Comprehensive Physiology Wiley Online Library

Role of Glia in the Regulation of Sleep in Health and Disease

Full Article on Wiley Online Library



Abstract

Sleep is a naturally occurring physiological state that is required to sustain physical and mental health. Traditionally viewed as strictly regulated by top‐down control mechanisms, sleep is now known to also originate locally. Glial cells are emerging as important contributors to the regulation of sleep‐wake cycles, locally and among dedicated neural circuits. A few pioneering studies revealed that astrocytes and microglia may influence sleep pressure, duration as well as intensity, but the precise involvement of these two glial cells in the regulation of sleep remains to be fully addressed, across contexts of health and disease. In this overview article, we will first summarize the literature pertaining to the role of astrocytes and microglia in the regulation of sleep under normal physiological conditions. Afterward, we will discuss the beneficial and deleterious consequences of glia‐mediated neuroinflammation, whether it is acute, or chronic and associated with brain diseases, on the regulation of sleep. Sleep disturbances are a main comorbidity in neurodegenerative diseases, and in several brain diseases that include pain, epilepsy, and cancer. Identifying the relationships between glia‐mediated neuroinflammation, sleep‐wake rhythm disruption and brain diseases may have important implications for the treatment of several disorders. © 2020 American Physiological Society. Compr Physiol 10:687‐712, 2020.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Schematic representation of the lactate/glutamate shuttle and glycogen metabolism, as well as pH and K+ buffering functions of astrocytes (i) pH buffering (orange pathway). Abundant carbonic anhydrase (CA) in astrocytes converts CO2 into H+ and HCO3. Two HCO3 are transported into the extracellular space along with one Na+ via the Na+‐HCO3 co‐transporter (NBC), thereby increasing the extracellular buffering power. Protons left in the glial compartment might drive the transport of lactate (Lac) outside of astrocytes and into neurons through monocarboxylate transporters (MCTs). Excess H+ in neurons is extruded via sodium‐hydrogen exchange (NHE). (ii) astrocyte‐neuron lactate shuttle (ANLS) (green pathway). Glutamate (Glu) uptake by astrocytes is accompanied by Na+ entry, which is extruded by the action of the Na+/K+ ATPase. This triggers glycolysis in astrocytes and glucose uptake from the circulation through GLUT1. The lactate produced is shuttled to neurons through MCTs, where it can be used as an energy substrate after its conversion to pyruvate (Pyr). Neurons can also take up glucose via the neuronal GLUT3. (iii) Glycogen metabolism (purple pathway). Astrocytes store glucose under the form of glycogen. Glycogen synthesis is controlled by glycogen synthase and by the noncatalytic subunit of the protein phosphatase 1 (PTG). The degradation is controlled by the glycogen phosphorylase (GPhos). (iv) Glu‐glutamine cycle (red pathway). Glu released into the synaptic cleft activates ionotropic glutamatergic receptors (GluR), producing a postsynaptic depolarization. Astrocytic excitatory amino acid transporters (EAATs) are responsible for the uptake of a large fraction of Glu at the synapse. Glu is converted into glutamine (Gln) by GS and shuttled back to neurons for glutamate resynthesis. (v) K+ buffering (blue pathway). Astrocytes buffer excess K+ released into the extracellular space as a result of neuronal activity [e.g., through inwardly rectifying K+ channels (Kir)]. K+ ions travel through the astrocytic network via gap junctions (GJ) down their concentration gradient and are released in sites of lower concentration. From Ref. 269.


Figure 1. Schematic representation of the lactate/glutamate shuttle and glycogen metabolism, as well as pH and K+ buffering functions of astrocytes (i) pH buffering (orange pathway). Abundant carbonic anhydrase (CA) in astrocytes converts CO2 into H+ and HCO3. Two HCO3 are transported into the extracellular space along with one Na+ via the Na+‐HCO3 co‐transporter (NBC), thereby increasing the extracellular buffering power. Protons left in the glial compartment might drive the transport of lactate (Lac) outside of astrocytes and into neurons through monocarboxylate transporters (MCTs). Excess H+ in neurons is extruded via sodium‐hydrogen exchange (NHE). (ii) astrocyte‐neuron lactate shuttle (ANLS) (green pathway). Glutamate (Glu) uptake by astrocytes is accompanied by Na+ entry, which is extruded by the action of the Na+/K+ ATPase. This triggers glycolysis in astrocytes and glucose uptake from the circulation through GLUT1. The lactate produced is shuttled to neurons through MCTs, where it can be used as an energy substrate after its conversion to pyruvate (Pyr). Neurons can also take up glucose via the neuronal GLUT3. (iii) Glycogen metabolism (purple pathway). Astrocytes store glucose under the form of glycogen. Glycogen synthesis is controlled by glycogen synthase and by the noncatalytic subunit of the protein phosphatase 1 (PTG). The degradation is controlled by the glycogen phosphorylase (GPhos). (iv) Glu‐glutamine cycle (red pathway). Glu released into the synaptic cleft activates ionotropic glutamatergic receptors (GluR), producing a postsynaptic depolarization. Astrocytic excitatory amino acid transporters (EAATs) are responsible for the uptake of a large fraction of Glu at the synapse. Glu is converted into glutamine (Gln) by GS and shuttled back to neurons for glutamate resynthesis. (v) K+ buffering (blue pathway). Astrocytes buffer excess K+ released into the extracellular space as a result of neuronal activity [e.g., through inwardly rectifying K+ channels (Kir)]. K+ ions travel through the astrocytic network via gap junctions (GJ) down their concentration gradient and are released in sites of lower concentration. From Ref. 269.
References
 1.Abboud F, Kumar R. Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity. J Clin Invest 124: 1454‐1457, 2014.
 2.Ahnaou A, Drinkenburg WHIM. Disruption of glycogen synthase kinase‐3‐beta activity leads to abnormalities in physiological measures in mice. Behav Brain Res 221: 246‐252, 2011.
 3.Alam MN, McGinty D, Bashir T, Kumar S, Imeri L, Opp MR, Szymusiak R. Interleukin‐1beta modulates state‐dependent discharge activity of preoptic area and basal forebrain neurons: Role in sleep regulation. Eur J Neurosci 20: 207‐216, 2004.
 4.Alt JA, Obal F, Traynor TR, Gardi J, Majde JA, Krueger JM. Alterations in EEG activity and sleep after influenza viral infection in GHRH receptor‐deficient mice. J Appl Physiol Bethesda Md 1985 95: 460‐468, 2003.
 5.Andréasson A, Arborelius L, Erlanson‐Albertsson C, Lekander M. A putative role for cytokines in the impaired appetite in depression. Brain Behav Immun 21: 147‐152, 2007.
 6.Angulo MC, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci 24: 6920‐6927, 2004.
 7.Apted FIC. Treatment of human trypanosomiasis. In: Mulligan HW, Potts WH, editors. The African Trypanosomiasis. London: George Allen Unwin, 1970, p. 684‐710, 1970.
 8.Araque A, Castillo PE, Manzoni OJ, Tonini R. Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124: 13‐24, 2017.
 9.Arbonés L, Picatoste F, García A. Histamine stimulates glycogen breakdown and increases 45Ca2+ permeability in rat astrocytes in primary culture. Mol Pharmacol 37: 921‐927, 1990.
 10.Arentsen T, Qian Y, Gkotzis S, Femenia T, Wang T, Udekwu K, Forssberg H, Diaz HR. The bacterial peptidoglycan‐sensing molecule Pglyrp2 modulates brain development and behavior. Mol Psychiatry 22: 257‐266, 2017.
 11.Armstrong TS, Shade MY, Breton G, Gilbert MR, Mahajan A, Scheurer ME, Vera E, Berger AM. Sleep‐wake disturbance in patients with brain tumors. Neuro‐Oncol 19: 323‐335, 2017.
 12.Aronica E, Sandau US, Iyer A, Boison D. Glial adenosine kinase – A neuropathological marker of the epileptic brain. Neurochem Int 63: 688‐695, 2013.
 13.Arrigoni E, Rainnie DG, McCarley RW, Greene RW. Adenosine‐mediated presynaptic modulation of glutamatergic transmission in the laterodorsal tegmentum. J Neurosci 21: 1076‐1085, 2001.
