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Current Neurology and Neuroscience Reports
Published in: Current Neurology and Neuroscience Reports 9/2018

01-09-2018 | Sleep (M Thorpy and M Billiard, Section Editors)

Cerebral Metabolic Changes During Sleep

Authors: Nadia Nielsen Aalling, Maiken Nedergaard, Mauro DiNuzzo

Published in: Current Neurology and Neuroscience Reports | Issue 9/2018

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Abstract

Purpose of Review

The goal of the present paper is to review current literature supporting the occurrence of fundamental changes in brain energy metabolism during the transition from wakefulness to sleep.

Recent Findings

Latest research in the field indicates that glucose utilization and the concentrations of several brain metabolites consistently change across the sleep-wake cycle. Lactate, a product of glycolysis that is involved in synaptic plasticity, has emerged as a good biomarker of brain state. Sleep-induced changes in cerebral metabolite levels result from a shift in oxidative metabolism, which alters the reliance of brain metabolism upon carbohydrates.

Summary

We found wide support for the notion that brain energetics is state dependent. In particular, fatty acids and ketone bodies partly replace glucose as cerebral energy source during sleep. This mechanism plausibly accounts for increases in biosynthetic pathways and functional alterations in neuronal activity associated with sleep. A better account of brain energy metabolism during sleep might help elucidate the long mysterious restorative effects of sleep for the whole organism.
Literature
1.
Chatelle C, Laureys S, Schnakers C. Disorders of consciousness: what do we know? In: Dehaene S, Christen Y, editors. Characterizing consciousness: from cognition to the clinic? Berlin: Springer; 2011. p. 85–98.CrossRef
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Morland C, Lauritzen KH, Puchades M, Holm-Hansen S, Andersson K, Gjedde A, et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J Neurosci Res. 2015;93(7):1045–55. https://​doi.​org/​10.​1002/​jnr.​23593.
14.
15.
16.
17.
18.
19.
Hibi M, Kubota C, Mizuno T, Aritake S, Mitsui Y, Katashima M, et al. Effect of shortened sleep on energy expenditure, core body temperature, and appetite: a human randomised crossover trial. Sci Rep. 2017;7:39640. https://​doi.​org/​10.​1038/​srep39640.
20.
21.
22.
Wildenhoff KE, Johansen JP, Karstoft H, Yde H, Sorensen NS. Diurnal variations in the concentrations of blood acetoacetate and 3-hydroxybutyrate. The ketone body peak around midnight and its relationship to free fatty acids, glycerol, insulin, growth hormone and glucose in serum and plasma. Acta Med Scand. 1974;195:25–8.PubMedCrossRef
23.
24.
Iwata S, Ozawa K, Shimahara Y, Mori K, Kobayashi N, Kumada K, et al. Diurnal fluctuations of arterial ketone body ratio in normal subjects and patients with liver dysfunction. Gastroenterology. 1991;100:1371–8.
25.
De Gasquet P, Griglio S, Pequignot-Planche E, Malewiak MI. Diurnal changes in plasma and liver lipids and lipoprotein lipase activity in heart and adipose tissue in rats fed a high and low fat diet. J Nutr. 1977;107:199–212.PubMedCrossRef
26.
27.
28.
29.
30.
• Bellesi M, Pfister-Genskow M, Maret S, Keles S, Tononi G, Cirelli C. Effects of sleep and wake on oligodendrocytes and their precursors. J Neurosci. 2013;33(36):14288–300. https://​doi.​org/​10.​1523/​JNEUROSCI.​5102-12.​2013. Using translating ribosome affinity purification (TRAP) technology combined with microarray analysis, this study generated cell-type specific transcriptomic profiles of oligodendrocytes after longer periods of sleep, wake, or acute sleep deprivation. They show that genes involved in phospholipid synthesis and myelination or promoting OPC proliferation are transcribed preferentially during sleep, and experimentally validate some of their findings. PubMedPubMedCentralCrossRef
31.
