [2011] and Mongeon et al. [2016] as well as in vivo by Díaz-García et al. [2017]); this decreases the rate of neuronal glycolysis in a way that would not represent the normal effect in”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
In the citing paper
“Inhibition of MCT in vivo in the cortical neurons of awake mice also blocks the NADHCYT response to exogenous lactate but not to sensory stimulation.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
In the citing paper
“These blockers instead lead to enhancement of the NADHCYT transients, suggesting that neurons normally export lactate when stimulated.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
In the citing paper
“With brief neuronal excitation in an acute hippocampal slice, NADHCYT rises rapidly and remains elevated for ∼2–3 min, reflecting a temporary imbalance favoring production of NADH over its recycling back to NAD+.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
In the citing paper
“The NADHCYT transients decrease with inhibition of glycolysis but not of the MAS, indicating that increased neuronal glycolysis upon stimulation is the main cause of the NADHCYT transients.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
In the citing paper
“Pharmacologic blockade of MCT or of LDH abolishes the elevation of NADHCYT in response to exogenous lactate but not in response to stimulation, which rules out a role of lactate import in producing the transient increases in neuronal NADHCYT.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
In the citing paper
“In dentate granule neurons, MCT inhibition led to higher peaks of NADHCYT as well as smaller dips in glucose, suggesting that the elevated NADHCYT also exerted back pressure on glycolysis, presumably on the GAPDH equilibrium (Díaz-García et al., 2017).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Díaz-García et al., 2017
Citations
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Nonoxidative Glucose Consumption During Focal Physiologic Neural Activity
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Intracellular Oxidation-Reduction States in Vivo
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Herrero-Mendez, A., Almeida, A., Fernández, E., Maestre, C., Moncada, S., & Bolaños, J. P. (2009) · Nature Cell Biology · doi:10.1038/ncb1881 · Cited by 844 · cited 2×
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Activity-dependent regulation of energy metabolism by astrocytes: an update
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“Astrocyte release of lactate is thought to be stimulated by synaptic release of glutamate, which is then transported into astrocytes with Na ions, stimulating astrocytic glycolysis (Pellerin and Magistretti, 1994; Pellerin et al., 2007).”
InfluentialCell type- and brain region-resolved mouse brain proteome
Sharma, K., Schmitt, S., Bergner, C. G., Tyanova, S., Kannaiyan, N., Manrique-Hoyos, N., Kongi, K., Cantuti, L., Hanisch, U.-K., Philips, M.-A., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4160 · Cited by 785 · cited 1×
“…(Salway, 2004; in neurons, mainly the malate-aspartate shuttle [MAS], McKenna et al., 2006); unbiased proteomics and transcriptomics surveys of central neurons reveal that these are by far the dominant NADH dehydrogenase enzymes in the cytosol (Sharma et al., 2015; Zeisel et al., 2015; Figure S1).”
Evidence Supporting the Existence of an Activity-Dependent Astrocyte-Neuron Lactate Shuttle
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“…an ‘‘astrocyte-neuron lactate shuttle’’ (ANLS), which proposes that astrocytes are stimulated by neuronal glutamate release to convert more glucose to lactate, which is then Cell released by the astrocytes to serve as fuel for the neighboring neurons (Bélanger et al., 2011; Pellerin et al., 1998).”
InfluentialNeural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis
Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R., & Webb, W. W. (2004) · Science · doi:10.1126/science.1096485 · Cited by 742 · cited 2×
“While some have attributed this overshoot to glycolytic NADH production in the cytosol of astrocytes (Kasischke et al., 2004), it is almost certainly due instead to replenishment of mitochondrial NADH in neurons bymultiplemeans (Brennan et al., 2006; Shuttleworth, 2010; Berndt et al., 2015):…”
Akerboom, J., Calderón, N. C., Tian, L., Wabnig, S., Prigge, M., Tolö, J., Gordus, A. G., Orger, M. B., Severi, K. E., Macklin, J. J., et al. (2013) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2013.00002 · Cited by 736 · cited 8×
“(B) Individual traces from a cell in the filmstrip illustrate the time course of synaptically stimulated transients in Peredox (top) and RCaMP1h lifetimes (bottom).”
InfluentialCirculation and Energy Metabolism of the Brain
Clarke, D. D., & Sokoloff, L. (1999) · Cited by 732
Regulation of Corepressor Function by Nuclear NADH
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In vivo evidence for a lactate gradient from astrocytes to neurons
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Chemical energetics of slow- and fast-twitch muscles of the mouse.