 14.Baracchi F, Opp MR. Sleep‐wake behavior and responses to sleep deprivation of mice lacking both interleukin‐1 beta receptor 1 and tumor necrosis factor‐alpha receptor 1. Brain Behav Immun 22: 982‐993, 2008.
 15.Barberino RS, Menezes VG, Ribeiro AEAS, Palheta RC, Jiang X, Smitz JEJ, Matos MHT. Melatonin protects against cisplatin‐induced ovarian damage in mice via the MT1 receptor and antioxidant activity. Biol Reprod 96: 1244‐1255, 2017.
 16.Basheer R, Porkka‐Heiskanen T, Strecker RE, Thakkar MM, McCarley RW. Adenosine as a biological signal mediating sleepiness following prolonged wakefulness. Biol Signals Recept 9: 319‐327, 2000.
 17.Bauer J, Hohagen F, Gimmel E, Bruns F, Lis S, Krieger S, Ambach W, Guthmann A, Grunze H, Fritsch‐Montero R. Induction of cytokine synthesis and fever suppresses REM sleep and improves mood in patients with major depression. Biol Psychiatry 38: 611‐621, 1995.
 18.Baumann CR, Stocker R, Imhof H‐G, Trentz O, Hersberger M, Mignot E, Bassetti CL. Hypocretin‐1 (orexin A) deficiency in acute traumatic brain injury. Neurology 65: 147‐149, 2005.
 19.Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: Focus on astrocyte‐neuron metabolic cooperation. Cell Metab 14: 724‐738, 2011.
 20.Bellesi M, de Vivo L, Chini M, Gilli F, Tononi G, Cirelli C. Sleep loss promotes astrocytic phagocytosis and microglial activation in mouse cerebral cortex. J Neurosci 37: 5263‐5273, 2017.
 21.Bellesi M, de Vivo L, Tononi G, Cirelli C. Effects of sleep and wake on astrocytes: Clues from molecular and ultrastructural studies. BMC Biol 13: 66, 2015.
 22.Ben Achour S, Pascual O. Astrocyte‐neuron communication: Functional consequences. Neurochem Res 37: 2464‐2473, 2012.
 23.Benington JH, Craig HH. Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol 45: 347‐360, 1995.
 24.Benington JH, Kodali SK, Heller HC. Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation. Brain Res 692: 79‐85, 1995.
 25.Benveniste H, Liu X, Koundal S, Sanggaard S, Lee H, Wardlaw J. The glymphatic system and waste clearance with brain aging: A review. Gerontology 65: 106‐119, 2019.
 26.Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch 463: 121‐137, 2012.
 27.Bessman SP, Skolnik SJ. Gamma hydroxybutyrate and gamma butyrolactone: Concentration in rat tissues during anesthesia. Science 143: 1045‐1047, 1964.
 28.Betschart C, Hintermann S, Behnke D, Cotesta S, Fendt M, Gee CE, Jacobson LH, Laue G, Ofner S, Chaudhari V, Badiger S, Pandit C, Wagner J, Hoyer D. Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia. J Med Chem 56: 7590‐7607, 2013.
 29.Bisht K, Sharma K, Tremblay M‐È. Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia‐mediated synaptic remodeling, inflammation, and oxidative stress. Neurobiol Stress 9: 9‐21, 2018.
 30.Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H, Milior G, Olmos‐Alonso A, Gómez‐Nicola D, Luheshi G, Vallières L, Branchi I, Maggi L, Limatola C, Butovsky O, Tremblay M‐È. Dark microglia: A new phenotype predominantly associated with pathological states. Glia 64: 826‐839, 2016.
 31.Bittner CX, Valdebenito R, Ruminot I, Loaiza A, Larenas V, Sotelo‐Hitschfeld T, Moldenhauer H, San Martín A, Gutiérrez R, Zambrano M, Barros LF. Fast and reversible stimulation of astrocytic glycolysis by K+ and a delayed and persistent effect of glutamate. J Neurosci 31: 4709‐4713, 2011.
 32.Bjorness TE, Kelly CL, Gao T, Poffenberger V, Greene RW. Control and function of the homeostatic sleep response by adenosine A1 receptors. J Neurosci 29: 1267‐1276, 2009.
 33.Blatteis C. Thermal responses of hamsters to endotoxin. J Therm Biol 8: 195‐197, 1983.
 34.Block ML, Hong J‐S. Microglia and inflammation‐mediated neurodegeneration: Multiple triggers with a common mechanism. Prog Neurobiol 76: 77‐98, 2005.
 35.Bluthé R‐M, Kelley KW, Dantzer R. Effects of insulin‐like growth factor‐I on cytokine‐induced sickness behavior in mice. Brain Behav Immun 20: 57‐63, 2006.
 36.Boison D, Aronica E. Comorbidities in neurology: Is adenosine the common link? Neuropharmacology 97: 18‐34, 2015.
 37.Bolaños JP, Almeida A, Moncada S. Glycolysis: A bioenergetic or a survival pathway? Trends Biochem Sci 35: 145‐149, 2010.
 38.Bonanni E, Maestri M, Tognoni G, Fabbrini M, Nucciarone B, Manca ML, Gori S, Iudice A, Murri L. Daytime sleepiness in mild and moderate Alzheimer's disease and its relationship with cognitive impairment. J Sleep Res 14: 311‐317, 2005.
 39.Borbély AA. Endogenous sleep‐substances and sleep regulation. J Neural Transm Suppl 21: 243‐254, 1986.
 40.Borbély AA, Tobler I. Endogenous sleep‐promoting substances and sleep regulation. Physiol Rev 69: 605‐670, 1989.
 41.Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24: 197‐211, 2003.
 42.Brambilla D, Barajon I, Bianchi S, Opp MR, Imeri L. Interleukin‐1 inhibits putative cholinergic neurons in vitro and REM sleep when microinjected into the rat laterodorsal tegmental nucleus. Sleep 33: 919‐929, 2010.
 43.Bredow S, Guha‐Thakurta N, Taishi P, Obál F, Krueger JM. Diurnal variations of tumor necrosis factor alpha mRNA and alpha‐tubulin mRNA in rat brain. Neuroimmunomodulation 4: 84‐90, 1997.
 44.Bryant AS, Li B, Beenhakker MP, Huguenard JR. Maintenance of thalamic epileptiform activity depends on the astrocytic glutamate‐glutamine cycle. J Neurophysiol 102: 2880‐2888, 2009.
 45.Butchart J, Brook L, Hopkins V, Teeling J, Püntener U, Culliford D, Sharples R, Sharif S, McFarlane B, Raybould R, Thomas R, Passmore P, Perry VH, Holmes C. Etanercept in Alzheimer disease: A randomized, placebo‐controlled, double‐blind, phase 2 trial. Neurology 84: 2161‐2168, 2015.
 46.Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL. Identification of a unique TGF‐β dependent molecular and functional signature in microglia. Nat Neurosci 17: 131‐143, 2014.
 47.Cady AB, Kotani S, Shiba T, Kusumoto S, Krueger JM. Somnogenic activities of synthetic lipid A. Infect Immun 57: 396‐403, 1989.
 48.Calcagno N, Baufeld C, Madore C, Butovsky O. TREMendous 2 Be Social. Immunity 48: 842‐843, 2018.
 49.Cantero JL, Hita‐Yañez E, Moreno‐Lopez B, Portillo F, Rubio A, Avila J. Tau protein role in sleep‐wake cycle. J Alzheimers Dis JAD 21: 411‐421, 2010.
 50.Carroll JE, Irwin MR, Levine M, Seeman TE, Absher D, Assimes T, Horvath S. Epigenetic aging and immune senescence in women with insomnia symptoms: Findings from the women's health initiative study. Biol Psychiatry 81: 136‐144, 2017.
 51.Castriotta RJ, Murthy JN. Sleep disorders in patients with traumatic brain injury: A review. CNS Drugs 25: 175‐185, 2011.
 52.Cearley C, Churchill L, Krueger JM. Time of day differences in IL1beta and TNFalpha mRNA levels in specific regions of the rat brain. Neurosci Lett 352: 61‐63, 2003.
 53.Chen Y‐C, Su M‐C, Liou C‐W, Liu S‐F, Chen C‐J, Lin H‐C, Hsiao C‐C, Wang T‐Y, Wang C‐C, Chin C‐H, Huang K‐T, Lin A‐S, Lin M‐C. Co‐upregulation of Toll‐like receptors 2 and 6 on peripheral blood cells in patients with obstructive sleep apnea. Sleep Breath Schlaf Atm 19: 873‐882, 2015.