Poduslo SE, Miller K. Ketone bodies as precursors for lipid synthesis in neurons, astrocytes, and oligodendroglia (myelin) in hyperthyroidism, hyperketonemia and hypoketonemia. Neurochem Int. 1991;18(1):85–8.PubMedCrossRef
32.
33.
Netchiporouk L, Shram N, Salvert D, Cespuglio R. Brain extracellular glucose assessed by voltammetry throughout the rat sleep-wake cycle. Eur J Neurosci. 2001;13(7):1429–34.PubMedCrossRef
34.
Van den Noort S, Brine K. Effect of sleep on brain labile phosphates and metabolic rate. Am J Phys. 1970;218(5):1434–9.
35.
36.
Cespuglio R, Netchiporouk L, Glucose SN. Lactate monitoring across the rat sleep–wake cycle. In: Marinesco S, Dale N, editors. Microelectrode Biosensors. Totowa, NJ: Humana Press; 2013. p. 241–56.CrossRef
37.
38.
McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci U S A. 2000;97(6):2881–5.PubMedPubMedCentralCrossRef
39.
40.
Merboldt KD, Bruhn H, Hanicke W, Michaelis T, Frahm J. Decrease of glucose in the human visual cortex during photic stimulation. Magn Reson Med. 1992;25(1):187–94.PubMedCrossRef
41.
Clegern WC, Moore ME, Schmidt MA, Wisor J. Simultaneous electroencephalography, real-time measurement of lactate concentration and optogenetic manipulation of neuronal activity in the rodent cerebral cortex. J Vis Exp. 2012;70:e4328. https://​doi.​org/​10.​3791/​4328.CrossRef
42.
Shram N, Netchiporouk L, Cespuglio R. Lactate in the brain of the freely moving rat: voltammetric monitoring of the changes related to the sleep-wake states. Eur J Neurosci. 2002;16(3):461–6.PubMedCrossRef
43.
44.
45.
Richter D, Dawson RM. Brain metabolism in emotional excitement and in sleep. Am J Phys. 1948;154(1):73–9.
46.
47.
48.
Frahm J, Kruger G, Merboldt KD, Kleinschmidt A. Dynamic uncoupling and recoupling of perfusion and oxidative metabolism during focal brain activation in man. Magn Reson Med. 1996;35(2):143–8.PubMedCrossRef
49.
Frahm J, Krueger G, Merboldt KD, Kleinschmidt A. Dynamic NMR studies of perfusion and oxidative metabolism during focal brain activation. Advances in Experimental Medicine and Biology. 1997;413:195–203.PubMedCrossRef
50.
Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, Avison M, et al. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci U S A. 1991;88(13):5829–31.
51.
Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW. Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 1992;12(4):584–92.PubMedCrossRef
52.
•• Hinard V, Mikhail C, Pradervand S, Curie T, Houtkooper RH, Auwerx J, et al. Key electrophysiological, molecular, and metabolic signatures of sleep and wakefulness revealed in primary cortical cultures. J Neurosci. 2012;32(36):12506–17. https://​doi.​org/​10.​1523/​JNEUROSCI.​2306-12.​2012. This is the only study that have investigated how sleep deprivation affects the mouse cortex metabolome. Based on results of this study and from stimulation of neuronal cell cultures, the authors suggest that sleep might play a major role in reestablishing the neuronal membrane homeostasis.
53.
54.
Maquet P, Dive D, Salmon E, Sadzot B, Franco G, Poirrier R, et al. Cerebral glucose utilization during stage 2 sleep in man. Brain Res. 1992;571(1):149–53.
55.
Buchsbaum MS, Gillin JC, Wu J, Hazlett E, Sicotte N, Dupont RM, et al. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography. Life Sci. 1989;45(15):1349–56.
56.
Franck G, Salmon E, Poirrier R, Sadzot B, Franco G. Study of regional cerebral glucose metabolism, in man, while awake or asleep, by positron emission tomography. Rev Electroencephalogr Neurophysiol Clin. 1987;17(1):71–7.PubMedCrossRef
57.
Maquet P, Dive D, Salmon E, Sadzot B, Franco G, Poirrier R, et al. Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method. Brain Res. 1990;513(1):136–43.
58.
Kennedy C, Gillin JC, Mendelson W, Suda S, Miyaoka M, Ito M, et al. Local cerebral glucose utilization in non-rapid eye movement sleep. Nature. 1982;297(5864):325–7.
59.
Ramm P, Frost BJ. Cerebral and local cerebral metabolism in the cat during slow wave and REM sleep. Brain Res. 1986;365(1):112–24.PubMedCrossRef
60.
Heiss WD, Pawlik G, Herholz K, Wagner R, Wienhard K. Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming. Brain Res. 1985;327(1–2):362–6.PubMedCrossRef