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Imaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor
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InfluentialBrain lactate metabolism: the discoveries and the controversies
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“The ultimate fate of the exported lactate may be a combination of ‘‘catch-up’’ oxidation by many neighboring brain cells (and by the stimulated neurons themselves), as well as some net lactate excretion from the brain (Dienel, 2012; Glenn et al., 2015), particularly when activation is strong and synchronous, as in epi…”
Neural Activity in Barrel Cortex Underlying Vibrissa-Based Object Localization in Mice
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Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism
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InfluentialCa2+-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons
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“…lactate dehydrogenase (LDH) activity, and mitochondrial NADH shuttles (Salway, 2004; in neurons, mainly the malate-aspartate shuttle [MAS], McKenna et al., 2006); unbiased proteomics and transcriptomics surveys of central neurons reveal that these are by far the dominant NADH…”
GLUT4 Mobilization Supports Energetic Demands of Active Synapses
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Glycolytic enzymes localize to synapses under energy stress to support synaptic function
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Astrocytes Couple Synaptic Activity to Glucose Utilization in the Brain
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“Proponents of the ANLS have argued that neurons preferentially use this astrocyte-produced lactate rather than glucose (Magistretti and Pellerin, 1999).”
Salway, J. G. (1993) · Cited by 261
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“Next we applied the MCT inhibitor AR-C155858 (2 mM), and observed a small decline in the resting NADHCYT (as discussed below, this is consistent with some astrocyte-toneuron lactate shuttling at rest, as previously suspected; Mongeon et al., 2016).”
InfluentialThe CA3 “backprojection” to the dentate gyrus
Scharfman, H. E. (2007) · Progress in brain research · doi:10.1016/s0079-6123(07)63034-9 · Cited by 254 · cited 2×
“Nevertheless, it is known that hilar stimulation triggers synaptic transmission between mossy fibers (DGNs axons) and CA3 pyramidal neurons, which send backprojections to the dentate gyrus (Scharfman, 2007).”
Chronic cellular imaging of mouse visual cortex during operant behavior and passive viewing
Andermann, M. L. (2010) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2010.00003 · Cited by 226
Chuquet, J., Quilichini, P., Nimchinsky, E. A., & Buzsáki, G. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0762-10.2010 · Cited by 217 · cited 2×
“In vivomeasurements to learn which cell type shows greater stimulated uptake of glucose analogs have given conflicting results (Chuquet et al., 2010; Lundgaard et al., 2015), perhaps because the fluorescent glucose derivatives used are substantially different from glucose in structure and size;…”
Bittner, C. X., Valdebenito, R., Ruminot, I., Loaiza, A., Larenas, V., Sotelo-Hitschfeld, T., Moldenhauer, H. J., Martín, A. S., Gutiérrez, R., Zambrano, M., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5311-10.2011 · Cited by 190 · cited 2×
“Lactate Import Does Not Contribute to Neuronal NADHCYT Transients It remains possible that astrocytes depend on other stimuli (e.g., K+ release from neurons) for strong stimulation of lactate release (Peng et al., 1994; Bittner et al., 2011).”
Patel, A. B., Lai, J. C. K., Chowdhury, G. M. I., Hyder, F., Rothman, D. L., Shulman, R. G., & Behar, K. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403576111 · Cited by 186 · cited 1×
“The ANLS hypothesis continues to generate controversy in the literature (Hertz, 2004; Chuquet et al., 2010; Patel et al., 2014; Lundgaard et al., 2015).”
Glenn, T. C., Martin, N. A., Horning, M. A., McArthur, D. L., Hovda, D. A., Vespa, P. M., & Brooks, G. A. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2014.3483 · Cited by 184 · cited 2×
“The ultimate fate of the exported lactate may be a combination of ‘‘catch-up’’ oxidation by many neighboring brain cells (and by the stimulated neurons themselves), as well as some net lactate excretion from the brain (Dienel, 2012; Glenn et al., 2015), particularly when activation is strong and synchronous, as in epi…”
Madsen, P. L., Cruz, N. F., Sokoloff, L., & Dienel, G. A. (1999) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199904000-00005 · Cited by 174 · cited 1×
“It is generally agreed that the ‘‘resting’’ brain, under normal metabolic circumstances, consumes glucose and metabolizes it nearly completely to CO2 (Clarke and Sokoloff, 1994; Madsen et al., 1999).”
Dienel, G. A. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24015 · Cited by 168 · cited 1×
“Although there are strong arguments against the logic of the ANLS on its face (Dienel, 2017), there has been little conclusive evidence at the cellular level.”
Mapping oxygen concentration in the awake mouse brain
Lyons, D. G., Parpaleix, A., Roche, M., & Charpak, S. (2016) · eLife · doi:10.7554/elife.12024 · Cited by 165
The redox switch/redox coupling hypothesis
Cerdán, S., Rodrigues, T. B., Sierra, A., Benito, M., Fonseca, L. L., Fonseca, C. P., & García-Martín, M. L. (2006) · Neurochemistry International · doi:10.1016/j.neuint.2005.12.036 · Cited by 146 · cited 1×
“These observations under resting conditions are compatible with higher lactate production by astrocytes and a redox gradient that would favor lactate transfer to neurons (see also Cerdán et al., 2006).”
