Lactate in the brain: from metabolic end-product to signalling molecule


Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Glucose metabolism in astrocytes and neurons.
Figure 2: Lactate-mediated metabolic coupling and signalling between neurons and astrocytes.
Figure 3: Lactate transfer from astrocytes to neurons modulates the excitability of pyramidal cells.
Figure 4: Lactate transfer from astrocytes to neurons in memory consolidation.


  1. 1

    Kety, S. S. & Schmidt, C. F. The nitrous oxide method for the quantitative determination of cerebral blood flow in man; theory, procedure and normal values. J. Clin. Invest. 27, 476–483 (1948).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Sokoloff, L. Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. J. Cereb. Blood Flow Metab. 1, 7–36 (1981).

    CAS  Article  Google Scholar 

  3. 3

    Allaman, I. & Magistretti, P. J. in Fundamental Neuroscience (eds Squire, L. R. et al.) 261–284 (Academic Press, San Diego, 2013).

  4. 4

    Weber, B. & Barros, L. F. The astrocyte: powerhouse and recycling center. Cold Spring Harb. Perspect. Biol. 7, a020396 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5

    Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015). This recent review provides a multiscale integration of brain energy metabolism, with an emphasis on neuron–glia metabolic coupling and its relevance for brain physiology and functional brain imaging.

    CAS  Article  Google Scholar 

  6. 6

    Nehlig, A., Wittendorp-Rechenmann, E. & Lam, C. D. Selective uptake of [14C]2-deoxyglucose by neurons and astrocytes: high-resolution microautoradiographic imaging by cellular 14C-trajectography combined with immunohistochemistry. J. Cereb. Blood Flow Metab. 24, 1004–1014 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Chuquet, J., Quilichini, P., Nimchinsky, E. A. & Buzsaki, G. Predominant enhancement of glucose uptake in astrocytes versus neurons during activation of the somatosensory cortex. J. Neurosci. 30, 15298–15303 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Voutsinos-Porche, B. et al. Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37, 275–286 (2003).

    CAS  Article  Google Scholar 

  9. 9

    Zimmer, E. R. et al. [18F]FDG PET signal is driven by astroglial glutamate transport. Nat. Neurosci. 20, 393–395 (2017). This article presents an in vivo imaging study of glucose metabolism using 18F-FDG PET in rodents and shows that glucose consumption is driven by the activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT1 (also known as SLC1A2).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Howarth, C., Gleeson, P. & Attwell, D. Updated energy budgets for neural computation in the neocortex and cerebellum. J. Cereb. Blood Flow Metab. 32, 1222–1232 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Gjedde, A. & Magistretti, P. in Youmans Neurological Surgery (ed. Winn, H. R.) 123–146 (Elsevier Saunders, Philadelphia, 2011).

  12. 12

    Brooks, G. A. Lactate shuttles in nature. Biochem. Soc. Trans. 30, 258–264 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Gladden, L. B. Lactate metabolism: a new paradigm for the third millennium. J. Physiol. 558, 5–30 (2004). A broad overview of lactate metabolism and intercellular lactate shuttling in different tissues, with an emphasis on the brain.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Hirschhaeuser, F., Sattler, U. G. & Mueller-Klieser, W. Lactate: a metabolic key player in cancer. Cancer Res. 71, 6921–6925 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Brooks, G. A. Cell–cell and intracellular lactate shuttles. J. Physiol. 587, 5591–5600 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Hamberger, A. & Hyden, H. Inverse enzymatic changes in neurons and glia during increased function and hypoxia. J. Cell Biol. 16, 521–525 (1963).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Hyden, H. & Lange, P. W. A kinetic study of the neuronglia relationship. J. Cell Biol. 13, 233–237 (1962).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Lovatt, D. et al. The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J. Neurosci. 27, 12255–12266 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Itoh, Y. et al. Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo. Proc. Natl Acad. Sci. USA 100, 4879–4884 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Lopez-Fabuel, I. et al. Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Proc. Natl Acad. Sci. USA 113, 13063–13068 (2016).

    CAS  Article  Google Scholar 

  22. 22

    Supplie, L. M. et al. Respiration-deficient astrocytes survive as glycolytic cells in vivo. J. Neurosci. 37, 4231–4242 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Schurr, A. & Payne, R. S. Lactate, not pyruvate, is neuronal aerobic glycolysis end product: an in vitro electrophysiological study. Neuroscience 147, 613–619 (2007).

    CAS  Article  Google Scholar 

  24. 24

    Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994). This article presents the first study of the ANLS model, demonstrating that glutamate uptake by astrocytes promotes aerobic glycolysis and lactate release.

    CAS  Article  Google Scholar 

  25. 25

    Bittar, P. G., Charnay, Y., Pellerin, L., Bouras, C. & Magistretti, P. J. Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J. Cereb. Blood Flow Metab. 16, 1079–1089 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Laughton, J. D. et al. Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase. BMC Neurosci. 8, 35 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27

    Pierre, K. & Pellerin, L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J. Neurochem. 94, 1–14 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Mongeon, R., Venkatachalam, V. & Yellen, G. Cytosolic NADH-NAD+ redox visualized in brain slices by two-photon fluorescence lifetime biosensor imaging. Antioxid. Redox Signal. 25, 553–563 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Jakoby, P. et al. Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices. Cereb. Cortex 24, 222–231 (2014).

