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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.
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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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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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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In the paper
“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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- It may state two separate claims as one. 18
- Probably not a substantial claim. 15
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In the paper
“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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In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“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
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In the paper
“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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In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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
What the sources say
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In the paper
“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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In the paper
“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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In the paper
“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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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
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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
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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
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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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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”
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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
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Bidirectional astrocytic GLUT1 activation by elevated extracellular K+
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“Also within seconds of synaptic activity, neurons activate their own glycolysis (Baeza-Lehnert et al., 2019) and increase their NADH/NAD+ ratio (Diaz-Garcia et al., 2017).”
BackgroundWdfy3 regulates glycophagy, mitophagy, and synaptic plasticity
Napoli, E., Panoutsopoulos, A. A., Kysar, P. E., Satriya, N., Sterling, K., Shibata, B., Imai, D. M., Ruskin, D. N., Zarbalis, K. S., & Giulivi, C. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x211027384 · Cited by 24
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β-amyloid monomers drive up neuronal aerobic glycolysis in response to energy stressors
Santangelo, R., Giuffrida, M. L., Satriano, C., Tomasello, M. F., Zimbone, S., & Copani, A. (2021) · Aging · doi:10.18632/aging.203330 · Cited by 21
“It remains to be determined what would be the ultimate effects of the released lactate, which can be captured by neighboring neurons as metabolic fuel [12], is potentially able to”
BackgroundMetabolic partitioning in the brain and its hijacking by glioblastomaPreprint
Swain, J. D. R., Michalopoulou, E., Noch, E., Lukey, M. J., & Aelst, L. V. (2023) · Genes & Development · doi:10.1101/gad.350693.123 · Cited by 24
“Arguing against the ANLS, recent work has shown that neurons respond to stimulation by increasing glucose consumption and glycolysis without a requirement for lactate respiration (Díaz-García et al. 2017).”
MethodFrazier, H. N., Ghoweri, A. O., Anderson, K. L., Lin, R., Popa, G. J., Mendenhall, M. D., Reagan, L. P., Craven, R. J., & Thibault, O. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00668 · Cited by 21
Enlightening brain energy metabolism
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York, E. M., Miller, A., Stopka, S. A., Martínez‐François, J. R., Hossain, M. A., Baquer, G., Regan, M. S., Agar, N. Y. R., & Yellen, G. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.16004 · Cited by 21
“While we cannot conclude neuronal specificity of these results, this data supports the proposal that neurons increase glycolysis upon stimulation rather than rely on astrocytic lactate (Diaz-Garcia et al., 2017 ; Li et al., 2023 ; Lundgaard et al., 2015 ; Rae et al., 2009).”
BackgroundResultSelf-citationZera, K. A., & Zastre, J. A. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.07.004 · Cited by 20
Looser, Z. J., Barrett, M. J. P., Hirrlinger, J., Weber, B., & Saab, A. S. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00377 · Cited by 21
“Genetically-encoded optical sensors enable real-time monitoring of cellular metabolite dynamics and are becoming invaluable neurobiological tools to study intercellular mechanisms governing brain energy homeostasis (Hou et al., 2011; SanMartin et al., 2014b; Sotelo-Hitschfeld et al., 2015;Mächler et al., 2016; Díaz-Ga…”
BackgroundThe Structure and the Regulation of Glycogen Phosphorylases in Brain
Mathieu, C., Dupret, J., & Rodrigues‐Lima, F. (2019) · Advances in neurobiology · doi:10.1007/978-3-030-27480-1_4 · Cited by 20
Imaging Approaches for the Study of Metabolism in Real Time Using Genetically Encoded Reporters
Chandris, P., Giannouli, C. C., & Panayotou, G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.725114 · Cited by 19
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Remote control of glucose-sensing neurons to analyze glucose metabolism
Alvarsson, A., & Stanley, S. A. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00469.2017 · Cited by 22
“Recent work indicates that glucose can also undergo glycolysis in activated neurons (33).”
BackgroundDiversification of Potassium Currents in Excitable Cells via Kvβ Proteins
Dwenger, M. M., Raph, S. M., Baba, S. P., Moore, J. B., & Nystoriak, M. A. (2022) · Cells · doi:10.3390/cells11142230 · Cited by 22
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Defining and characterizing neuronal senescence, ‘neurescence’, as GX arrested cells
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Computational singular perturbation analysis of brain lactate metabolism
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The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
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“As a rate-limiting factor in the activity of the MAS, additional aspartate was supplemented into mTeSR at 1, 2, or 5 mM for 24 hours, either alone, or in combination with 500 μM AOA.”