 54.Chen Z, Gardi J, Kushikata T, Fang J, Krueger JM. Nuclear factor‐kappaB‐like activity increases in murine cerebral cortex after sleep deprivation. Am J Physiol 276: R1812‐R1818, 1999.
 55.Chever O, Lee C‐Y, Rouach N. Astroglial connexin43 hemichannels tune basal excitatory synaptic transmission. J Neurosci 34: 11228‐11232, 2014.
 56.Chitu V, Stanley ER. Regulation of embryonic and postnatal development by the CSF‐1 receptor. Curr Top Dev Biol 123: 229‐275, 2017.
 57.Choi HB, Ryu JK, Kim SU, McLarnon JG. Modulation of the purinergic P2X7 receptor attenuates lipopolysaccharide‐mediated microglial activation and neuronal damage in inflamed brain. J Neurosci Off J Soc Neurosci 27: 4957‐4968, 2007.
 58.Choi S‐H, Aid S, Bosetti F. The distinct roles of cyclooxygenase‐1 and ‐2 in neuroinflammation: Implications for translational research. Trends Pharmacol Sci 30: 174‐181, 2009.
 59.Choudhury ME, Miyanishi K, Takeda H, Islam A, Matsuoka N, Kubo M, Matsumoto S, Kunieda T, Nomoto M, Yano H, Tanaka J. Phagocytic elimination of synapses by microglia during sleep. Glia. DOI: 10.1002/glia.23698.
 60.Chounlamountry K, Kessler J‐P. The ultrastructure of perisynaptic glia in the nucleus tractus solitarii of the adult rat: Comparison between single synapses and multisynaptic arrangements. Glia 59: 655‐663, 2011.
 61.Churchill L, Rector DM, Yasuda K, Fix C, Rojas MJ, Yasuda T, Krueger JM. Tumor necrosis factor alpha: Activity dependent expression and promotion of cortical column sleep in rats. Neuroscience 156: 71‐80, 2008.
 62.Ciccarelli R, Ballerini P, Sabatino G, Rathbone MP, D'Onofrio M, Caciagli F, Di Iorio P. Involvement of astrocytes in purine‐mediated reparative processes in the brain. Int J Dev Neurosci Off J Int Soc Dev Neurosci 19: 395‐414, 2001.
 63.Cirelli C. Sleep disruption, oxidative stress, and aging: New insights from fruit flies. Proc Natl Acad Sci U S A 103: 13901‐13902, 2006.
 64.Clasadonte J, Scemes E, Wang Z, Boison D, Haydon PG. Connexin 43‐mediated astroglial metabolic networks contribute to the regulation of the sleep‐wake cycle. Neuron 95: 1365‐1380.e5, 2017.
 65.Clinton JM, Davis CJ, Zielinski MR, Jewett KA, Krueger JM. Biochemical regulation of sleep and sleep biomarkers. J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med 7: S38‐S42, 2011.
 66.Cornell‐Bell AH, Finkbeiner SM. Ca2+ waves in astrocytes. Cell Calcium 12: 185‐204, 1991.
 67.Corps KN, Roth TL, McGavern DB. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol 72: 355‐362, 2015.
 68.Crotti A, Benner C, Kerman BE, Gosselin D, Lagier‐Tourenne C, Zuccato C, Cattaneo E, Gage FH, Cleveland DW, Glass CK. Mutant huntingtin promotes autonomous microglia activation via myeloid lineage‐determining factors. Nat Neurosci 17: 513‐521, 2014.
 69.Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y, Takayanagi R, Ozawa K, Tanaka K, Aizawa H. Glial dysfunction in the mouse habenula causes depressive‐like behaviors and sleep disturbance. J Neurosci 34: 16273‐16285, 2014.
 70.Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci 9: 46‐56, 2008.
 71.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 29: 620‐629, 2009.
 72.Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, Cui N, Middleton B, Ackermann K, Kayser M, Thumser AE, Raynaud FI, Skene DJ. Effect of sleep deprivation on the human metabolome. Proc Natl Acad Sci U S A 111: 10761‐10766, 2014.
 73.de Groot M, Iyer A, Zurolo E, Anink J, Heimans JJ, Boison D, Reijneveld JC, Aronica E. Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor‐associated epilepsy. Epilepsia 53: 58‐66, 2012.
 74.De Sarro G, Gareri P, Sinopoli VA, David E, Rotiroti D. Comparative, behavioural and electrocortical effects of tumor necrosis factor‐alpha and interleukin‐1 microinjected into the locus coeruleus of rat. Life Sci 60: 555‐564, 1997.
 75.de Vivo L, Bellesi M, Marshall W, Bushong EA, Ellisman MH, Tononi G, Cirelli C. Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science 355: 507‐510, 2017.
 76.Deadwyler SA, Porrino L, Siegel JM, Hampson RE. Systemic and nasal delivery of orexin‐A (Hypocretin‐1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 27: 14239‐14247, 2007.
 77.Deczkowska A, Keren‐Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease‐associated microglia: A universal immune sensor of neurodegeneration. Cell 173: 1073‐1081, 2018.
 78.Di Meco A, Joshi YB, Praticò D. Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles. Neurobiol Aging 35: 1813‐1820, 2014.
 79.Díaz‐García CM, Mongeon R, Lahmann C, Koveal D, Zucker H, Yellen G. Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab 26: 361‐374.e4, 2017.
 80.Dickstein JB, Moldofsky H, Lue FA, Hay JB. Intracerebroventricular injection of TNF‐alpha promotes sleep and is recovered in cervical lymph. Am J Physiol 276: R1018‐R1022, 1999.
 81.Dienel GA. Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain. J Neurosci Res 95: 2103‐2125, 2017.
 82.Dinarello CA. Interleukin‐1 and interleukin‐1 antagonism. Blood 77: 1627‐1652, 1991.
 83.Dinarello CA. Proinflammatory cytokines. Chest 118: 503‐508, 2000.
 84.Dinarello CA. Overview of the IL‐1 family in innate inflammation and acquired immunity. Immunol Rev 281: 8‐27, 2018.
 85.Donnelly RJ, Friedhoff AJ, Beer B, Blume AJ, Vitek MP. Interleukin‐1 stimulates the beta‐amyloid precursor protein promoter. Cell Mol Neurobiol 10: 485‐495, 1990.
 86.Donzis EJ, Tronson NC. Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences. Neurobiol Learn Mem 115: 68‐77, 2014.
 87.Dossi E, Vasile F, Rouach N. Human astrocytes in the diseased brain. Brain Res Bull 136: 139‐156, 2018.
 88.Duchêne A, Mouthon F, Charvériat M, Jeanson T, Picoli C, Perier M, Zhao Y, Lin J‐S, Giaume C, Liu X, Lagarde D, Thomasson J, Piérard C, Chauveau F, Dauvilliers Y. Impact of astroglial connexins on modafinil pharmacological properties. Sleep 39: 1283‐1292, 2016.
 89.Dworak M, McCarley RW, Kim T, Kalinchuk AV, Basheer R. Sleep and brain energy levels: ATP changes during sleep. J Neurosci Off J Soc Neurosci 30: 9007‐9016, 2010.
 90.Eban‐Rothschild A, Appelbaum L, de Lecea L. Neuronal mechanisms for sleep/wake regulation and modulatory drive. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 43: 937‐952, 2018.
 91.Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev 265: 35‐52, 2015.
 92.Everson CA. Sustained sleep deprivation impairs host defense. Am J Physiol 265: R1148‐R1154, 1993.
 93.Everson CA, Toth LA. Systemic bacterial invasion induced by sleep deprivation. Am J Physiol Regul Integr Comp Physiol 278: R905‐R916, 2000.
 94.Fang J, Bredow S, Taishi P, Majde JA, Krueger JM. Synthetic influenza viral double‐stranded RNA induces an acute‐phase response in rabbits. J Med Virol 57: 198‐203, 1999.
 95.Fang J, Wang Y, Krueger JM. Effects of interleukin‐1 beta on sleep are mediated by the type I receptor. Am J Physiol 274: R655‐R660, 1998.