61.
Fox PT, Raichle ME, Mintun MA, Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science. 1988;241(4864):462–4.PubMedCrossRef
62.
Madsen PL, Schmidt JF, Wildschiodtz G, Friberg L, Holm S, Vorstrup S, et al. Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep. J Appl Physiol (Bethesda, Md: 1985). 1991;70(6):2597–601.CrossRef
63.
Madsen PL, Schmidt JF, Holm S, Vorstrup S, Lassen NA, Wildschiodtz G. Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2). Brain Res. 1991;557(1–2):217–20.PubMedCrossRef
64.
65.
Fox PT, Raichle ME. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A. 1986;83(4):1140–4.PubMedPubMedCentralCrossRef
66.
Roland PE, Eriksson L, Stone-Elander S, Widen L. Does mental activity change the oxidative metabolism of the brain? J Neurosci. 1987;7(8):2373–89.PubMed
67.
•• Cirelli C, Gutierrez CM, Tononi G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron. 2004;41(1):35–43. Using microarray technology, a neat experimental design and clever contextual integration, this study shows that ~10% of transcripts in the rat cerebral cortex are differentially expressed between day and night and that half of these are modulated by sleep and wakefulness independent of circadian rythms. PubMedCrossRef
68.
69.
70.
71.
Neufeld-Cohen A, Robles MS, Aviram R, Manella G, Adamovich Y, Ladeuix B, et al. Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins. Proc Natl Acad Sci U S A. 2016;113(12):E1673–82. https://​doi.​org/​10.​1073/​pnas.​1519650113.
72.
73.
74.
75.
76.
Clarke DD, Sokoloff L. Basic neurochemistry. In: Agranoff BW, Fisher RW, Uhler MD, editors. Siegel GJ. Philadelphia: Lippincott Williams & Wilkins; 1999.
77.
78.
Siesjo DP. Brain energy metabolism. New York: Wiley; 1978.
79.
80.
81.
Kerpel-Fronius S. Discussion. In: Wolstenholme GEW, editor. Somatic stability in the newly born. London: J. & a. Churchill LTD; 1961. p. 73.
82.
Edmond J. Energy metabolism in developing brain cells. Can J Physiol Pharmacol. 1992;70(Suppl):S118–29.PubMedCrossRef
83.
84.
85.
86.
87.
Kong J, Shepel PN, Holden CP, Mackiewicz M, Pack AI, Geiger JD. Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J Neurosci. 2002;22(13):5581–7. doi:20026500.PubMedCrossRef
88.
89.
90.
91.
92.
93.
94.
Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci. 2003;23:5928–35.PubMedCrossRef
95.
•• Miller JC, Gnaedinger JM, Rapoport SI. Utilization of plasma fatty acid in rat brain: distribution of [14C]palmitate between oxidative and synthetic pathways. J Neurochem. 1987;49:1507–14. Building on knowlegde from prior in vitro studies, this study shows that intravenously injected [14C]palmitate into awake rats are taken up by the brain in vivo, about 50% undergo beta-oxidation and are temporally incoorporated into aqueous metabolite pools. The rest is incoorporated into stable lipid and protein compartments.
96.
Gnaedinger J, Miller J. Cerebral metabolism of plasma palmitate in awake, adult rat: subcellular localization. Neurochem Res. 1988;13:21–9.PubMedCrossRef
97.
98.
Arai T, Wakabayashi S-i, Channing MA, Dunn BB, Der MG, Bell JM, et al. Incorporation of [1-carbon-11]palmitate in monkey brain using PET. J Nucl Med. 1995;36:2261–7.PubMed
99.
• Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding Ba, Virtanen K et al. Increased brain fftty acid uptake in etabolic syndrome. 2010;59. https://​doi.​org/​10.​2337/​db09-0138. Using positron emission tomography (PE) this study shows that [ 11 C]-palmitate and [ 18 F]fluoro-6-thia-heptadecanoic acid are taken up by the human brain primarily in gray matter regions.
100.
101.
102.
Seelig A. The role of size and charge for blood-brain barrier permeation of drugs and fatty acids. J Mol Neurosci. 2007;33(1):32–41.PubMedCrossRef
103.
104.
105.
106.
107.
108.
Auestad N, Korsak RA, Morrow JW, Edmond J. Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem. 1991;56(4):1376–86.PubMedCrossRef
109.
110.
111.
112.
113.
114.