MethodInfluentialA Dual Nanosensor Approach to Determine the Cytosolic Concentration of ATP in Astrocytes
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Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport
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Energetic substrate availability regulates synchronous activity in an excitatory neural network
Tourigny, D. S., Karim, M. K. A., Echeveste, R., Kotter, M., & O'Neill, J. S. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220937 · Cited by 17
“[19][20][21]), and advancements in fluorescent imaging demonstrate that activity stimulates glycolysis, but not lactate uptake [22].”
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Lactate-Mediated Signaling in the Brain—An Update
Cardoso, B. V., Antipina, M., Teschemacher, A. G., & Kasparov, S. (2022) · Brain Sciences · doi:10.3390/brainsci13010049 · Cited by 20
Local glycolysis fuels actomyosin contraction during axonal retraction
Santos, R., Lokmane, L., Ozdemir, D., Traoré, C., Agesilas, A., Hakibilen, C., Lenkei, Z., & Zala, D. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202206133 · Cited by 18
“Despite that, local glycolysis provides ATP for several active processes that require a transient and fast increase in energy (D´ ı az-Garc´ ı a et al., 2017; Ivannikov et al., 2010; Zala et al., 2017; Yellen, 2018).”
Unveiling lactylation modification: A new hope for cancer treatment
Luo, Y., Zhang, N., Ye, J., Wang, Z. L., Zhou, X., Liu, J., Cai, J., Li, C., & Chen, L. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117934 · Cited by 16
Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia
Schoknecht, K., Baeza‐Lehnert, F., Hirrlinger, J., Dreier, J. P., & Eilers, J. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2415358122 · Cited by 16
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“Fluorescent biosensors (FLII12Pglu, SoNar) achieve real-time single-cell metabolic profiling [18,212,213].”
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An organic neurophysiological tool for neuronal metabolic activity monitoring
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Fernández-López, L., Molina‐Carballo, A., Cubero-Millán, I., Checa-Ros, A., Machado-Casas, I., Blanca-Jover, E., Jerez-Calero, A. E., Madrid-Fernández, Y., Uberos, J., & Muñoz‐Hoyos, A. (2020) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2019.0072 · Cited by 15
“Neuronal metabolic responses to stimulation increase direct neuronal glycolysis (Diaz-Garcia et al. 2017).”
Oscillations and Dynamic Symbiosis in Cellular Metabolism in Cancer
Amemiya, T., & Yamaguchi, T. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.783908 · Cited by 15
Bower, A. J., Renteria, C. A., Li, J., Marjanović, M., Barkalifa, R., & Boppart, S. A. (2021) · Applied Physics Letters · doi:10.1063/5.0031348 · Cited by 16
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Physiological and Pathological Role of mTOR Signaling in Astrocytes
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Dienel, G. A. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24432 · Cited by 14
“For example, activated neurons in brain slices and in vivo consume more glucose, not extracellular lactate derived from either glucose or glycogen (Diaz‐Garcia et al., 2017; Diaz‐Garcia & Yellen, 2018).”
BackgroundDescalzi, G. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00559-7 · Cited by 14
“Nevertheless, the functional significance and direction of lactate shuttling in vivo is currently under debate [5, 11], and our understanding of astrocyte–neuronal metabolic coupling in stress-induced neuronal changes remains limited.”
BackgroundGil, A. M., Martín‐Montañez, E., Valverde, N., Lara, E., Boraldi, F., Claros, S., Romero‐Zerbo, S., Fernández, Ó., Pavı́a, J., & Garcia‐Fernandez, M. I. (2020) · Cells · doi:10.3390/cells10010034 · Cited by 14
Dienel, G. A., Schousboe, A., McKenna, M. C., & Rothman, D. L. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15812 · Cited by 14
“In fact, when carefully assessed, activated neurons were shown to up-regulate glycolysis, not lactate import (Ashrafi et al., 2017 ; Ashrafi & Ryan, 2017 ; Diaz-Garcia et al., 2017; Diaz-Garcia & Yellen, 2019; Yellen, 2018).”
BackgroundThe metabolic engine of cognition: microglia–neuron interactions in health, ageing and disease
Asimakidou, E., Pluchino, S., Silva, B. A., & Peruzzotti‐Jametti, L. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01409-4 · Cited by 24
“Glucose is used for ATP production, which mostly happens via OXPHOS 50,51 .”
Zhang, Y., Sun, M., Zhao, H., Wang, Z., Shi, Y., Dong, J., Wang, K., Wang, X., Li, X., Qi, H., et al. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s439728 · Cited by 13
“105 Jia et al found that inhibition of PDH in Schwann cells leads to a sustained and massive accumulation of lactate, which drives a sustained increase in neuronal mitochondrial activity and an increase in ROS, leading to neuronal oxidative stress and axonal destruction.”