    Article  Google Scholar 

  30. 30

    Bittner, C. X. et al. Fast and reversible stimulation of astrocytic glycolysis by K+ and a delayed and persistent effect of glutamate. J. Neurosci. 31, 4709–4713 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Barros, L. F. et al. Preferential transport and metabolism of glucose in Bergmann glia over Purkinje cells: a multiphoton study of cerebellar slices. Glia 57, 962–970 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Herrero-Mendez, A. et al. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1. Nat. Cell Biol. 11, 747–752 (2009). This in vitro study shows that PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphate 3; a key activator of glycolysis) is expressed in astrocytes but is absent from neurons in the rat cortex owing to constitutive proteasomal degradation by the anaphase-promoting complex (APC/C)–CDH1 complex, providing the molecular basis for the low glycolytic rate in neurons compared with astrocytes.

    CAS  Article  Google Scholar 

  33. 33

    Funfschilling, U. et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517–521 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34

    Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014). This study is an RNA-sequencing transcriptome analysis of glia, neurons and vascular cells of the mouse cerebral cortex, providing insights as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Mamczur, P. et al. Astrocyte–neuron crosstalk regulates the expression and subcellular localization of carbohydrate metabolism enzymes. Glia 63, 328–340 (2015).

    Article  Google Scholar 

  36. 36

    Volkenhoff, A. et al. Glial glycolysis is essential for neuronal survival in Drosophila. Cell Metab. 22, 437–447 (2015). This study in D. melanogaster demonstrates that glycolytically active glial cells produce alanine and lactate from trehalose to fuel neurons and that alteration of this metabolic shuttling by knockdown of glycolytic genes in glia, but not in neurons, leads to severe neurodegeneration.

    CAS  Article  Google Scholar 

  37. 37

    Hasel, P. et al. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. Nat. Commun. 8, 15132 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Ruminot, I., Schmalzle, J., Leyton, B., Barros, L. F. & Deitmer, J. W. Tight coupling of astrocyte energy metabolism to synaptic activity revealed by genetically encoded FRET nanosensors in hippocampal tissue. J. Cereb. Blood Flow Metab. (2017).

    Article  Google Scholar 

  39. 39

    Suzuki, A. et al. Astrocyte–neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011). This study demonstrates that the formation of glycogen-derived lactate by, and its release from, astrocytes is essential for long-term but not short-term memory formation and for the maintenance of LTP in vivo.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Newman, L. A., Korol, D. L. & Gold, P. E. Lactate produced by glycogenolysis in astrocytes regulates memory processing. PLoS ONE 6, e28427 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Choi, H. B. et al. Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron 75, 1094–1104 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Sotelo-Hitschfeld, T. et al. Channel-mediated lactate release by K+-stimulated astrocytes. J. Neurosci. 35, 4168–4178 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Lerchundi, R. et al. NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting. Proc. Natl Acad. Sci. USA 112, 11090–11095 (2015).

    CAS  Article  Google Scholar 

  44. 44

    Machler, P. et al. In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab. 23, 94–102 (2016). Using the genetically encoded fluorescence resonance energy transfer (FRET) sensor Laconic in combination with two-photon microscopy, this study provides the first in vivo evidence for a lactate gradient from astrocytes to neurons.

    CAS  Article  Google Scholar 

  45. 45

    Mazuel, L. et al. A neuronal MCT2 knockdown in the rat somatosensory cortex reduces both the NMR lactate signal and the BOLD response during whisker stimulation. PLoS ONE 12, e0174990 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46

    Bouzier-Sore, A. K. et al. Competition between glucose and lactate as oxidative energy substrates in both neurons and astrocytes: a comparative NMR study. Eur. J. Neurosci. 24, 1687–1694 (2006).

    Article  Google Scholar 

  47. 47

    van Hall, G. et al. Blood lactate is an important energy source for the human brain. J. Cereb. Blood Flow Metab. 29, 1121–1129 (2009).

    CAS  Article  Google Scholar 

  48. 48

    Wyss, M. T., Jolivet, R., Buck, A., Magistretti, P. J. & Weber, B. In vivo evidence for lactate as a neuronal energy source. J. Neurosci. 31, 7477–7485 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Saab, Aiman, S. et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91, 119–132 (2016).

    CAS  Article  Google Scholar 

  51. 51

    Clasadonte, J., Scemes, E., Wang, Z., Boison, D. & Haydon, P. G. Connexin 43-mediated astroglial metabolic networks contribute to the regulation of the sleep–wake cycle. Neuron 95, 1365–1380.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Barros, L. F. & Weber, B. CrossTalk proposal: an important astrocyte-to-neuron lactate shuttle couples neuronal activity to glucose utilisation in the brain. J. Physiol. 596, 347–350 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Barros, L. F. & Deitmer, J. W. Glucose and lactate supply to the synapse. Brain Res. Rev. 63, 149–159 (2010).

    CAS  Article  Google Scholar 

  54. 54

    Bolanos, J. P., Almeida, A. & Moncada, S. Glycolysis: a bioenergetic or a survival pathway? Trends Biochem. Sci. 35, 145–149 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Halestrap, A. P. Monocarboxylic acid transport. Compr. Physiol. 3, 1611–1643 (2013).

    Article  Google Scholar 

  56. 56

    Garcia, C. K., Goldstein, J. L., Pathak, R. K., Anderson, R. G. & Brown, M. S. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 76, 865–873 (1994).

    CAS  Article  Google Scholar 

  57. 57

    Fishbein, W. N., Foellmer, J. W., Davis, J. I., Fishbein, T. M. & Armbrustmacher, P. Clinical assay of the human erythrocyte lactate transporter. I. Principles, procedure, and validation. Biochem. Med. Metab. Biol. 39, 338–350 (1988).

    CAS  Article  Google Scholar 

  58. 58

    Cholet, N. et al. Local injection of antisense oligonucleotides targeted to the glial glutamate transporter GLAST decreases the metabolic response to somatosensory activation. J. Cereb. Blood Flow Metab. 21, 404–412 (2001).

