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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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“This produced a large and prompt increase in NADHCYT, likely mediated by the rapid action of LDH, which converts NAD to NADH in parallel with the conversion of lactate to pyruvate (Williamson et al., 1967; Hung et al., 2011).”
Nonoxidative Glucose Consumption During Focal Physiologic Neural Activity
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“In fact, employing an NADH biosensor, Díaz-García et al. demonstrated that transient NADH production from glycolysis exceeds the rate of NADH shuttling to mitochondria, 47 indicating that increased glycolysis relative to MAS activity leads to a net reduction in NAD + .”
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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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