BackgroundPrinciple and Application of Fluorescence Lifetime Imaging for Neuroscience
Yasuda, R. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-48067-3.00003-2 · Cited by 13
Shifted Dynamics of Glucose Metabolism in the Hippocampus During Aging
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Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation
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Genetically Encoded Tools for Research of Cell Signaling and Metabolism under Brain Hypoxia
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Role of Histone Lactylation in Neurological Disorders
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Kamijo, Y., Mächler, P., Ness, N., Vu, C. Q., Kusakizako, T., Mannuthodikayil, J., Ku, Z., Boisvert, M., Grebenik, E. A., Miyazaki, I., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64484-x · Cited by 14
Oxidative Stress in the Pathogenesis of Neurodegenerative Diseases
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Astrocytes at the heart of sleep: from genes to network dynamics
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“Neurons are, however, directly sensitive to glucose [55] and may even prefer glucose over lactate as the primary energy source during periods of sustained activity [111].”
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Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy
Furukawa, K., Ikoma, Y., Niino, Y., Hiraoka, Y., Tanaka, K., Miyawaki, A., Hirrlinger, J., & Matsui, K. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70044 · Cited by 11
“Studies also indicate that when neurons are stimulated, they rely more on their glucose metabolism than on lactate derived from astrocytes for energy production (Díaz-García et al. 2017).”
Glycogen supports glycolytic plasticity in neurons
Singh, M. K., Wolfe, A. D., Vishwanath, A. A., Tsives, A., Gonzalez, I. J., Emerson, S. E., Goodman, R. H., & Colón‐Ramos, D. A. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2509003122 · Cited by 11
Dienel, G. A., & Lauritzen, M. (2025) · Fluids and Barriers of the CNS · doi:10.1186/s12987-025-00647-8 · Cited by 13
“These findings are supported by the demonstration that activated cultured neurons increase glycolysis to produce and release lactate; they do not oxidize extracellular lactate [127, 128].”
Wierczeiko, A., Gammel, L., Radyushkin, K., Nguyen, V. T. T., Todorov, H., Gerber, S., & Endres, K. (2021) · Cells · doi:10.3390/cells10030693 · Cited by 11
Doulias, P., Nakamura, T., Scott, H. R., McKercher, S. R., Sultan, A., Deal, A. K., Albertolle, M. E., Ischiropoulos, H., & Lipton, S. A. (2021) · Journal of NeuroVirology · doi:10.1007/s13365-021-00970-4 · Cited by 11
Zhao, M., Tanourlouee, S. B., McCracken, S., & Williams, P. R. (2025) · Neurophotonics · doi:10.1117/1.nph.12.s2.s22805 · Cited by 9
“55 In a neuronal culture model of Wolfram syndrome, Peredox was used to observe reduced NAD+/ NADH ratios in Wolfram syndrome disease modeled neurons that displayed defective communication between endoplasmic reticulum and mitochondria.”
Rose, H., Ferrán, B., Ranjit, R., Masingale, A. M., Owen, D. B., Hussong, S. A., Kinter, M. T., Galván, V., Logan, S., & Díaz‐García, C. M. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15901 · Cited by 10
“The MAS is highly active in neurons, and dentate granule cells in particular (Díaz-García et al., 2017 ; McKenna et al., 2006 ), and may contribute to respiration by increasing the mitochondrial NADH/NAD + ratio at the expense of glycolytic NADH, especially in conditions of high cytosolic but low…”
BackgroundSelf-citationMetabolic remodeling in astrocytes: Paving the path to brain tumor development
Jaraíz-Rodríguez, M., del Prado, L., & Balsa, E. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106327 · Cited by 12
Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome
Xu, W., & Borges, K. (2024) · Epilepsia · doi:10.1111/epi.18013 · Cited by 10
“The ANLS hypothesis was developed based on in vitro data, but has not been supported by in vivo experiments, 25–29 and therefore is not further discussed here.”
Low‐Glucose Culture Conditions Bias Neuronal Energetics Towards Oxidative Phosphorylation
Swain, S., Roberts, D. M., Chowdhry, S., Durbin, R. J., Boyd, R., Petereit, J., & Renden, R. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70125 · Cited by 10
“Previous reports also suggest glycolysis can be rapidly accelerated, a clear benefit where activity rates are highly dynamic (Connolly et al. 2014; Díaz-García et al. 2017).”
EPO has multiple positive effects on astrocytes in an experimental model of ischemia
Blixt, J., Song, Y., Wanecek, M., & Gunnarson, E. (2022) · Brain Research · doi:10.1016/j.brainres.2022.148207 · Cited by 10
“Glutamate uptake is highly dependent on sodium gradient across the plasma membrane (Danbolt, 2001; Belov Kirdajova et al., 2020; Schousboe, 2020).”