    CAS  Article  Google Scholar 

  59. 59

    Gurden, H., Uchida, N. & Mainen, Z. F. Sensory-evoked intrinsic optical signals in the olfactory bulb are coupled to glutamate release and uptake. Neuron 52, 335–345 (2006).

    CAS  Article  Google Scholar 

  60. 60

    Morgenthaler, F. D., Kraftsik, R., Catsicas, S., Magistretti, P. J. & Chatton, J. Y. Glucose and lactate are equally effective in energizing activity-dependent synaptic vesicle turnover in purified cortical neurons. Neuroscience 141, 157–165 (2006).

    CAS  Article  Google Scholar 

  61. 61

    Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008).

    CAS  Article  Google Scholar 

  62. 62

    Sada, N., Lee, S., Katsu, T., Otsuki, T. & Inoue, T. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347, 1362–1367 (2015). This study demonstrates that lactate shuttling from astrocytes to neurons controls the excitability of excitatory neurons in the subthalamic nucleus and the hippocampus.

    CAS  Article  Google Scholar 

  63. 63

    Dienel, G. A. Brain lactate metabolism: the discoveries and the controversies. J. Cereb. Blood Flow Metab. 32, 1107–1138 (2012).

    CAS  Article  Google Scholar 

  64. 64

    Dienel, G. A. Lack of appropriate stoichiometry: strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain. J. Neurosci. Res. 95, 2103–2125 (2017).

    CAS  Article  Google Scholar 

  65. 65

    Bak, L. K. & Walls, A. B. CrossTalk opposing view: lack of evidence supporting an astrocyte-to-neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain. J. Physiol. 596, 351–353 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Chatton, J. Y., Pellerin, L. & Magistretti, P. J. GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission. Proc. Natl Acad. Sci. USA 100, 12456–12461 (2003).

    CAS  Article  Google Scholar 

  67. 67

    Peng, L., Zhang, X. & Hertz, L. High extracellular potassium concentrations stimulate oxidative metabolism in a glutamatergic neuronal culture and glycolysis in cultured astrocytes but have no stimulatory effect in a GABAergic neuronal culture. Brain Res. 663, 168–172 (1994).

    CAS  Article  Google Scholar 

  68. 68

    Lundgaard, I. et al. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat. Commun. 6, 6807 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Kovar, J. L., Volcheck, W., Sevick-Muraca, E., Simpson, M. A. & Olive, D. M. Characterization and performance of a near-infrared 2-deoxyglucose optical imaging agent for mouse cancer models. Anal. Biochem. 384, 254–262 (2009).

    CAS  Article  Google Scholar 

  70. 70

    Patel, A. B. et al. Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle. Proc. Natl Acad. Sci. USA 111, 5385–5390 (2014).

    CAS  Article  Google Scholar 

  71. 71

    Sokoloff, L. et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 897–916 (1977).

    CAS  Article  Google Scholar 

  72. 72

    Voutsinos-Porche, B. et al. Glial glutamate transporters and maturation of the mouse somatosensory cortex. Cereb. Cortex 13, 1110–1121 (2003).

    Article  Google Scholar 

  73. 73

    Speizer, L., Haugland, R. & Kutchai, H. Asymmetric transport of a fluorescent glucose analogue by human erythrocytes. Biochim. Biophys. Acta 815, 75–84 (1985).

    CAS  Article  Google Scholar 

  74. 74

    Kim, W. H., Lee, J., Jung, D. W. & Williams, D. R. Visualizing sweetness: increasingly diverse applications for fluorescent-tagged glucose bioprobes and their recent structural modifications. Sensors 12, 5005–5027 (2012).

    CAS  Article  Google Scholar 

  75. 75

    Aller, C. B., Ehmann, S., Gilman-Sachs, A. & Snyder, A. K. Flow cytometric analysis of glucose transport by rat brain cells. Cytometry 27, 262–268 (1997).

    CAS  Article  Google Scholar 

  76. 76

    Porras, O. H., Loaiza, A. & Barros, L. F. Glutamate mediates acute glucose transport inhibition in hippocampal neurons. J. Neurosci. 24, 9669–9673 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Díaz-García, C. M. et al. Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab. 26, 361–374.e4 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78

    Magistretti, P. J. & Chatton, J. Y. Relationship between L-glutamate-regulated intracellular Na+ dynamics and ATP hydrolysis in astrocytes. J. Neural Transm. 112, 77–85 (2005).

    CAS  Article  Google Scholar 

  79. 79

    Morland, C. et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J. Neurosci. Res. 93, 1045–1055 (2015).

    CAS  Article  Google Scholar 

  80. 80

    Tang, F. et al. Lactate-mediated glia–neuronal signalling in the mammalian brain. Nat. Commun. 5, 3284 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    San Martin, A., Arce-Molina, R., Galaz, A., Perez-Guerra, G. & Barros, L. F. Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism. J. Biol. Chem. 292, 9432–9438 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Karagiannis, A. et al. Hemichannel-mediated release of lactate. J. Cereb. Blood Flow Metab. 36, 1202–1211 (2016).

    CAS  Article  Google Scholar 

  83. 83

    Liu, L., MacKenzie, K. R., Putluri, N., Maletic-Savatic, M. & Bellen, H. J. The glia–neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE/D. Cell Metab. 26, 719–737.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Nave, K. A., Tzvetanova, I. D. & Schirmeier, S. Glial cell evolution: the origins of a lipid store. Cell Metab. 26, 701–702 (2017).