 96.Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol 28: 138‐145, 2007.
 97.Fedele DE, Li T, Lan JQ, Fredholm BB, Boison D. Adenosine A1 receptors are crucial in keeping an epileptic focus localized. Exp Neurol 200: 184‐190, 2006.
 98.Fellin T, Halassa MM, Terunuma M, Succol F, Takano H, Frank M, Moss SJ, Haydon PG. Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo. Proc Natl Acad Sci 106: 15037‐15042, 2009.
 99.Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43: 729‐743, 2004.
 100.Fellin T, Sul JY, D'Ascenzo M, Takano H, Pascual O, Haydon PG. Bidirectional astrocyte‐neuron communication: The many roles of glutamate and ATP. Novartis Found Symp 276: 208‐217; discussion 217‐21, 233‐7, 275‐81, 2006.
 101.Fencl V, Koski G, Pappenheimer JR. Factors in cerebrospinal fluid from goats that affect sleep and activity in rats. J Physiol 216: 565‐589, 1971.
 102.Ferre A, Ribó M, Rodríguez‐Luna D, Romero O, Sampol G, Molina CA, Álvarez‐Sabin J. Strokes and their relationship with sleep and sleep disorders. Neurol Barc Spain 28: 103‐118, 2013.
 103.Filosa JA, Morrison HW, Iddings JA, Du W, Kim KJ. Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neuroscience 323: 96‐109, 2016.
 104.Foley J, Blutstein T, Lee S, Erneux C, Halassa MM, Haydon P. Astrocytic IP3/Ca2+ signaling modulates theta rhythm and REM sleep. Front Neural Circuits 11, 2017.
 105.Fonken LK, Frank MG, Kitt MM, Barrientos RM, Watkins LR, Maier SF. Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain Behav Immun 45: 171‐179, 2015.
 106.Fourgeaud L, Través PG, Tufail Y, Leal‐Bailey H, Lew ED, Burrola PG, Callaway P, Zagórska A, Rothlin CV, Nimmerjahn A, Lemke G. TAM receptors regulate multiple features of microglial physiology. Nature 532: 240‐244, 2016.
 107.Franco‐Pérez J, Ballesteros‐Zebadúa P, Fernández‐Figueroa EA, Ruiz‐Olmedo I, Reyes‐Grajeda P, Paz C. Sleep deprivation and sleep recovery modifies connexin36 and connexin43 protein levels in rat brain. NeuroReport 23: 103‐107, 2012.
 108.Franken P, Gip P, Hagiwara G, Ruby NF, Heller HC. Glycogen content in the cerebral cortex increases with sleep loss in C57BL/6J mice. Neurosci Lett 402: 176‐179, 2006.
 109.Friedman E, Boinski S, Coe C. Interleukin‐1 induces sleep‐like behaviour and alters call structure in juvenile rhesus macaques. Am J Primatol 35: 145‐153, 1995.
 110.Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz J‐L, Emery E, Touze E, Vivien D, Gauberti M. Impaired glymphatic perfusion after strokes revealed by contrast‐enhanced MRI: A new target for fibrinolysis? Stroke 45: 3092‐3096, 2014.
 111.Galati S, Salvadè A, Pace M, Sarasso S, Baracchi F, Bassetti CL, Kaelin‐Lang A, Städler C, Stanzione P, Möller JC. Evidence of an association between sleep and levodopa‐induced dyskinesia in an animal model of Parkinson's disease. Neurobiol Aging 36: 1577‐1589, 2015.
 112.Gao Y, Xiao X, Zhang C, Yu W, Guo W, Zhang Z, Li Z, Feng X, Hao J, Zhang K, Xiao B, Chen M, Huang W, Xiong S, Wu X, Deng W. Melatonin synergizes the chemotherapeutic effect of 5‐fluorouracil in colon cancer by suppressing PI3K/AKT and NF‐κB/iNOS signaling pathways. J Pineal Res 62: e12380, 2017.
 113.Gapstur R, Gross CR, Ness K. Factors associated with sleep‐wake disturbances in child and adult survivors of pediatric brain tumors: A review. Oncol Nurs Forum 36: 723‐731, 2009.
 114.García‐Marín V, García‐López P, Freire M. Cajal's contributions to glia research. Trends Neurosci 30: 479‐487, 2007.
 115.Gemma C, Imeri L, de Simoni MG, Mancia M. Interleukin‐1 induces changes in sleep, brain temperature, and serotonergic metabolism. Am J Physiol 272: R601‐R606, 1997.
 116.Gemma C, Opp MR. Human immunodeficiency virus glycoproteins 160 and 41 alter sleep and brain temperature of rats. J Neuroimmunol 97: 94‐101, 1999.
 117.Giaume C, Liu X. From a glial syncytium to a more restricted and specific glial networking. J Physiol‐Paris 106: 34‐39, 2012.
 118.Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330: 841‐845, 2010.
 119.Gip P, Hagiwara G, Ruby NF, Heller HC. 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, 2002.
 120.Glotzbach SF, Heller HC. Central nervous regulation of body temperature during sleep. Science 194: 537‐539, 1976.
 121.Gómez‐Gonzalo M, Navarrete M, Perea G, Covelo A, Martín‐Fernández M, Shigemoto R, Luján R, Araque A. Endocannabinoids induce lateral long‐term potentiation of transmitter release by stimulation of gliotransmission. Cereb Cortex 25: 3699‐3712, 2014.
 122.Guan Z, Peng X, Fang J. Sleep deprivation impairs spatial memory and decreases extracellular signal‐regulated kinase phosphorylation in the hippocampus. Brain Res 1018: 38‐47, 2004.
 123.Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PloS One 10: e0130624, 2015.
 124.Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep 30: 1145‐1152, 2007.
 125.Hakim F, Wang Y, Zhang SXL, Zheng J, Yolcu ES, Carreras A, Khalyfa A, Shirwan H, Almendros I, Gozal D. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor‐associated macrophages and TLR4 signaling. Cancer Res 74: 1329‐1337, 2014.
 126.Halassa MM, Fellin T, Takano H, Dong J‐H, Haydon PG. Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27: 6473‐6477, 2007.
 127.Halassa MM, Florian C, Fellin T, Munoz JR, Lee S‐Y, Abel T, Haydon PG, Frank MG. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61: 213‐219, 2009.
 128.Halász P. How sleep activates epileptic networks? Epilepsy Res Treat 2013: 425697, 2013.
 129.Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19: 20‐27, 2016.
 130.Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: Translational implications of the impact of inflammation on behavior. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 37: 137‐162, 2012.
 131.Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron 75: 762‐777, 2012.
 132.Hayaishi O, Urade Y. Prostaglandin D2 in sleep‐wake regulation: Recent progress and perspectives. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry 8: 12‐15, 2002.
 133.Hayashi T. The relationship between circadian sleep and gamma‐hydroxybutyrate (4 HB) in brain. Exp Med Surg 25: 148‐155, 1967.
 134.Hayashi Y. Diurnal spatial rearrangement of microglial processes through the rhythmic expression of P2Y12 receptors. J Neurol Disord 01, 2013.
 135.Hayashi Y, Koyanagi S, Kusunose N, Okada R, Wu Z, Tozaki‐Saitoh H, Ukai K, Kohsaka S, Inoue K, Ohdo S, Nakanishi H. The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S. Sci Rep 3: 2744, 2013.
 136.Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan W‐B, Julius D. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9: 1512‐1519, 2006.
 137.Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S. Species‐specific recognition of single‐stranded RNA via toll‐like receptor 7 and 8. Science 303: 1526‐1529, 2004.
 138.Herrero‐Mendez A, Almeida A, Fernández E, Maestre C, Moncada S, Bolaños JP. 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, 2009.
 139.Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y. Extracellular ATP triggers tumor necrosis factor‐α release from rat microglia. J Neurochem 75: 965‐972, 2000.
 140.Holth J, Patel T, Holtzman DM. Sleep in Alzheimer's disease ‐ beyond amyloid. Neurobiol Sleep Circadian Rhythms 2: 4‐14, 2017.
 141.Iadecola C. The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease. Neuron 96: 17‐42, 2017.
 142.Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane R, Nedergaard M. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci Off J Soc Neurosci 34: 16180‐16193, 2014.
