Abstract
The cellular mechanisms governing the expression, regulation, and function of sleep are not entirely understood. The traditional view is that these mechanisms are neuronal. An alternative view is that glial brain cells may play important roles in these processes. Their ubiquity in the central nervous system makes them well positioned to modulate neuronal circuits that gate sleep and wake. Their ability to respond to chemical neuronal signals suggests that they form feedback loops with neurons that may globally regulate neuronal activity. Their potential role in detoxifying the brain, regulating neuronal metabolism, and promoting synaptic plasticity raises the intriguing possibility that glia mediate important functions ascribed to sleep.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Achariyar TM, Li B, Peng W et al (2016) Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 11:74. https://doi.org/10.1186/s13024-016-0138-8
Amzica F (2002) In vivo electrophysiological evidences for cortical neuron-glia interactions during slow (<1 Hz) and paroxysmal sleep oscillations. J Physiol Paris 96:209–219
Amzica F, Massimini M (2002) Glial and neuronal interactions during slow wave and paroxysmal activities in the neocortex. Cereb Cortex 12:1101–1113
Amzica F, Neckelmann D (1999) Membrane capacitance of cortical neurons and glia during sleep oscillations and spike-wave seizures. J Neurophysiol 82:2731–2746
Bazargani N, Attwell D (2016) Astrocyte calcium signaling: the third wave. Nat Neurosci 19:182–189. https://doi.org/10.1038/nn.4201
Bazargani N, Attwell D (2017) Amines, astrocytes, and arousal. Neuron 94:228–231. https://doi.org/10.1016/j.neuron.2017.03.035
Bellesi M, Pfister-Genskow M, Maret S, Keles S, Tononi G, Cirelli C (2013) Effects of sleep and wake on oligodendrocytes and their precursors. J Neurosci 33:14288–14300
Bellesi M, de Vivo L, Tononi G, Cirelli C (2015) Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies. BMC Biol 13:66. https://doi.org/10.1186/s12915-015-0176-7
Bellesi M, de Vivo L, Chini M, Gilli F, Tononi G, Cirelli C (2017) Sleep loss promotes astrocytic phagocytosis and microglial activation in mouse cerebral cortex. J Neurosci 37:5263
Benington J, Heller HC (1995) Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol 45:347–360
Borbély AA, Achermann P (2000) Sleep homeostasis and models of sleep regulation. In: Kryger M, Roth T, Dement WC (eds) Principles and practice of sleep medicine, 3rd edn. Saunders, Philadelphia, pp 377–390
Clasadonte J, Scemes E, Wang Z, Boison D, Haydon PG (2017) Connexin 43-mediated astroglial metabolic networks contribute to the regulation of the sleep-wake cycle. Neuron 95:1365–1380.e1365. https://doi.org/10.1016/j.neuron.2017.08.022
Clegern WC, Moore ME, Schmidt MA, Wisor J (2012) Simultaneous electroencephalography, real-time measurement of lactate concentration and optogenetic manipulation of neuronal activity in the rodent cerebral cortex. J Vis Exp 70:e4328. https://doi.org/10.3791/4328
Crunelli V, Hughes SW (2010) The slow (<1 Hz) rhythm of non-REM sleep: a dialogue between three cardinal oscillators. Nat Neurosci 13:9–17. https://doi.org/10.1038/nn.2445
Crunelli V, Blethyn KL, Cope DW et al (2002) Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics. Philos Trans R Soc Lond Ser B Biol Sci 357:1675–1693. https://doi.org/10.1098/rstb.2002.1155
Crunelli V, Errington AC, Hughes SW, Tóth TI (2011) The thalamic low-threshold Ca2+ potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks. Philos Trans R Soc A Math Phys Eng Sci 369:3820–3839
Dale E, Staal RGW, Eder C, Möller T (2016) KCa3.1 – a microglial target ready for drug repurposing? Glia 64:1733–1741. https://doi.org/10.1002/glia.22992
Dash MB, Tononi G, Cirelli C (2012) Extracellular levels of lactate, but not oxygen, reflect sleep homeostasis in the rat cerebral cortex. Sleep 35:909–919. https://doi.org/10.5665/sleep.1950
De Roo M, Klauser P, Garcia PM, Poglia L, Muller D (2008) Spine dynamics and synapse remodeling during LTP and memory processes. Prog Brain Res 169:199–207
Dijk DJ, Lockley SW (2002) Integration of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol 92:852–862