    CAS  Article  Google Scholar 

  85. 85

    Tsacopoulos, M., Coles, J. A. & van de Werve, G. The supply of metabolic substrate from glia to photoreceptors in the retina of the honeybee drone. J. Physiol. 82, 279–287 (1987).

    CAS  Google Scholar 

  86. 86

    Saab, A. S., Tzvetanova, I. D. & Nave, K. A. The role of myelin and oligodendrocytes in axonal energy metabolism. Curr. Opin. Neurobiol. 23, 1065–1072 (2013).

    CAS  Article  Google Scholar 

  87. 87

    Morrison, B. M. et al. Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush. Exp. Neurol. 263, 325–338 (2015).

    CAS  Article  Google Scholar 

  88. 88

    Magistretti, P. J., Morrison, J. H., Shoemaker, W. J., Sapin, V. & Bloom, F. E. Vasoactive intestinal polypeptide induces glycogenolysis in mouse cortical slices: a possible regulatory mechanism for the local control of energy metabolism. Proc. Natl Acad. Sci. USA 78, 6535–6539 (1981).

    CAS  Article  Google Scholar 

  89. 89

    Hof, P. R., Pascale, E. & Magistretti, P. J. K+ at concentrations reached in the extracellular space during neuronal activity promotes a Ca2+-dependent glycogen hydrolysis in mouse cerebral cortex. J. Neurosci. 8, 1922–1928 (1988).

    CAS  Article  Google Scholar 

  90. 90

    Sorg, O. & Magistretti, P. J. Characterization of the glycogenolysis elicited by vasoactive intestinal peptide, noradrenaline and adenosine in primary cultures of mouse cerebral cortical astrocytes. Brain Res. 563, 227–233 (1991).

    CAS  Article  Google Scholar 

  91. 91

    Sorg, O., Pellerin, L., Stolz, M., Beggah, S. & Magistretti, P. J. Adenosine triphosphate and arachidonic acid stimulate glycogenolysis in primary cultures of mouse cerebral cortical astrocytes. Neurosci. Lett. 188, 109–112 (1995).

    CAS  Article  Google Scholar 

  92. 92

    Ruminot, I. et al. NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K+. J. Neurosci. 31, 14264–14271 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Gao, V. et al. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation. Proc. Natl Acad. Sci. USA 113, 8526–8531 (2016).

    CAS  Article  Google Scholar 

  94. 94

    Lalo, U. et al. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 12, e1001747 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Papouin, T., Dunphy, J., Tolman, M., Foley, J. C. & Haydon, P. G. Astrocytic control of synaptic function. Phil. Trans. R. Soc. B 372, 20160154 (2017).

    Article  CAS  Google Scholar 

  96. 96

    Papouin, T. et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150, 633–646 (2012).

    CAS  Article  Google Scholar 

  97. 97

    Wolosker, H., Balu, D. T. & Coyle, J. T. Astroglial versus neuronal d-serine: check your controls! Trends Neurosci. 40, 520–522 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Cerdan, S. et al. The redox switch/redox coupling hypothesis. Neurochem. Int. 48, 523–530 (2006).

    CAS  Article  Google Scholar 

  99. 99

    Dringen, R. & Hirrlinger, J. Glutathione pathways in the brain. Biol. Chem. 384, 505–516 (2003).

    CAS  Article  Google Scholar 

  100. 100

    Gibbs, M. E., Anderson, D. G. & Hertz, L. Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens. Glia 54, 214–222 (2006).

    Article  Google Scholar 

  101. 101

    O'Dowd, B. S., Gibbs, M. E., Ng, K. T., Hertz, E. & Hertz, L. Astrocytic glycogenolysis energizes memory processes in neonate chicks. Brain Res. Dev. Brain Res. 78, 137–141 (1994).

    CAS  Article  Google Scholar 

  102. 102

    Tadi, M., Allaman, I., Lengacher, S., Grenningloh, G. & Magistretti, P. J. Learning-induced gene expression in the hippocampus reveals a role of neuron–astrocyte metabolic coupling in long term memory. PLoS ONE 10, e0141568 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103

    Boury-Jamot, B. et al. Disrupting astrocyte–neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol. Psychiatry 21, 1070–1076 (2016).

    CAS  Article  Google Scholar 

  104. 104

    Zhang, Y. et al. Inhibition of lactate transport erases drug memory and prevents drug relapse. Biol. Psychiatry 79, 928–939 (2016).

    CAS  Article  Google Scholar 

  105. 105

    Boutrel, B. & Magistretti, P. J. A role for lactate in the consolidation of drug-related associative memories. Biol. Psychiatry 79, 875–877 (2016).

    Article  Google Scholar 

  106. 106

    Wang, J. et al. Astrocytic l-lactate signaling facilitates amygdala–anterior cingulate cortex synchrony and decision making in rats. Cell Rep. 21, 2407–2418 (2017).

    CAS  Article  Google Scholar 

  107. 107

    Foote, S. L., Bloom, F. E. & Aston-Jones, G. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol. Rev. 63, 844–914 (1983).

    CAS  Article  Google Scholar 

  108. 108

    Magistretti, P. J. & Morrison, J. H. Noradrenaline- and vasoactive intestinal peptide-containing neuronal systems in neocortex: functional convergence with contrasting morphology. Neuroscience 24, 367–378 (1988).

    CAS  Article  Google Scholar 

  109. 109

    McGaugh, J. L. Consolidating memories. Annu. Rev. Psychol. 66, 1–24 (2015).