 143.Imeri L, Bianchi S, Opp MR. Inhibition of caspase‐1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide. Am J Physiol Regul Integr Comp Physiol 291: R197‐R204, 2006.
 144.Imeri L, Opp MR. How (and why) the immune system makes us sleep. Nat Rev Neurosci 10: 199‐210, 2009.
 145.Imeri L, Opp MR, Krueger JM. An IL‐1 receptor and an IL‐1 receptor antagonist attenuate muramyl dipeptide‐ and IL‐1‐induced sleep and fever. Am J Physiol 265: R907‐R913, 1993.
 146.Ingiosi AM, Opp MR. Sleep and immunomodulatory responses to systemic lipopolysaccharide in mice selectively expressing interleukin‐1 receptor 1 on neurons or astrocytes. Glia 64: 780‐791, 2016.
 147.Ingiosi AM, Opp MR, Krueger JM. Sleep and immune function: Glial contributions and consequences of aging. Curr Opin Neurobiol 23: 806‐811, 2013.
 148.Ingiosi AM, Raymond RM, Pavlova MN, Opp MR. Selective contributions of neuronal and astroglial interleukin‐1 receptor 1 to the regulation of sleep. Brain Behav Immun 48: 244‐257, 2015.
 149.Irwin MR. Why sleep is important for health: A psychoneuroimmunology perspective. Annu Rev Psychol 66: 143‐172, 2015.
 150.Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 11: 625‐632, 2011.
 151.Jewett KA, Krueger JM. Humoral sleep regulation; interleukin‐1 and tumor necrosis factor. Vitam Horm 89: 241‐257, 2012.
 152.Jhaveri KA, Ramkumar V, Trammell RA, Toth LA. Spontaneous, homeostatic, and inflammation‐induced sleep in NF‐kappaB p50 knockout mice. Am J Physiol Regul Integr Comp Physiol 291: R1516‐R1526, 2006.
 153.Johannsen L, Labischinski H, Krueger JM. Somnogenic activity of pseudomurein in rabbits. Infect Immun 59: 2502‐2504, 1991.
 154.Johannsen L, Obál F, Kapás L, Kovalzon V, Krueger JM. Somnogenic activity of muramyl peptide‐derived immune adjuvants. Int J Immunopharmacol 16: 109‐116, 1994.
 155.Johannsen L, Rosenthal RS, Martin SA, Cady AB, Obal F, Guinand M, Krueger JM. Somnogenic activity of O‐acetylated and dimeric muramyl peptides. Infect Immun 57: 2726‐2732, 1989.
 156.Johannsen L, Toth LA, Rosenthal RS, Opp MR, Obal F, Cady AB, Krueger JM. Somnogenic, pyrogenic, and hematologic effects of bacterial peptidoglycan. Am J Physiol 258: R182‐R186, 1990.
 157.Joost E, Jordão MJC, Mages B, Prinz M, Bechmann I, Krueger M. Microglia contribute to the glia limitans around arteries, capillaries and veins under physiological conditions, in a model of neuroinflammation and in human brain tissue. Brain Struct Funct 224: 1301‐1314, 2019.
 158.Jouvet M. Biogenic amines and the states of sleep. Science 163: 32‐41, 1969.
 159.Jouvet M. Neuromediators and hypnogenic factors. Rev Neurol (Paris) 140: 389‐400, 1984.
 160.Jungquist CR, O'Brien C, Matteson‐Rusby S, Smith MT, Pigeon WR, Xia Y, Lu N, Perlis ML. The efficacy of cognitive‐behavioral therapy for insomnia in patients with chronic pain. Sleep Med 11: 302‐309, 2010.
 161.Kaisho T, Akira S. Pleiotropic function of Toll‐like receptors. Microbes Infect 6: 1388‐1394, 2004.
 162.Kang D, Liu G, Lundström A, Gelius E, Steiner H. A peptidoglycan recognition protein in innate immunity conserved from insects to humans. Proc Natl Acad Sci U S A 95: 10078‐10082, 1998.
 163.Kapás L, Bohnet SG, Traynor TR, Majde JA, Szentirmai E, Magrath P, Taishi P, Krueger JM. Spontaneous and influenza virus‐induced sleep are altered in TNF‐alpha double‐receptor deficient mice. J Appl Physiol Bethesda Md 1985 105: 1187‐1198, 2008.
 164.Karacan I, Wolff SM, Williams RL, Hursch CJ, Webb WB. The effects of fever on sleep and dream patterns. Psychosomatics 9: 331‐339, 1968.
 165.Karnovsky ML, Reich P, Anchors JM, Burrows BL. Changes in brain glycogen during slow‐wave sleep in the rat. J Neurochem 41: 1498‐1501, 1983.
 166.Karrer M, Lopez MA, Meier D, Mikhail C, Ogunshola OO, Müller AF, Strauss L, Tafti M, Fontana A. Cytokine‐induced sleep: Neurons respond to TNF with production of chemokines and increased expression of Homer1a in vitro. Brain Behav Immun 47: 186‐192, 2015.
 167.Kawai T, Akira S. Pathogen recognition with Toll‐like receptors. Curr Opin Immunol 17: 338‐344, 2005.
 168.Kent S, Price M, Satinoff E. Fever alters characteristics of sleep in rats. Physiol Behav 44: 709‐715, 1988.
 169.Kim J, Kim Y, Yang KI, Kim D, Kim SA. The relationship between sleep disturbance and functional status in mild stroke patients. Ann Rehabil Med 39: 545‐552, 2015.
 170.Kimura‐Takeuchi M, Majde JA, Toth LA, Krueger JM. Influenza virus‐induced changes in rabbit sleep and acute phase responses. Am J Physiol 263: R1115‐R1121, 1992.
 171.Kimura‐Takeuchi M, Majde JA, Toth LA, Krueger JM. The role of double‐stranded RNA in induction of the acute‐phase response in an abortive influenza virus infection model. J Infect Dis 166: 1266‐1275, 1992.
 172.Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement N Y N 4: 575‐590, 2018.
 173.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 22: 5581‐5587, 2002.
 174.Korkutata M, Saitoh T, Cherasse Y, Ioka S, Duo F, Qin R, Murakoshi N, Fujii S, Zhou X, Sugiyama F, Chen J‐F, Kumagai H, Nagase H, Lazarus M. Enhancing endogenous adenosine A2A receptor signaling induces slow‐wave sleep without affecting body temperature and cardiovascular function. Neuropharmacology 144: 122‐132, 2019.
 175.Kőszeghy Á, Kovács A, Bíró T, Szücs P, Vincze J, Hegyi Z, Antal M, Pál B. Endocannabinoid signaling modulates neurons of the pedunculopontine nucleus (PPN) via astrocytes. Brain Struct Funct 220: 3023‐3041, 2015.
 176.Kovács A, Bordás C, Bíró T, Hegyi Z, Antal M, Szücs P, Pál B. Direct presynaptic and indirect astrocyte‐mediated mechanisms both contribute to endocannabinoid signaling in the pedunculopontine nucleus of mice. Brain Struct Funct 222: 247‐266, 2017.
 177.Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76: 845‐861, 2014.
 178.Krueger JM. The role of cytokines in sleep regulation. Curr Pharm Des 14: 3408‐3416, 2008.
 179.Krueger JM, Bacsik J, García‐Arrarás J. Sleep‐promoting material from human urine and its relation to factor S from brain. Am J Physiol 238: E116‐E123, 1980.
 180.Krueger JM, Frank MG, Wisor JP, Roy S. Sleep function: Toward elucidating an enigma. Sleep Med Rev 28: 46‐54, 2016.
 181.Krueger JM, Johannsen L. Bacterial products, cytokines and sleep. J Rheumatol Suppl 19: 52‐57, 1989.
 182.Krueger JM, Karnovsky ML, Martin SA, Pappenheimer JR, Walter J, Biemann K. Peptidoglycans as promoters of slow‐wave sleep. II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination. J Biol Chem 259: 12659‐12662, 1984.
 183.Krueger JM, Kubillus S, Shoham S, Davenne D. Enhancement of slow‐wave sleep by endotoxin and lipid A. Am J Physiol 251: R591‐R597, 1986.
 184.Krueger JM, Majde JA. Humoral links between sleep and the immune system: Research issues. Ann N Y Acad Sci 992: 9‐20, 2003.