Glutamate mediates acute glucose transport inhibition in hippocampal neurons
Porras, O. H., Loaiza, A., & Barros, L. F. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1882-04.2004 · Cited by 139 · cited 1×
“This argues that the two effects are mechanistically connected, and thus it argues against the idea that the glucose dips result from a reported activity-induced decrease in glucose transport (Porras et al., 2004).”
The astrocyte-neuron lactate shuttle: a challenge of a challenge
Hertz, L. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200411000-00008 · Cited by 124 · cited 1×
“The ANLS hypothesis continues to generate controversy in the literature (Hertz, 2004; Chuquet et al., 2010; Patel et al., 2014; Lundgaard et al., 2015).”
Ivanov, A. I., Malkov, A. E., Waseem, T., Mukhtarov, M., Buldakova, S., Gubkina, O., Zilberter, M., & Zilberter, Y. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.222 · Cited by 113 · cited 4×
“Measurements of oxygen levels in brain slices indicate that oxygen consumption does increase promptly in response to stimulation (Hall et al., 2012; Ivanov et al., 2014), suggesting a coordinated response of both glycolysis and oxidative phosphorylation to meet increased demand.”
InfluentialDirect Measurement of Extracellular Lactate in the Human Hippocampus During Spontaneous Seizures
During, M. J., Fried, I., Leone, P., Katz, A., & Spencer, D. D. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.62062356.x · Cited by 111 · cited 2×
“, 2015), particularly when activation is strong and synchronous, as in epilepsy (Collins et al., 1970; During et al., 1994).”
Cerebral energy metabolism during electroshock seizures in mice
Collins, R., Jb, P., & Plum, F. (1970) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1970.218.4.943 · Cited by 110 · cited 2×
“, 2015), particularly when activation is strong and synchronous, as in epilepsy (Collins et al., 1970; During et al., 1994).”
Peng, L., Zhang, X., & Leif, H. (1994) · Brain Research · doi:10.1016/0006-8993(94)90475-8 · Cited by 109 · cited 2×
“Lactate Import Does Not Contribute to Neuronal NADHCYT Transients It remains possible that astrocytes depend on other stimuli (e.g., K+ release from neurons) for strong stimulation of lactate release (Peng et al., 1994; Bittner et al., 2011).”
Shuttleworth, C. W. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2009.12.015 · Cited by 104 · cited 7×
“, 2004), it is almost certainly due instead to replenishment of mitochondrial NADH in neurons bymultiplemeans (Brennan et al., 2006; Shuttleworth, 2010; Berndt et al., 2015): stimulation of tricarboxylic acid cycle dehydrogenases by calcium as well as increased shuttling of NADH from the cytosol (which may itself be s…”
InfluentialMongeon, R., Venkatachalam, V., & Yellen, G. (2016) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6593 · Cited by 100 · cited 4×
“The fluorescence lifetime (LT) of the sensor protein, measured in nanoseconds, gives a direct report of sensor occupancy and thus of the cytosolic NADH:NAD+ ratio (Mongeon et al., 2016).”
InfluentialSelf-citationBrennan, A. M., Connor, J. A., & Shuttleworth, C. W. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600292 · Cited by 97 · cited 3×
“…of astrocytes (Kasischke et al., 2004), it is almost certainly due instead to replenishment of mitochondrial NADH in neurons bymultiplemeans (Brennan et al., 2006; Shuttleworth, 2010; Berndt et al., 2015): stimulation of tricarboxylic acid cycle dehydrogenases by calcium as well as…”
Ovens, M. J., Manoharan, C., Wilson, M. C., Murray, C. M., & Halestrap, A. P. (2010) · Biochemical Journal · doi:10.1042/bj20100890 · Cited by 92 · cited 5×
“Next we applied the MCT inhibitor AR-C155858 (2 mM), and observed a small decline in the resting NADHCYT (as discussed below, this is consistent with some astrocyte-toneuron lactate shuttling at rest, as previously suspected; Mongeon et al., 2016).”
InfluentialQuantitative two-photon imaging of fluorescent biosensors
Yellen, G., & Mongeon, R. (2015) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.05.024 · Cited by 85 · cited 8×
“(B) Individual traces from a cell in the filmstrip illustrate the time course of synaptically stimulated transients in Peredox (top) and RCaMP1h lifetimes (bottom).”