    Article  Google Scholar 

  110. 110

    Aston-Jones, G. & Waterhouse, B. Locus coeruleus: from global projection system to adaptive regulation of behavior. Brain Res. 1645, 75–78 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111

    Roozendaal, B. & McGaugh, J. L. Memory modulation. Behav. Neurosci. 125, 797–824 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112

    Cali, C. et al. Three-dimensional immersive virtual reality for studying cellular compartments in 3D models from EM preparations of neural tissues. J. Comp. Neurol. 524, 23–38 (2016).

    CAS  Article  Google Scholar 

  113. 113

    Yang, J. et al. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc. Natl Acad. Sci. USA 111, 12228–12233 (2014). This study provides evidence that lactate stimulates expression of synaptic-plasticity-related genes in neurons through a mechanism involving redox changes and potentiation of NMDAR activity and its downstream signalling cascade through extracellular signal-regulated kinase 1and 2 (ERK1/2).

    CAS  Article  Google Scholar 

  114. 114

    Goyal, M. S., Hawrylycz, M., Miller, J. A., Snyder, A. Z. & Raichle, M. E. Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 19, 49–57 (2014). This study in human brain provides evidence that aerobic glycolysis is very active throughout the brain during childhood, persists in neotenous adult brain regions and spatially correlates with gene expression related to synapse formation and neurite growth.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115

    Goyal, M. S. et al. Loss of brain aerobic glycolysis in normal human aging. Cell Metab. 26, 353–360.e3 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116

    Petralia, R. S., Mattson, M. P. & Yao, P. J. Communication breakdown: the impact of ageing on synapse structure. Ageing Res. Rev. 14, 31–42 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117

    Petit, J. M. & Magistretti, P. J. Regulation of neuron–astrocyte metabolic coupling across the sleep-wake cycle. Neuroscience 323, 135–156 (2016).

    CAS  Article  Google Scholar 

  118. 118

    Nagase, M., Takahashi, Y., Watabe, A. M., Kubo, Y. & Kato, F. On-site energy supply at synapses through monocarboxylate transporters maintain excitatory synaptic transmission. J. Neurosci. 34, 2605–2617 (2014).

    CAS  Article  Google Scholar 

  119. 119

    Parsons, M. P. & Hirasawa, M. ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal. J. Neurosci. 30, 8061–8070 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120

    Bozzo, L., Puyal, J. & Chatton, J. Y. Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway. PLoS ONE 8, e71721 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121

    Devarakonda, K. & Mobbs, C. V. Mechanisms and significance of brain glucose signaling in energy balance, glucose homeostasis, and food-induced reward. Mol. Cell. Endocrinol. 438, 61–69 (2016).

    CAS  Article  Google Scholar 

  122. 122

    Mobbs, C. V., Kow, L. M. & Yang, X. J. Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses. Am. J. Physiol. Endocrinol. Metab. 281, E649–E654 (2001).

    CAS  Article  Google Scholar 

  123. 123

    Ainscow, E. K., Mirshamsi, S., Tang, T., Ashford, M. L. & Rutter, G. A. Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K+ channels. J. Physiol. 544, 429–445 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124

    Borg, M. A., Tamborlane, W. V., Shulman, G. I. & Sherwin, R. S. Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 52, 663–666 (2003).

    CAS  Article  Google Scholar 

  125. 125

    Lam, T. K., Gutierrez-Juarez, R., Pocai, A. & Rossetti, L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947 (2005).

    CAS  Article  Google Scholar 

  126. 126

    Hiyama, T. Y. & Noda, M. Sodium sensing in the subfornical organ and body-fluid homeostasis. Neurosci. Res. 113, 1–11 (2016).

    CAS  Article  Google Scholar 

  127. 127

    Pellerin, L. & Magistretti, P. J. Glutamate uptake stimulates Na+,K+-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain. J. Neurochem. 69, 2132–2137 (1997).

    CAS  Article  Google Scholar 

  128. 128

    Shimizu, H. et al. Glial NaX channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54, 59–72 (2007).

    CAS  Article  Google Scholar 

  129. 129

    Tu, N. H. et al. Na+/K+-ATPase coupled to endothelin receptor type B stimulates peripheral nerve regeneration via lactate signalling. Eur. J. Neurosci. 46, 2096–2107 (2017).

    Article  Google Scholar 

  130. 130

    Erlichman, J. S. et al. Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte–neuron lactate-shuttle hypothesis. J. Neurosci. 28 4888–4896 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131

    Dalsgaard, M. K. Fuelling cerebral activity in exercising man. J. Cereb. Blood Flow Metab. 26, 731–750 (2006). This review article provides an overview of in vivo evidence that increasing blood lactate levels through physical exercise leads to its utilization by the brain at the expense of glucose utilization.

    CAS  Article  Google Scholar 

  132. 132

    Hassel, B. & Brathe, A. Cerebral metabolism of lactate in vivo: evidence for neuronal pyruvate carboxylation. J. Cereb. Blood Flow Metab. 20, 327–336 (2000).

    CAS  Article  Google Scholar 

  133. 133

    Boumezbeur, F. et al. The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J. Neurosci. 30, 13983–13991 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    Ide, K. & Secher, N. H. Cerebral blood flow and metabolism during exercise. Prog. Neurobiol. 61, 397–414 (2000).

    CAS  Article  Google Scholar 

  135. 135

    Kemppainen, J. et al. High intensity exercise decreases global brain glucose uptake in humans. J. Physiol. 568, 323–332 (2005). This human study provides evidence that increasing blood lactate levels through (moderate-to-vigorous) exercise linearly shifts cerebral metabolism from using glucose to using other energy substrates.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136

    Smith, D. et al. Lactate: a preferred fuel for human brain metabolism in vivo. J. Cereb. Blood Flow Metab. 23, 658–664 (2003).