 185.Krueger JM, Nguyen JT, Dykstra‐Aiello CJ, Taishi P. Local sleep. Sleep Med Rev 43: 14‐21, 2019.
 186.Krueger JM, Obál FJ, Fang J, Kubota T, Taishi P. The role of cytokines in physiological sleep regulation. Ann N Y Acad Sci 933: 211‐221, 2001.
 187.Krueger JM, Opp MR. Sleep and microbes. Int Rev Neurobiol 131: 207‐225, 2016.
 188.Krueger JM, Pappenheimer JR, Karnovsky ML. Sleep‐promoting factor S: Purification and properties. Proc Natl Acad Sci U S A 75: 5235‐5238, 1978.
 189.Krueger JM, Pappenheimer JR, Karnovsky ML. Sleep‐promoting effects of muramyl peptides. Proc Natl Acad Sci U S A 79: 6102‐6106, 1982.
 190.Krueger JM, Rector DM, Roy S, Van Dongen HPA, Belenky G, Panksepp J. Sleep as a fundamental property of neuronal assemblies. Nat Rev Neurosci 9: 910‐919, 2008.
 191.Krueger JM, Taishi P, De A, Davis CJ, Winters BD, Clinton J, Szentirmai E, Zielinski MR. ATP and the purine type 2 X7 receptor affect sleep. J Appl Physiol Bethesda Md 1985 109: 1318‐1327, 2010.
 192.Krueger JM, Toth LA, Floyd R, Fang J, Kapás L, Bredow S, Obál F. Sleep, microbes and cytokines. Neuroimmunomodulation 1: 100‐109, 1994.
 193.Krueger JM, Walter J, Dinarello CA, Wolff SM, Chedid L. Sleep‐promoting effects of endogenous pyrogen (interleukin‐1). Am J Physiol 246: R994‐R999, 1984.
 194.Kubota T, Li N, Guan Z, Brown RA, Krueger JM. Intrapreoptic microinjection of TNF‐alpha enhances non‐REM sleep in rats. Brain Res 932: 37‐44, 2002.
 195.Kubota T, Majde JA, Brown RA, Krueger JM. Tumor necrosis factor receptor fragment attenuates interferon‐gamma‐induced non‐REM sleep in rabbits. J Neuroimmunol 119: 192‐198, 2001.
 196.Kumar S, Rai S, Hsieh K‐C, McGinty D, Alam MN, Szymusiak R. Adenosine A2A receptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus. Am J Physiol‐Regul Integr Comp Physiol 305: R31‐R41, 2013.
 197.Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Annu Rev Med 69: 437‐449, 2018.
 198.Lalo U, Palygin O, Rasooli‐Nejad S, Andrew J, Haydon PG, Pankratov Y. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLOS Biol 12: e1001747, 2014.
 199.Lancel M, Mathias S, Faulhaber J, Schiffelholz T. Effect of interleukin‐1 beta on EEG power density during sleep depends on circadian phase. Am J Physiol 270: R830‐R837, 1996.
 200.Langston JW, Forno LS. The hypothalamus in Parkinson disease. Ann Neurol 3: 129‐133, 1978.
 201.Lauro C, Cipriani R, Catalano M, Trettel F, Chece G, Brusadin V, Antonilli L, van Rooijen N, Eusebi F, Fredholm BB, Limatola C. Adenosine A1 receptors and microglial cells mediate CX3CL1‐induced protection of hippocampal neurons against Glu‐induced death. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 35: 1550‐1559, 2010.
 202.Lazar AS, Panin F, Goodman AOG, Lazic SE, Lazar ZI, Mason SL, Rogers L, Murgatroyd PR, Watson LPE, Singh P, Borowsky B, Shneerson JM, Barker RA. Sleep deficits but no metabolic deficits in premanifest Huntington's disease. Ann Neurol 78: 630‐648, 2015.
 203.Lecours C, Bordeleau M, Cantin L, Parent M, Paolo TD, Tremblay M‐È. Microglial implication in Parkinson's disease: Loss of beneficial physiological roles or gain of inflammatory functions? Front Cell Neurosci 12: 282, 2018.
 204.Legendre R, Piéron H. Le problème des facteurs du sommeil. Résultats d'injections vasculaires et intracérébrales de liquides insomniques. C R Soc Biol 68: 1077‐1079, 1910.
 205.Legendre R, Piéron H. Recherches sur le besoin de sommeil consecutif a une vielle prolongee. Z Allg Physiol 14: 235‐262, 1913.
 206.Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G. Functional morphology of the blood–brain barrier in health and disease. Acta Neuropathol (Berl) 135: 311‐336, 2018.
 207.Liguori C, Mercuri NB, Albanese M, Olivola E, Stefani A, Pierantozzi M. Daytime sleepiness may be an independent symptom unrelated to sleep quality in Parkinson's disease. J Neurol 266: 636‐641, 2019.
 208.Lin J‐S, Sakai K, Vanni‐Mercier G, Arrang J‐M, Garbarg M, Schwartz J‐C, Jouvet M. Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3‐receptor ligands in the cat. Brain Res 523: 325‐330, 1990.
 209.Lin S‐C, Sun C‐A, You S‐L, Hwang L‐C, Liang C‐Y, Yang T, Bai C‐H, Chen C‐H, Wei C‐Y, Chou Y‐C. The link of self‐reported insomnia symptoms and sleep duration with metabolic syndrome: A Chinese population‐based study. Sleep 39: 1261‐1266, 2016.
 210.Liu YU, Ying Y, Li Y, Eyo UB, Chen T, Zheng J, Umpierre AD, Zhu J, Bosco DB, Dong H, Wu L‐J. Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Nat Neurosci. DOI: 10.1038/s41593‐019‐0511‐3.
 211.Lundgaard I, Lu ML, Yang E, Peng W, Mestre H, Hitomi E, Deane R, Nedergaard M. Glymphatic clearance controls state‐dependent changes in brain lactate concentration. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 37: 2112‐2124, 2017.
 212.Magistretti PJ, Pellerin L. Astrocytes couple synaptic activity to glucose utilization in the brain. Physiology 14: 177‐182, 1999.
 213.Majde JA, Brown RK, Jones MW, Dieffenbach CW, Maitra N, Krueger JM, Cady AB, Smitka CW, Maassab HF. Detection of toxic viral‐associated double‐stranded RNA (dsRNA) in influenza‐infected lung. Microb Pathog 10: 105‐115, 1991.
 214.Majde JA, Kapás L, Bohnet SG, De A, Krueger JM. Attenuation of the influenza virus sickness behavior in mice deficient in Toll‐like receptor 3. Brain Behav Immun 24: 306‐315, 2010.
 215.Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin Immunol 116: 1188‐1198, 2005.
 216.Manfridi A, Brambilla D, Bianchi S, Mariotti M, Opp MR, Imeri L. Interleukin‐1beta enhances non‐rapid eye movement sleep when microinjected into the dorsal raphe nucleus and inhibits serotonergic neurons in vitro. Eur J Neurosci 18: 1041‐1049, 2003.
 217.Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin‐1 and related cytokines in the regulation of inflammation and immunity. Immunity 50: 778‐795, 2019.
 218.Maret S, Dorsaz S, Gurcel L, Pradervand S, Petit B, Pfister C, Hagenbuchle O, O'Hara BF, Franken P, Tafti M. Homer1a is a core brain molecular correlate of sleep loss. Proc Natl Acad Sci U S A 104: 20090‐20095, 2007.
 219.Maret S, Faraguna U, Nelson AB, Cirelli C, Tononi G. Sleep and waking modulate spine turnover in the adolescent mouse cortex. Nat Neurosci 14: 1418‐1420, 2011.
 220.Martin SA, Karnovsky ML, Krueger JM, Pappenheimer JR, Biemann K. Peptidoglycans as promoters of slow‐wave sleep. I. Structure of the sleep‐promoting factor isolated from human urine. J Biol Chem 259: 12652‐12658, 1984.
 221.Masri S, Sassone‐Corsi P. The emerging link between cancer, metabolism, and circadian rhythms. Nat Med 24: 1795‐1803, 2018.
 222.Mathys H, Adaikkan C, Gao F, Young JZ, Manet E, Hemberg M, De Jager PL, Ransohoff RM, Regev A, Tsai L‐H. Temporal tracking of microglia activation in neurodegeneration at single‐cell resolution. Cell Rep 21: 366‐380, 2017.