Dworak M, McCarley RW, Kim T, Kalinchuk AV, Basheer R (2010) Sleep and brain energy levels: ATP changes during sleep. J Neurosci 30:9007–9016
Faraguna U, Vyazovskiy VV, Nelson AB, Tononi G, Cirelli C (2008) A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. J Neurosci 28:4088–4095
Fellin T, Halassa MM, Terunuma M et al (2009) Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo. Proc Natl Acad Sci U S A 106:15037–15042. https://doi.org/10.1073/pnas.0906419106
Fiacco TA, Agulhon C, McCarthy KD (2009) Sorting out astrocyte physiology from pharmacology. Annu Rev Pharmacol Toxicol 49:151–174. https://doi.org/10.1146/annurev.pharmtox.011008.145602
Frank MG (2006) The mystery of sleep function: current perspectives and future directions. Rev Neurosci 17:375–392
Frank MG (2010) The functions of sleep. In: Winkelman JW, Plante DT (eds) Foundations of psychiatric sleep medicine. Cambridge University Press, Cambridge, pp 59–78
Frank M (2015) Sleep and synaptic plasticity in the developing and adult brain. Curr Top Behav Neurosci 25:123–149. https://doi.org/10.1007/7854_2014_305
Franken P, Gip P, Hagiwara G, Ruby NF, Heller HC (2003) Changes in brain glycogen after sleep deprivation vary with genotype. Am J Physiol Regul Integr Comp Physiol 285:R413–R419
Fuller P, Sherman D, Pedersen NP, Saper CB, Lu J (2011) Reassessment of the structural basis of the ascending arousal system. J Comp Neurol 519:933–956. https://doi.org/10.1002/cne.22559
García-Marín V, García-López P, Freire M (2007) Cajal’s contributions to glia research. Trends Neurosci 30:479–487
Gerstner JR, Vanderheyden WM, LaVaute T et al (2012) Time of day regulates subcellular trafficking, tripartite synaptic localization, and polyadenylation of the astrocytic Fabp7 mRNA. J Neurosci 32:1383
Gerstner JR, Perron IJ, Riedy S et al (2017) Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7. Sci Adv 3(4):e1602663
Gip P, Hagiwara G, Ruby NF, Heller HC (2002) Sleep deprivation decreases glycogen in the cerebellum but not in the cortex of young rats. Am J Physiol Regul Integr Comp Physiol 283:R54–R59
Gip P, Hagiwara G, Sapolsky RM, Cao VH, Heller HC, Ruby NF (2004) Glucocorticoids influence brain glycogen levels during sleep deprivation. Am J Physiol Regul Integr Comp Physiol 286:R1057–R1062
Greene RW, Bjorness TE, Suzuki A (2017) The adenosine-mediated, neuronal-glial, homeostatic sleep response. Curr Opin Neurobiol 44:236–242. https://doi.org/10.1016/j.conb.2017.05.015
Gyoneva S, Orr AG, Traynelis SF (2009) Differential regulation of microglial motility by ATP/ADP and adenosine. Parkinsonism Relat Disord 15(Suppl 3):S195–S199
Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355. https://doi.org/10.1146/annurev-physiol-021909-135843
Halassa MM, Fellin T, Haydon PG (2009a) Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 57:343–346. https://doi.org/10.1016/j.neuropharm.2009.06.031
Halassa MM, Florian C, Fellin T et al (2009b) Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61:213–219. https://doi.org/10.1016/j.neuron.2008.11.024
Hamilton NB, Atwell D (2010) Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11:227–238
Hayaishi O (2002) Functional genomics of sleep and circadian rhythm: invited review: molecular genetic studies on sleep-wake regulation, with special emphasis on the prostaglandin D2 system. J Appl Physiol 92:863–868
Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan W-B, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519
Huang Z-L, Qu W-M, Eguchi N et al (2005) Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8:858–859
Huang Z-L, Urade Y, Hayaishi O (2007) Prostaglandins and adenosine in the regulation of sleep and wakefulness. Curr Opin Pharmacol 7:33–38
Hyden H, Lange PW (1965) Rhythmic enzyme changes in neurons and glia during sleep. Science 149:654–656
Hyder F, Fulbright RK, Shulman RG, Rothman DL (2013) Glutamatergic function in the resting awake human brain is supported by uniformly high oxidative energy. J Cereb Blood Flow Metab 33(3):339–347
Imamura K, Mataga N, Watanabe Y (1993) Gliotoxin-induced suppression of ocular dominance plasticity in kitten visual cortex. Neurosci Res 16:117–124
Inagaki N, Wada H (1994) Histamine and prostanoid receptors on glial cells. Glia 11:102–109