    CAS  Article  Google Scholar 

  137. 137

    Gonzalez-Alonso, J. et al. Brain and central haemodynamics and oxygenation during maximal exercise in humans. J. Physiol. 557, 331–342 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    Bouzier-Sore, A. K., Voisin, P., Canioni, P., Magistretti, P. J. & Pellerin, L. Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J. Cereb. Blood Flow Metab. 23, 1298–1306 (2003).

    CAS  Article  Google Scholar 

  139. 139

    Rodrigues, T. B., Valette, J. & Bouzier-Sore, A. K. 13C NMR spectroscopy applications to brain energy metabolism. Front. Neuroenerg. 5, 9 (2013).

    Article  CAS  Google Scholar 

  140. 140

    Serres, S., Bezancon, E., Franconi, J. M. & Merle, M. Ex vivo analysis of lactate and glucose metabolism in the rat brain under different states of depressed activity. J. Biol. Chem. 279, 47881–47889 (2004).

    CAS  Article  Google Scholar 

  141. 141

    Sampol, D. et al. Glucose and lactate metabolism in the awake and stimulated rat: a 13C-NMR study. Front. Neuroenerg. 5, 5 (2013). This nuclear magnetic resonance (NMR) study demonstrates that, during whisker stimulation in rats, an increase in lactate produced from plasma 13C-labelled glucose occurs in the corresponding somatosensory cortex, implying that neuronal activity increases brain glucose uptake and intracortical lactate production.

    CAS  Article  Google Scholar 

  142. 142

    Cotman, C. W., Berchtold, N. C. & Christie, L. A. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472 (2007).

    CAS  Article  Google Scholar 

  143. 143

    Coco, M. et al. Elevated blood lactate is associated with increased motor cortex excitability. Somatosens. Mot. Res. 27, 1–8 (2010).

    Article  Google Scholar 

  144. 144

    Singh, A. M. & Staines, W. R. The effects of acute aerobic exercise on the primary motor cortex. J. Mot. Behav. 47, 328–339 (2015).

    Article  Google Scholar 

  145. 145

    Morland, C. et al. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat. Commun. 8, 15557 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146

    Jourdain, P. et al. L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade. Sci. Rep. 6, 21250 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147

    Gordon, G. R., Choi, H. B., Rungta, R. L., Ellis-Davies, G. C. & MacVicar, B. A. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148

    Ros, J., Pecinska, N., Alessandri, B., Landolt, H. & Fillenz, M. Lactate reduces glutamate-induced neurotoxicity in rat cortex. J. Neurosci. Res. 66, 790–794 (2001).

    CAS  Article  Google Scholar 

  149. 149

    Berthet, C. et al. Neuroprotective role of lactate after cerebral ischemia. J. Cereb. Blood Flow Metab. 29, 1780–1789 (2009).

    CAS  Article  Google Scholar 

  150. 150

    Berthet, C., Castillo, X., Magistretti, P. J. & Hirt, L. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Cerebrovasc. Dis. 34, 329–335 (2012).

    CAS  Article  Google Scholar 

  151. 151

    Izumi, Y., Benz, A. M., Katsuki, H. & Zorumski, C. F. Endogenous monocarboxylates sustain hippocampal synaptic function and morphological integrity during energy deprivation. J. Neurosci. 17, 9448–9457 (1997).

    CAS  Article  Google Scholar 

  152. 152

    Izumi, Y., Benz, A. M., Zorumski, C. F. & Olney, J. W. Effects of lactate and pyruvate on glucose deprivation in rat hippocampal slices. Neuroreport 5, 617–620 (1994).

    CAS  Article  Google Scholar 

  153. 153

    Sala, N. et al. Cerebral extracellular lactate increase is predominantly nonischemic in patients with severe traumatic brain injury. J. Cereb. Blood Flow Metab. 33, 1815–1822 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154

    Carpenter, K. L., Jalloh, I. & Hutchinson, P. J. Glycolysis and the significance of lactate in traumatic brain injury. Front. Neurosci. 9, 112 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  155. 155

    Glenn, T. C. et al. Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism. J. Cereb. Blood Flow Metab. 23, 1239–1250 (2003).

    CAS  Article  Google Scholar 

  156. 156

    Gallagher, C. N. et al. The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain 132, 2839–2849 (2009).

    Article  Google Scholar 

  157. 157

    Bouzat, P. et al. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensive Care Med. 40, 412–421 (2014).

    CAS  Article  Google Scholar 

  158. 158

    Ichai, C. et al. Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial. Intensive Care Med. 39, 1413–1422 (2013).

    CAS  Article  Google Scholar 

  159. 159

    Dienel, G. A., Rothman, D. L. & Nordstrom, C. H. Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients. J. Cereb. Blood Flow Metab. 36, 1844–1864 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160

    Rajkowska, G. & Miguel-Hidalgo, J. J. Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets. 6, 219–233 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161

    Rajkowska, G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777 (2000).

    CAS  Article  Google Scholar 

  162. 162

    Banasr, M. et al. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol. Psychiatry 15, 501–511 (2010).

    CAS  Article  Google Scholar 

  163. 163

    Banasr, M. & Duman, R. S. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol. Psychiatry 64, 863–870 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  164. 164

    Elsayed, M. & Magistretti, P. J. A. New outlook on mental illnesses: glial involvement beyond the glue. Front. Cell. Neurosci. 9, 468 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  165. 165

    Konarski, J. Z. et al. Relationship between regional brain metabolism, illness severity and age in depressed subjects. Psychiatry Res. 155, 203–210 (2007).

    CAS  Article  Google Scholar 

  166. 166

    Drevets, W. C. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr. Opin. Neurobiol. 11, 240–249 (2001).