 223.Mazziotta JC. Imaging: Window on the brain. Arch Neurol 57: 1413‐1421, 2000.
 224.Mingam R, De Smedt V, Amédée T, Bluthé R‐M, Kelley KW, Dantzer R, Layé S. In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL‐1 beta in the murine brain. Brain Behav Immun 22: 234‐244, 2008.
 225.Miyata S, Kitagawa H. Formation and remodeling of the brain extracellular matrix in neural plasticity: Roles of chondroitin sulfate and hyaluronan. Biochim Biophys Acta Gen Subj 1861: 2420‐2434, 2017.
 226.Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22: 240‐273, Table of Contents, 2009.
 227.Möller T, Bard F, Bhattacharya A, Biber K, Campbell B, Dale E, Eder C, Gan L, Garden GA, Hughes ZA, Pearse DD, Staal RGW, Sayed FA, Wes PD, Boddeke HWGM. Critical data‐based re‐evaluation of minocycline as a putative specific microglia inhibitor. Glia 64: 1788‐1794, 2016.
 228.Morgenthaler FD, Lanz BR, Petit J‐M, Frenkel H, Magistretti PJ, Gruetter R. Alteration of brain glycogen turnover in the conscious rat after 5h of prolonged wakefulness. Neurochem Int 55: 45‐51, 2009.
 229.Morse AM, Kothare SV. Sleep disorders and concussion. Handb Clin Neurol 158: 127‐134, 2018.
 230.Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, Pollmächer T. Dose‐dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Comp Physiol 278: R947‐R955, 2000.
 231.Murillo‐Rodríguez E, Millán‐Aldaco D, Di Marzo V, Drucker‐Colín R. The anandamide membrane transporter inhibitor, VDM‐11, modulates sleep and c‐Fos expression in the rat brain. Neuroscience 157: 1‐11, 2008.
 232.Nadeem R, Molnar J, Madbouly EM, Nida M, Aggarwal S, Sajid H, Naseem J, Loomba R. Serum inflammatory markers in obstructive sleep apnea: A meta‐analysis. J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med 9: 1003‐1012, 2013.
 233.Nadjar A, Bluthé R‐M, May MJ, Dantzer R, Parnet P. Inactivation of the cerebral NFkappaB pathway inhibits interleukin‐1beta‐induced sickness behavior and c‐Fos expression in various brain nuclei. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 30: 1492‐1499, 2005.
 234.Nadjar A, Blutstein T, Aubert A, Laye S, Haydon PG. Astrocyte‐derived adenosine modulates increased sleep pressure during inflammatory response. Glia 61: 724‐731, 2013.
 235.Nadjar A, Tridon V, May MJ, Ghosh S, Dantzer R, Amédée T, Parnet P. NFkappaB activates in vivo the synthesis of inducible Cox‐2 in the brain. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 25: 1047‐1059, 2005.
 236.Nadjar A, Wigren H‐KM, Tremblay M‐E. Roles of microglial phagocytosis and inflammatory mediators in the pathophysiology of sleep disorders. Front Cell Neurosci 11: 250, 2017.
 237.Nagasaki H, Iriki M, Inoue S, Uchizono K. Proceedings: Sleep promoting substances in the brain stem of rats. Nihon Seirigaku Zasshi J Physiol Soc Jpn 36: 293, 1974.
 238.Nagasaki H, Kitahama K, Valatx JL, Jouvet M. Sleep‐promoting effect of the sleep‐promoting substance (SPS) and delta sleep‐inducing peptide (DSIP) in the mouse. Brain Res 192: 276‐280, 1980.
 239.Nagelhus EA, Ottersen OP. Physiological roles of aquaporin‐4 in brain. Physiol Rev 93: 1543‐1562, 2013.
 240.Nakazato R, Takarada T, Yamamoto T, Hotta S, Hinoi E, Yoneda Y. Selective upregulation of Per1 mRNA expression by ATP through activation of P2X7 purinergic receptors expressed in microglial cells. J Pharmacol Sci 116: 350‐361, 2011.
 241.Nedergaard M. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263: 1768‐1771, 1994.
 242.Nijs J, Mairesse O, Neu D, Leysen L, Danneels L, Cagnie B, Meeus M, Moens M, Ickmans K, Goubert D. Sleep disturbances in chronic pain: Neurobiology, assessment, and treatment in physical therapist practice. Phys Ther 98: 325‐335, 2018.
 243.Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314‐1318, 2005.
 244.Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet Lond Engl 355: 39‐40, 2000.
 245.Nonaka K, Nakazawa Y, Kotorii T. Effects of antibiotics, minocycline and ampicillin, on human sleep. Brain Res 288: 253‐259, 1983.
 246.Norman SE, Chediak AD, Kiel M, Cohn MA. Sleep disturbances in HIV‐infected homosexual men. AIDS Lond Engl 4: 775‐781, 1990.
 247.Obál F, Fang J, Payne LC, Krueger JM. Growth‐hormone‐releasing hormone mediates the sleep‐promoting activity of interleukin‐1 in rats. Neuroendocrinology 61: 559‐565, 1995.
 248.Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12: 829‐834, 2006.
 249.Onen SH, Alloui A, Gross A, Eschallier A, Dubray C. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res 10: 35‐42, 2001.
 250.Oosterhof N, Kuil LE, van der Linde HC, Burm SM, Berdowski W, van Ijcken WFJ, van Swieten JC, Hol EM, Verheijen MHG, van Ham TJ. Colony‐stimulating factor 1 receptor (CSF1R) regulates microglia density and distribution, but not microglia differentiation in vivo. Cell Rep 24: 1203‐1217.e6, 2018.
 251.Opp MR. Cytokines and sleep. Sleep Med Rev 9: 355‐364, 2005.
 252.Opp MR, Obal F, Krueger JM. Interleukin 1 alters rat sleep: Temporal and dose‐related effects. Am J Physiol 260: R52‐R58, 1991.
 253.Opp MR, Rady PL, Hughes TK, Cadet P, Tyring SK, Smith EM. Human immunodeficiency virus envelope glycoprotein 120 alters sleep and induces cytokine mRNA expression in rats [published errata appear in Am J Physiol 1996 Aug;271(2 Pt 2):section R following table of contents and 1996 Dec;271(6 Pt 3):section R following table of contents]. Am J Physiol 270: R963‐R970, 1996.
 254.Pabst MJ, Beranova‐Giorgianni S, Krueger JM. Effects of muramyl peptides on macrophages, monokines, and sleep. Neuroimmunomodulation 6: 261‐283, 1999.
 255.Palchykova S, Winsky‐Sommerer R, Shen H‐Y, Boison D, Gerling A, Tobler I. Manipulation of adenosine kinase affects sleep regulation in mice. J Neurosci Off J Soc Neurosci 30: 13157‐13165, 2010.
 256.Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry ‐ novel perspectives on brain disorders. Nat Rev Neurol 15: 317‐328, 2019.
 257.Pappenheimer JR, Koski G, Fencl V, Karnovsky ML, Krueger J. Extraction of sleep‐promoting factor S from cerebrospinal fluid and from brains of sleep‐deprived animals. J Neurophysiol 38: 1299‐1311, 1975.
 258.Pappenheimer JR, Miller TB, Goodrich CA. Sleep‐promoting effects of cerebrospinal fluid from sleep‐deprived goats. Proc Natl Acad Sci U S A 58: 513‐517, 1967.
 259.Parmeggiani PL. Thermoregulation and sleep. Front Biosci J Virtual Libr 8: s557‐s567, 2003.
 260.Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate‐mediated astrocyte‐neuron signalling. Nature 369: 744‐747, 1994.
 261.Parri HR, Crunelli V. Pacemaker calcium oscillations in thalamic astrocytes in situ. NeuroReport 12: 3897‐3900, 2001.
 262.Pascual O, Casper KB, Kubera C, Zhang J, Revilla‐Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG. Astrocytic purinergic signaling coordinates synaptic networks. Science 310: 113‐116, 2005.
 263.Pekny M, Pekna M. Astrocyte reactivity and reactive astrogliosis: Costs and benefits. Physiol Rev 94: 1077‐1098, 2014.
 264.Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci 91: 10625‐10629, 1994.