BackgroundPersistent changes in extracellular lactate dynamics following synaptic potentiation
Bingul, D., Kalra, K., Murata, E. M., Belser, A., & Dash, M. B. (2020) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2020.107314 · Cited by 13
“Some researchers have argued that acute increases in extracellular [lac] arise following neuronal glycolysis or from a combination of neuronal/astrocytic glycolysis (Lundgaard et al., 2015; Díaz-García et al., 2017; Díaz‐García and Yellen, 2019).”
BackgroundAndersen, J. V., & McKenna, M. C. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70255 · Cited by 11
“These observations are consistent with previous observations in vivo (Mangia et al. 2009) and in hippocampal slices (Diaz-Garcia et al. 2017; Yellen 2018) and not only suggest that neurons can be net producers of lactate, but also that neurons can release lactate and hereby contribute to the surge…”
de Muniain, L. S., Escalada, P., Ramírez, M. J., & Solas, M. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70252 · Cited by 11
“However, during activation, neurons prefer direct glucose oxidation (Díaz-García et al. 2017).”
Liao, S., Liu, G., Tan, B., et al. (2022) · Animal nutrition · doi:10.1016/j.aninu.2022.06.017 · Cited by 9
Modern optical approaches in redox biology: Genetically encoded sensors and Raman spectroscopy
Kostyuk, A. I., Rapota, D. D., Morozova, K. I., Fedotova, A. A., Jappy, D., Semyanov, A. V., Belousov, V. V., Brazhe, N. A., & Bilan, D. S. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.03.010 · Cited by 10
Sharma, A., Sah, N., Sharma, R. B., Vyas, P., Liyanage, W., Kannan, S., & Kannan, R. M. (2024) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10655 · Cited by 10
Genetically encoded fluorescence lifetime biosensors: overview, advances, and opportunities
Mo, Y., Zhou, H., Xu, J., Chen, X., Li, L., & Zhang, S. (2023) · The Analyst · doi:10.1039/d3an01201h · Cited by 9
Gliozzi, M., Coppoletta, A. R., Cardamone, A., Musolino, V., Carresi, C., Nucera, S., Ruga, S., Scarano, F., Bosco, F., Guarnieri, L., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107087 · Cited by 9
Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice
Fan, Z., Zhang, Z., Zhao, S., Zhu, Y., Guo, D. S., Yang, B., Zhuo, L., Han, J., Wang, R., Fang, Z., et al. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00587-3 · Cited by 9
Lodder, B., Lee, S. J., & Sabatini, B. L. (2021) · Current Protocols · doi:10.1002/cpz1.265 · Cited by 9
“In vivo two-photon (2P) fluorescence lifetime microscopy (FLIM) has been used for continuous imaging of biochemical state in vivo (Díaz-García et al., 2017; Laviv et al., 2020; Ma et al., 2018), but this powerful approach is challenging, mainly applicable to analysis of superficial neurons, and…”
MethodAstrocyte Bioenergetics and Major Psychiatric Disorders
Maly, I. V., Morales, M. J., & Pletnikov, M. V. (2021) · Advances in neurobiology · doi:10.1007/978-3-030-77375-5_9 · Cited by 10
Li, Y., Wu, T., Wu, C., et al. (2020) · Food & Function · doi:10.1039/d0fo01135e · Cited by 9
Yang, J., Davis, T., Kazerouni, A. S., Chen, Y., Bloom, M. J., Yeh, H., Yankeelov, T. E., & Virostko, J. M. (2021) · Molecular Imaging and Biology · doi:10.1007/s11307-021-01639-4 · Cited by 10
Scott, H. A., Novikov, B., Uğur, B., Allen, B., Мерцалов, И. Б., Monagas-Valentin, P., Koff, M., Robinson, S. B., Aoki, K., Veizaj, R., et al. (2023) · eLife · doi:10.7554/elife.78280 · Cited by 9
“…lactate, while neurons, the cells with the highest demand for energy, generally rely on oxidative phosphorylation for energy production (although some studies indicated that neurons could also upregulate glycolysis during stimulation; Diaz-García et al., 2017 ; Magistretti and Allaman, 2018 ).”
BackgroundMetabolic Reprogramming in Nerve Cells
Bhattacharya, S. (2023) · American Journal of Biomedical Science & Research · doi:10.34297/ajbsr.2023.18.002444 · Cited by 8
Chakraborty, A., Sreenivasmurthy, S. G., Miller, W., Huai, W., Biswas, T., Mandal, S. M., Boscá, L., Krishnan, B., Ghosh, G., & Hazra, T. K. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2406308121 · Cited by 8
“HDAC2 (Histone deacetylase 2; GTX109642, GeneTex) was used as nuclear loading control.”
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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