    CAS  Article  Google Scholar 

  167. 167

    Dunlop, B. W. & Mayberg, H. S. Neuroimaging-based biomarkers for treatment selection in major depressive disorder. Dialogues Clin. Neurosci. 16, 479–490 (2014).

    PubMed  PubMed Central  Google Scholar 

  168. 168

    Allaman, I., Fiumelli, H., Magistretti, P. J. & Martin, J. L. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology 216, 75–84 (2011).

    CAS  Article  Google Scholar 

  169. 169

    Carrard, A. et al. Peripheral administration of lactate produces antidepressant-like effects. Mol. Psychiatry 23, 392–399 (2018). This study demonstrates that peripheral administration of lactate produces antidepressant-like effects in different animal models of depression that respond to acute and chronic antidepressant treatment.

    CAS  Article  Google Scholar 

  170. 170

    Lowenbach, H. & Greenhill, M. H. The effect of oral administration of lactic acid upon the clinical course of depressive states. J. Nerv. Ment. Dis. 105, 343–358 (1947).

    CAS  Article  Google Scholar 

  171. 171

    Vollmer, L. L., Strawn, J. R. & Sah, R. Acid-base dysregulation and chemosensory mechanisms in panic disorder: a translational update. Transl Psychiatry 5, e572 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172

    Grant, B. F. et al. The epidemiology of DSM-IV panic disorder and agoraphobia in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J. Clin. Psychiatry 67, 363–374 (2006).

    Article  Google Scholar 

  173. 173

    Ziemann, A. E. et al. The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior. Cell 139, 1012–1021 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174

    Peskind, E. R. et al. Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder. Biol. Psychiatry 44, 1007–1016 (1998).

    CAS  Article  Google Scholar 

  175. 175

    Molosh, A. I. et al. Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder. Neuropsychopharmacology 35, 1333–1347 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  176. 176

    Mosienko, V., Teschemacher, A. G. & Kasparov, S. Is L-lactate a novel signaling molecule in the brain? J. Cereb. Blood Flow Metab. 35, 1069–1075 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177

    Barros, L. F. Metabolic signaling by lactate in the brain. Trends Neurosci. 36, 396–404 (2013).

    CAS  Article  Google Scholar 

  178. 178

    Bergersen, L. H. Lactate transport and signaling in the brain: potential therapeutic targets and roles in body–brain interaction. J. Cereb. Blood Flow Metab. 35, 176–185 (2015).

    CAS  Article  Google Scholar 

  179. 179

    Schurr, A. Cerebral glycolysis: a century of persistent misunderstanding and misconception. Front. Neurosci. 8, 360 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  180. 180

    McIlwain, H. Substances which support respiration and metabolic response to electrical impulses in human cerebral tissues. J. Neurol. Neurosurg. Psychiatry 16, 257–266 (1953).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181

    Dolivo, M. & Larrabee, M. G. Metabolism of glucose and oxygen in a mammalian sympathetic ganglion at reduced temperature and varied pH. J. Neurochem. 3, 72–88 (1958).

    CAS  Article  Google Scholar 

  182. 182

    Schurr, A., West, C. A. & Rigor, B. M. Lactate-supported synaptic function in the rat hippocampal slice preparation. Science 240, 1326–1328 (1988).

    CAS  Article  Google Scholar 

  183. 183

    Brown, A. M., Wender, R. & Ransom, B. R. Metabolic substrates other than glucose support axon function in central white matter. J. Neurosci. Res. 66, 839–843 (2001).

    CAS  Article  Google Scholar 

  184. 184

    Kadekaro, M., Crane, A. M. & Sokoloff, L. Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc. Natl Acad. Sci. USA 82, 6010–6013 (1985).

    CAS  Article  Google Scholar 

  185. 185

    Larrabee, M. G. Partitioning of CO2 production between glucose and lactate in excised sympathetic ganglia, with implications for brain. J. Neurochem. 67, 1726–1734 (1996).

    CAS  Article  Google Scholar 

  186. 186

    Hassel, B., Sonnewald, U. & Fonnum, F. Glial-neuronal interactions as studied by cerebral metabolism of [2-13C]acetate and [1-13C]glucose: an ex vivo 13C NMR spectroscopic study. J. Neurochem. 64, 2773–2782 (1995).

    CAS  Article  Google Scholar 

  187. 187

    Bouzier-Sore, A. K., Serres, S., Canioni, P. & Merle, M. Lactate involvement in neuron-glia metabolic interaction: 13C-NMR spectroscopy contribution. Biochimie 85, 841–848 (2003).

    CAS  Article  Google Scholar 

  188. 188

    Zilberter, Y., Zilberter, T. & Bregestovski, P. Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol. Sci. 31, 394–401 (2010).

    CAS  Article  Google Scholar 

  189. 189

    Abi-Saab, W. M. et al. Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia. J. Cereb. Blood Flow Metab. 22, 271–279 (2002).

    CAS  Article  Google Scholar 

  190. 190

    Reinstrup, P. et al. Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery 47, 701–710 (2000).

    CAS  Google Scholar 

  191. 191

    Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  192. 192

    Cremer, J. E., Cunningham, V. J., Pardridge, W. M., Braun, L. D. & Oldendorf, W. H. Kinetics of blood–brain barrier transport of pyruvate, lactate and glucose in suckling, weanling and adult rats. J. Neurochem. 33, 439–445 (1979).

    CAS  Article  Google Scholar 

  193. 193

    Shulman, R. G. & Rothman, D. L. The glycogen shunt maintains glycolytic homeostasis and the Warburg effect in cancer. Trends Cancer 3, 761–767 (2017).