InfluentialSelf-citationSingh, P. K., Salih, M., Leddy, J. J., & Tuana, B. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402282200 · Cited by 81 · cited 1×
“However, it remains to be learned whether this correlation is produced by a direct modulation of glycolytic rate by cytosolic calcium (e.g., Singh et al., 2004; Kim et al., 2016; Nicholson-Fish et al., 2016; Hu et al., 2016), by indirect effects due to Ca2+ uptake by mitochondria (Duchen, 1992;…”
Schuchmann, S., Kovacs, R., Kann, O., Heinemann, U., & Buchheim, K. (2001) · Brain Research Protocols · doi:10.1016/s1385-299x(01)00080-0 · Cited by 75 · cited 2×
“Transients in Cytosolic NADH Do Not Simply Reflect Mitochondrial NAD(P)H Transients Many studies of neurons and brain slices have used changes in ‘‘NAD(P)H’’ autofluorescence to monitor metabolic changes (Chance et al., 1962; Duchen, 1992; Schuchmann et al., 2001; Shuttleworth, 2010); these small fluorescence changes…”
Berndt, N., Kann, O., & Holzhütter, H.-G. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.70 · Cited by 56
Langemann, H., Alessandri, B., Mendelowitsch, A., Feuerstein, T. J., Landolt, H., & Gratzl, O. (2001) · Neurological Research · doi:10.1179/016164101101198785 · Cited by 50 · cited 3×
“These experiments were done in the presence of 2 mM lactate in the bath, comparable with measured extracellular lactate in the brain (Langemann et al., 2001), to provide continued support of mitochondrial oxidation, which is clearly important for sustained neuronal health.”
InfluentialATP utilization and provision in fast-twitch skeletal muscle during tetanic contractions
Spriet, L. L. (1989) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1989.257.4.e595 · Cited by 40 · cited 1×
“However, it is known that in the evolution of skeletal muscle, themuscle fibers with themost dynamic energy requirements (the fast-twitch fibers) tend to rely on glycolysis for prompt energy production (Crow and Kushmerick, 1982; Spriet, 1989).”
Satrústegui, J., & Bak, L. K. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1652-8 · Cited by 33 · cited 2×
“…glycolytic rate by cytosolic calcium (e.g., Singh et al., 2004; Kim et al., 2016; Nicholson-Fish et al., 2016; Hu et al., 2016), by indirect effects due to Ca2+ uptake by mitochondria (Duchen, 1992; Satrústegui and Bak, 2015), or simply by the ATP burden produced by the demands of Ca2+ extrusion.”
Nicholson-Fish, J. C., Cousin, M. A., & Smillie, K. J. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1663-5 · Cited by 25 · cited 2×
“However, it remains to be learned whether this correlation is produced by a direct modulation of glycolytic rate by cytosolic calcium (e.g., Singh et al., 2004; Kim et al., 2016; Nicholson-Fish et al., 2016; Hu et al., 2016), by indirect effects due to Ca uptake by mitochondria (Duchen, 1992; Satrústegui and Bak, 2015…”
AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells
Kim, N., Lee, J. O., Lee, H., Lee, Y. W., Kim, H. I., Kim, S. J., Park, S. H., Lee, C. S., Ryoo, S. W., Hwang, G., et al. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0302 · Cited by 22 · cited 2×
“However, it remains to be learned whether this correlation is produced by a direct modulation of glycolytic rate by cytosolic calcium (e.g., Singh et al., 2004; Kim et al., 2016; Nicholson-Fish et al., 2016; Hu et al., 2016), by indirect effects due to Ca uptake by mitochondria (Duchen, 1992; Satrústegui and Bak, 2015…”
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“Fluorescent biosensor measurement of NADHCYT in neurons during excitation has helped to resolve the role of glycolysis and intercellular lactate transport in the acute metabolic response (Díaz-García et al., 2017).”
BackgroundSelf-citation
Metadata
- Authors
- Díaz-García, C. M., Mongeon, R., Lahmann, C., Koveal, D., Zucker, H., & Yellen, G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Yellen, Gary
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 26
- Issue
- 2
- Pages
- 361-374.e4
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5559896
- OpenAlex
- W2739924689
- Semantic Scholar
- a96cd5dd74379072ec837b55007abc76f4f54521
- Cited by
- 466
- References
- 71
- Citations by year
- 2026: 39 · 2025: 62 · 2024: 50 · 2023: 52 · 2022: 51 · 2021: 62 · 2020: 60 · 2019: 40 · 2018: 42 · 2017: 7
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 NS055031, DP1 EB016985, F32 NS080455, F32 NS093784, F32 NS100331)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- lactate utilization, brain energy metabolism, neurostimulation, astrocytes, glutamate release, glucose utilization, oxidative metabolism, hippocampal slices, brain energy demand
- MeSH terms
- Animals, Glycolysis, Hippocampus, Male, Neurons, Lactic Acid, Mice
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