Inoue S, Honda K, Komoda Y (1995) Sleep as neuronal detoxification and restitution. Behav Brain Res 69:91–96
Ishimori K (1909) True cause of sleep: a hypnogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igakkai Zasshi 23:429–457
Kjaerby C, Rasmussen R, Andersen M, Nedergaard M (2017) Does global astrocytic calcium signaling participate in awake brain state transitions and neuronal circuit function? Neurochem Res 42:1810–1822. https://doi.org/10.1007/s11064-017-2195-y
Kong J, Shepel PN, Holden CP, Mackiewicz M, Pack AI, Geiger JD (2002) Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J Neurosci 22:5581–5587
Kreft M, Bak LK, Waagepetersen HS, Schousboe A (2012) Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation. ASN Neuro 4:e00086
Krueger JM (2008) The role of cytokines in sleep regulation. Curr Pharm Des 14:3408–3416
Krueger JM, Rector DM, Roy S, Van Dongen HP, Belenky G, Panksepp J (2008) Sleep as a fundamental property of neuronal assemblies. Nat Rev Neurosci 9:910–919. https://doi.org/10.1038/nrn2521
Krueger JM, Taishi P, De A et al (2010) ATP and the purine type 2 X7 receptor affect sleep. J Appl Physiol 109:1318–1327
Kushikata T, Fang J, Krueger JM (1999) Brain-derived neurotrophic factor enhances spontaneous sleep in rats and rabbits. Am J Physiol Regul Integr Comp Physiol 276:R1334–R1338
Losi G, Mariotti L, Sessolo M, Carmignoto G (2017) New tools to study astrocyte Ca2+ signal dynamics in brain networks in vivo. Front Cell Neurosci 11:134
Madhusudanan P, Reade S, Shankarappa SA (2017) Neuroglia as targets for drug delivery systems: a review. Nanomedicine 13:667–679. https://doi.org/10.1016/j.nano.2016.08.013
Magistretti PJ (2011) Neuronal-glia metabolic coupling and plasticity. Exp Physiol 96:407–410
Matsui T, Svensson CI, Hirata Y, Mizobata K, Hua X-Y, Yaksh TL (2010) Release of prostaglandin E2 and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase. Anesth Analg 111:554–560
Möller T, Boddeke HWGM (2016) Glial cells as drug targets: what does it take? Glia 64:1742–1754. https://doi.org/10.1002/glia.22993
Morozov A, Kellendonk C, Simpson E, Tronche F (2003) Using conditional mutagenesis to study the brain. Biol Psychiatry 54:1125–1133
Naylor E, Aillon DV, Barrett BS et al (2012) Lactate as a biomarker for sleep. Sleep 35:1209–1222. https://doi.org/10.5665/sleep.2072
Nedergaard M, Verkhratsky A (2012) Artifact versus reality – how astrocytes contribute to synaptic events. Glia 60:1013–1023. https://doi.org/10.1002/glia.22288
Parpura V, Zorec R (2010) Gliotransmission: exocytotic release from astrocytes. Brain Res Rev 63:83–92
Pascual O, Casper KB, Kubera C et al (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116
Pelluru D, Konadhode RR, Bhat NR, Shiromani PJ (2016) Optogenetic stimulation of astrocytes in the posterior hypothalamus increases sleep at night in C57BL/6J mice. Eur J Neurosci 43:1298–1306. https://doi.org/10.1111/ejn.13074
Petit J-M, Tobler I, Allaman I, Borbely AA, Magistretti PJ (2002) Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism. Eur J Neurosci 16:1163–1167
Petit JM, Tobler I, Kopp C, Morgenthaler F, Borbely AA, Magistretti PJ (2010) Metabolic response of the cerebral cortex following gentle sleep deprivation and modafinil administration. Sleep 33:901–908
Petit JM, Gyger J, Burlet-Godinot S, Fiumelli H, Martin J-M, Magistretti PJ (2013) Genes involved in the astrocyte-neuron lactate shuttle (ANLS) are specifically regulated in cortical astrocytes following sleep deprivation in mice. Sleep 36:1445–1458
Poskanzer KE, Yuste R (2016) Astrocytes regulate cortical state switching in vivo. Proc Natl Acad Sci 113:E2675–E2684
Ramm P, Smith CT (1990) Rates of cerebral protein synthesis are linked to slow-wave sleep in the rat. Physiol Behav 48:749–753
Reimund E (1994) The free radical theory of sleep. Med Hypotheses 43:231–233
Sala C, Segal M (2014) Dendritic spines: the locus of structural and functional plasticity. Physiol Rev 94:141–188
Scales SJ, Bock JB, Scheller RH (2000) The specifics of membrane fusion. Nature 407:144–146. https://doi.org/10.1038/35025176