    CAS  Article  Google Scholar 

  194. 194

    Halim, N. D. et al. Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons. Glia 58, 1168–1176 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  195. 195

    Vilchez, D. et al. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat. Neurosci. 10, 1407–1413 (2007).

    CAS  Article  Google Scholar 

  196. 196

    Duran, J. et al. Deleterious effects of neuronal accumulation of glycogen in flies and mice. EMBO Mol. Med. 4, 719–729 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197

    Magistretti, P. J. & Allaman, I. Glycogen: a Trojan horse for neurons. Nat. Neurosci. 10, 1341–1342 (2007).

    CAS  Article  Google Scholar 

  198. 198

    Duran, J., Gruart, A., Garcia-Rocha, M., Delgado-Garcia, J. M. & Guinovart, J. J. Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum. Mol. Genet. 23, 3147–3156 (2014).

    CAS  Article  Google Scholar 

  199. 199

    Hashimoto, T., Hussien, R., Oommen, S., Gohil, K. & Brooks, G. A. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mito-chondrial biogenesis. FASEB J. 21, 2602–2612 (2007).

    CAS  Article  Google Scholar 

  200. 200

    Baumann, F. et al. Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol. 11, 368–380 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201

    Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202

    Haas, R. et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 13, e1002202 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  203. 203

    Milovanova, T. N. et al. Lactate stimulates vasculogenic stem cells via the thioredoxin system and engages an autocrine activation loop involving hypoxia-inducible factor 1. Mol. Cell. Biol. 28, 6248–6261 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204

    Haas, R. et al. Intermediates of metabolism: from bystanders to signalling molecules. Trends Biochem. Sci. 41, 460–471 (2016).

    CAS  Article  Google Scholar 

  205. 205

    Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    CAS  Article  Google Scholar 

  206. 206

    Sonveaux, P. et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE 7, e33418 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207

    Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).

    CAS  Article  Google Scholar 

  208. 208

    Tholey, G., Roth-Schechter, B. F. & Mandel, P. Activity and isoenzyme pattern of lactate dehydrogenase in neurons and astroblasts cultured from brains of chick embryos. J. Neurochem. 36, 77–81 (1981).

    CAS  Article  Google Scholar 

Download references


Research in P.J.M.'s laboratory has been supported over the years by the Swiss National Science Foundation, King Abdullah University of Science and Technology (KAUST; Saudi Arabia), the University of Lausanne (UNIL; Switzerland), École Polytechnique Fédérale de Lausanne (EPFL; Switzerland), Centre Hospitalier Universitaire Vaudois (CHUV; Switzerland), the National Centre for Competence in Research (NCCR) Synapsy and the Préfargier Foundation. The authors thank H. Fiumelli and F. Barros for comments on the manuscript.

Author information




P.J.M. wrote the manuscript. P.J.M. and I.A. researched data for the article, made substantial contributions to the discussion of content and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Pierre J. Magistretti.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides


Pyruvate dehydrogenase

(PDH). The first component enzyme of the pyruvate dehydrogenase complex; it converts pyruvate into acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle for cellular respiration.

Glycolytic flux

The rate at which glucose and its metabolites proceed through the glycolytic pathway.

Flux analysis

A technique used to examine production and consumption rates of metabolites. It determines the transfer of moieties containing isotopic tracers from one metabolite into another using stoichiometric models of metabolism and mass spectrometry methods.

Mitochondrial respiratory chain (MRC) complexes

Complexes that operate the transfer of electrons from donors to acceptors via redox mechanisms, creating an electrochemical proton gradient that drives the synthesis of ATP.

Complex I

The first step in the mitrochondrial respiratory chain; it removes two electrons from NADH and operates their transfer to ubiquinone.


A property of monocarboxylate transporters whereby the presence of extracellular monocarboxylates (such as pyruvate) stimulates transporter efflux of the substrate (for example, lactate).

Warburg effect

Also called aerobic glycolysis. The metabolic pathway of glucose that results in the production of lactate in the presence of physiological concentrations of oxygen.

Fast glucose transport

Facilitated transmembrane transport of glucose via specific transporters.

Energy charge

An index that measures the energy status of cells. It is related to ATP, ADP and AMP concentrations.

Memory consolidation

A category of processes whereby a brain converts short-term memories into long-term memories (that is, stabilizing a memory trace after its initial acquisition).

Glycogen phosphorylase

The enzyme that catalyses the rate-limiting step in glycogenolysis.

Inhibitory avoidance

A behavioural task that is commonly used to investigate learning and memory processes in rodents and that is based on contextual fear conditioning.

Nucleus solitary tract

A major sensory nucleus in the dorsal medulla that receives cardiovascular, visceral, respiratory, gustatory and orotactile information.


Physiological concentration of glucose in the blood.

Ependymal cells

A glial cell type that lines the spinal cord and the ventricular system of the brain and that is involved in the creation, secretion and circulation of cerebrospinal fluid.

Subfornical organ

One of the highly vascularized circumventricular organs of the brain localized on the ventral surface of the fornix. It does not possess a blood–brain barrier.

Macrophage polarization

The process by which macrophages express different functional programmes in response to microenvironmental signals.

Carotid body

A chemosensory organ at the carotid artery bifurcation that is the major sensor of blood oxygen in mammals.

Minute ventilation

The volume of gas inhaled or exhaled by the lungs per minute.


The pathological process by which neurons are damaged or killed by excessive stimulation by glutamate or other excitatory neurotransmitters.

Middle cerebral artery occlusion

An experimental model of stroke based on focal cerebral ischaemia induced by permanent or transient occlusion of the middle cerebral artery in mice or rats.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Magistretti, P., Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19, 235–249 (2018).

Download citation

Further reading