Ishii-Iwamoto EL, Ferrarese MLL, Constantin J, Salgueiro-Pagadigorria C, Bracht A. Effects of norepinephrine on the metabolism of fatty acid with different chain lengths in the perfused rat liver. Mol Cell Biochem. 2000;205:13–23.PubMedCrossRef
115.
Chang MC, Wakabayashi S, Bell JM. The effect of methyl palmoxirate on incorporation of [U-14C] palmitate into rat brain. Neurochem Res. 1994;19(9):1217–23.PubMedCrossRef
116.
117.
118.
119.
120.
121.
122.
123.
Nomura T, Iguchi A, Sakamoto N, Harris RA. Effects of octanoate and acetate upon hepatic glycolysis and lipogenesis. Biochim Biophys Acta. 1983;754(3):315–20.PubMedCrossRef
124.
125.
126.
127.
128.
129.
130.
Guzman M, Blazquez C. Is there an astrocyte-neuron ketone body shuttle? Trends Endocrinol Metab. 2001;12(4):169–73.PubMedCrossRef
131.
Ruderman NB, Ross PS, Berger M, Goodman MN. Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats. Biochem J. 1974;138(1):1–10.PubMedPubMedCentralCrossRef
132.
133.
134.
135.
136.
• Dash MB, Douglas CL, Vyazovskiy VV, Cirelli C, Tononi G. Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. J Neurosci. 2009;29(3):620–9. https://​doi.​org/​10.​1523/​jneurosci.​5486-08.​2009. This study reports the glutamate concentration in two cortical areas of freely behaving rats, recorded with high temporal resolution simultaneously with local field potentials (LFPs) and electroencephalograms (EEGs) from the contralateral cortex. They show that the concentration of glutamate varies as a function of behavioral state. PubMedPubMedCentralCrossRef
137.
138.
139.
140.
141.
Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A. 2011;108(19):8030–5. https://​doi.​org/​10.​1073/​pnas.​1016088108.
142.
Trinder J, Kleiman J, Carrington M, Smith S, Breen S, Tan N, et al. Autonomic activity during human sleep as a function of time and sleep stage. J Sleep Res. 2001;10(4):253–64.
143.
144.
145.
146.
• Schulz JG, Laranjeira A, Van Huffel L, Gartner A, Vilain S, Bastianen J, et al. Glial beta-oxidation regulates Drosophila energy metabolism. Sci Rep. 2015;5:7805. https://​doi.​org/​10.​1038/​srep07805. Using Drosophila as a model organism, this is the first study showing that glial fatty acid beta-oxidation is important for energy-homeostasis and prevention of triacylglycerol build-up.
147.
148.
149.
150.
Miyagawa T, Miyadera H, Tanaka S, Kawashima M, Shimada M, Honda Y, et al. Abnormally low serum acylcarnitine levels in narcolepsy patients. Sleep. 2011;34:349–53A.
151.
152.
153.
154.
•• Knobloch M, Pilz GA, Ghesquiere B, Kovacs WJ, Wegleiter T, Moore DL, et al. A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell activity. Cell Rep. 2017;20(9):2144–55. https://​doi.​org/​10.​1016/​j.​celrep.​2017.​08.​029. The first study to show how fatty acid oxidation capacity changes the state and function of cell types in the mouse brain. Inhibition of fatty acid oxidation by increased malonyl-CoA levels shifts quiescents neural stem cells to become proliferative. PubMedPubMedCentralCrossRef
155.
Lamers JM, Stinis HT, Montfoort A, Hulsmann WC. The effect of lipid intermediates on Ca2+ and Na+ permeability and (Na+ / K+)-ATPase of cardiac sarcolemma. A possible role in myocardial ischemia. Biochim Biophys Acta. 1984;774(1):127–37.PubMedCrossRef
156.
157.
158.
159.
•• Díaz-Muñoz M, Hernández-Muñoz R, Suárez J, de Sánchez VC. Day-night cycle of lipid peroxidation in rat cerebral cortex and their relationship to the gperoxide dismutase activity. Neuroscience. 1985;16:859–63. https://​doi.​org/​10.​1016/​0306-4522(85)90100-9. This study measures the state of lipoperoxidation, glutathione cycle components and superoxide dismutase activity every four hour in the the cerebral cortex of the rat, and shows that these parameters exhibit day-night rhythms. PubMedCrossRef
160.
Metadata
Title
Cerebral Metabolic Changes During Sleep
Authors
Nadia Nielsen Aalling
Maiken Nedergaard
Mauro DiNuzzo
Publication date
01-09-2018
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 9/2018
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-018-0868-9

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