Schmitt LI, Sims RE, Dale N, Haydon PG (2012) Wakefulness affects synaptic and network activity by increasing extracellular astrocyte-derived adenosine. J Neurosci 32:4417–4425
Schulze G (2004) Sleep protects excitatory cortical circuits against oxidative damage. Med Hypotheses 63:203–207
Seibt J, Dumoulin M, Aton SJ, Naidoo J, Watson A, Coleman T, Frank MG (2012) Protein synthesis during sleep consolidates cortical plasticity in vivo. Curr Biol 22:676–682
Shannon BJ, Dosenbach RA, Su Y et al (2012) Morning-evening variation in human brain metabolism and memory circuits. J Neurophysiol 109:1444–1456
Sipe GO, Lowery RL, Tremblay MÈ, Kelly EA, Lamantia CE, Majewska AK (2016) Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun 7:10905. https://doi.org/10.1038/ncomms10905. https://www.nature.com/articles/ncomms10905#supplementary-information
Stogsdill JA, Eroglu C (2017) The interplay between neurons and glia in synapse development and plasticity. Curr Opin Neurobiol 42:1–8. https://doi.org/10.1016/j.conb.2016.09.016
Strecker RE, Morairty S, Thakkar MM et al (2000) Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res 115:183–204
Szabó Z, Héja L, Szalay G et al (2017) Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo. Sci Rep 7:6018. https://doi.org/10.1038/s41598-017-06073-7
Szymusiak R, Gvilia I, McGinty D (2007) Hypothalamic control of sleep. Sleep Med 8:291–301
Takano T, Tian G-F, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267
Tobler I, Borbély AA, Schwyzer M, Fontana A (1984) Interleukin-1 derived from astrocytes enhances slow wave activity in sleep EEG of the rat. Eur J Pharmacol 104:191–192
Urade Y, Hayaishi O (2011) Prostaglandin D2 and sleep/wake regulation. Sleep Med Rev 15:411–418
Verkhratsky A, Rodriguez J, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353:45–56
Verkman AS, Smith AJ, Phuan P-W, Tradtrantip L, Anderson MO (2017) The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets 21:1161–1170. https://doi.org/10.1080/14728222.2017.1398236
Volterra A (2013) Astrocytes: modulation of synaptic function and network activity. In: Kettenmann H, Ransom B (eds) Neuroglia. Oxford University Press, New York, pp 481–493
Wisor JP, Clegern WC (2011) Quantification of short-term slow wave sleep homeostasis and its disruption by minocycline in the laboratory mouse. Neurosci Lett 490:165–169. https://doi.org/10.1016/j.neulet.2010.11.034
Wisor JP, Clegern WC, Schmidt MA (2011a) Toll-like receptor 4 is a regulator of monocyte and electroencephalographic responses to sleep loss. Sleep 34:1335–1345. https://doi.org/10.5665/SLEEP.1274
Wisor JP, Schmidt MA, Clegern WC (2011b) Evidence for neuroinflammatory and microglial changes in the cerebral response to sleep loss. Sleep 34:261–272
Wisor JP, Rempe MJ, Schmidt MA, Moore ME, Clegern WC (2012) Sleep slow-wave activity regulates cerebral glycolytic metabolism. Cereb Cortex 23:1978–1987
Xie L, Kang H, Xu Q et al (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373–377. https://doi.org/10.1126/science.1241224
Yamamoto K, Miwa T, Ueno R, Hayaishi O (1988) Muramyl dipeptide-elicited production of PGD2 from astrocytes in culture. Biochem Biophys Res Commun 156:882–888
Yulug B, Hanoglu L, Kilic E (2017) Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer’s disease? Psychiatry Clin Neurosc 71(10):673–677. https://doi.org/10.1111/pcn.12539
Zhang Q, Haydon PG (2005) Roles for gliotransmission in the nervous system. J Neural Transm 112:121–125
Zimmerman JE, Mackiewicz M, Galante RJ et al (2004) Glycogen in the brain of Drosophila melanogaster: diurnal rhythm and the effect of rest deprivation. J Neurochem 88:32–40
Acknowledgments
This research was supported by a Sleep Research Society Elliot Weitzman Award and NIH MH099544.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Frank, M.G. (2018). The Role of Glia in Sleep Regulation and Function. In: Landolt, HP., Dijk, DJ. (eds) Sleep-Wake Neurobiology and Pharmacology . Handbook of Experimental Pharmacology, vol 253. Springer, Cham. https://doi.org/10.1007/164_2017_87
Download citation
DOI: https://doi.org/10.1007/164_2017_87
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-11270-7
Online ISBN: 978-3-030-11272-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)