 265.Pelluru D, Konadhode RR, Bhat NR, Shiromani PJ. Optogenetic stimulation of astrocytes in the posterior hypothalamus increases sleep at night in C57BL/6J mice. Eur J Neurosci 43: 1298‐1306, 2016.
 266.Perea G, Sur M, Araque A. Neuron‐glia networks: Integral gear of brain function. Front Cell Neurosci 8: 378, 2014.
 267.Petanceska S, Canoll P, Devi LA. Expression of rat cathepsin S in phagocytic cells. J Biol Chem 271: 4403‐4409, 1996.
 268.Petit J‐M, Burlet‐Godinot S, Magistretti PJ, Allaman I. Glycogen metabolism and the homeostatic regulation of sleep. Metab Brain Dis 30: 263‐279, 2015.
 269.Petit J‐M, Magistretti PJ. Regulation of neuron‐astrocyte metabolic coupling across the sleep‐wake cycle. Neuroscience 323: 135‐156, 2016.
 270.Pirttimaki TM, Sims RE, Saunders G, Antonio SA, Codadu NK, Parri HR. Astrocyte‐mediated neuronal synchronization properties revealed by false gliotransmitter release. J Neurosci 37: 9859‐9870, 2017.
 271.Pollmächer T, Schreiber W, Gudewill S, Vedder H, Fassbender K, Wiedemann K, Trachsel L, Galanos C, Holsboer F. Influence of endotoxin on nocturnal sleep in humans. Am J Physiol 264: R1077‐R1083, 1993.
 272.Porkka‐Heiskanen T, Alanko L, Kalinchuk A, Stenberg D. Adenosine and sleep. Sleep Med Rev 6: 321‐332, 2002.
 273.Porkka‐Heiskanen T, Strecker RE, Thakkar M, Bjørkum AA, Greene RW, McCarley RW. Adenosine: A mediator of the sleep‐inducing effects of prolonged wakefulness. Science 276: 1265‐1268, 1997.
 274.Poskanzer KE, Yuste R. Astrocytes regulate cortical state switching in vivo. Proc Natl Acad Sci 113: E2675‐E2684, 2016.
 275.Prospéro‐García O, Herold N, Waters AK, Phillips TR, Elder JH, Henriksen SJ. Intraventricular administration of a FIV‐envelope protein induces sleep architecture changes in rats. Brain Res 659: 254‐258, 1994.
 276.Radulovacki M, Virus RM, Djuricic‐Nedelson M, Green RD. Adenosine analogs and sleep in rats. J Pharmacol Exp Ther 228: 268‐274, 1984.
 277.Rao V, Spiro J, Vaishnavi S, Rastogi P, Mielke M, Noll K, Cornwell E, Schretlen D, Makley M. Prevalence and types of sleep disturbances acutely after traumatic brain injury. Brain Inj 22: 381‐386, 2008.
 278.Rehman A, Taishi P, Fang J, Majde JA, Krueger JM. The cloning of a rat peptidoglycan recognition protein (PGRP) and its induction in brain by sleep deprivation. Cytokine 13: 8‐17, 2001.
 279.Riedel O, Klotsche J, Spottke A, Deuschl G, Förstl H, Henn F, Heuser I, Oertel W, Reichmann H, Riederer P, Trenkwalder C, Dodel R, Wittchen H‐U. Frequency of dementia, depression, and other neuropsychiatric symptoms in 1,449 outpatients with Parkinson's disease. J Neurol 257: 1073‐1082, 2010.
 280.Rockstrom MD, Chen L, Taishi P, Nguyen JT, Gibbons CM, Veasey SC, Krueger JM. Tumor necrosis factor alpha in sleep regulation. Sleep Med Rev 40: 69‐78, 2018.
 281.Roodveldt C, Christodoulou J, Dobson CM. Immunological features of alpha‐synuclein in Parkinson's disease. J Cell Mol Med 12: 1820‐1829, 2008.
 282.Rotiroti D, Focà A, Mastroeni P, Fumarola D, Nisticò G. Behavioural and body temperature effects of meningococcal lipopolysaccharide after intraventricular injection in adult fowls Gallus domesticus. Res Commun Chem Pathol Pharmacol 33: 395‐402, 1981.
 283.Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322: 1551‐1555, 2008.
 284.Rye DB. Excessive daytime sleepiness and unintended sleep in Parkinson's disease. Curr Neurol Neurosci Rep 6: 169‐176, 2006.
 285.Sakai T, Tamura T, Kitamoto T, Kidokoro Y. A clock gene, period, plays a key role in long‐term memory formation in Drosophila. Proc Natl Acad Sci U S A 101: 16058‐16063, 2004.
 286.Sallanon M, Touret M, Didier‐Bazes M, Belin MF, Tardy M, Jouvet M. Paradoxical sleep deprivation increases glutamine synthetase in rat brain. C R Acad Sci III 315: 109‐114, 1992.
 287.Sallanon‐Moulin M, Touret M, Didier‐Bazes M, Roudier V, Fages C, Tardy M, Jouvet M. Glutamine synthetase modulation in the brain of rats subjected to deprivation of paradoxical sleep. Mol Brain Res 22: 113‐120, 1994.
 288.Sánchez‐Alavez M, Criado J, Gómez‐Chavarín M, Jiménez‐Anguiano A, Navarro L, Díaz‐Ruiz O, Galicia O, Sánchez‐Narváez F, Murillo‐Rodríguez E, Henriksen SJ, Elder JH, Prospéro‐García O. HIV‐ and FIV‐derived gp120 alter spatial memory, LTP, and sleep in rats. Neurobiol Dis 7: 384‐394, 2000.
 289.Sanz JM, Di Virgilio F. Kinetics and mechanism of ATP‐dependent IL‐1 beta release from microglial cells. J Immunol Baltim Md 1950 164: 4893‐4898, 2000.
 290.Sartorius T, Lutz SZ, Hoene M, Waak J, Peter A, Weigert C, Rammensee H‐G, Kahle PJ, Häring H‐U, Hennige AM. Toll‐like receptors 2 and 4 impair insulin‐mediated brain activity by interleukin‐6 and osteopontin and alter sleep architecture. FASEB J Off Publ Fed Am Soc Exp Biol 26: 1799‐1809, 2012.
 291.Schmitt LI, Sims RE, Dale N, Haydon PG. Wakefulness affects synaptic and network activity by increasing extracellular astrocyte‐derived adenosine. J Neurosci Off J Soc Neurosci 32: 4417‐4425, 2012.
 292.Schnedorf JG, Ivy AC. An examination of the hypnotoxin theory of sleep. Am J Physiol‐Leg Content 125: 491‐505, 1939.
 293.Schuh‐Hofer S, Wodarski R, Pfau DB, Caspani O, Magerl W, Kennedy JD, Treede R‐D. One night of total sleep deprivation promotes a state of generalized hyperalgesia: A surrogate pain model to study the relationship of insomnia and pain. Pain 154: 1613‐1621, 2013.
 294.Seifman MA, Adamides AA, Nguyen PN, Vallance SA, Cooper DJ, Kossmann T, Rosenfeld JV, Morganti‐Kossmann MC. Endogenous melatonin increases in cerebrospinal fluid of patients after severe traumatic brain injury and correlates with oxidative stress and metabolic disarray. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 28: 684‐696, 2008.
 295.Serrano A, Haddjeri N, Lacaille JC, Robitaille R. GABAergic network activation of glial cells underlies hippocampal heterosynaptic depression. J Neurosci 26: 5370‐5382, 2006.
 296.Shekleton JA, Parcell DL, Redman JR, Phipps‐Nelson J, Ponsford JL, Rajaratnam SMW. Sleep disturbance and melatonin levels following traumatic brain injury. Neurology 74: 1732‐1738, 2010.
 297.Shiromani PJ, Xu M, Winston EM, Shiromani SN, Gerashchenko D, Weaver DR. Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. Am J Physiol Regul Integr Comp Physiol 287: R47‐R57, 2004.
 298.Shoham S, Davenne D, Cady AB, Dinarello CA, Krueger JM. Recombinant tumor necrosis factor and interleukin 1 enhance slow‐wave sleep. Am J Physiol 253: R142‐R149, 1987.
 299.Simmons DA, Casale M, Alcon B, Pham N, Narayan N, Lynch G. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease. Glia 55: 1074‐1084, 2007.
 300.Sipe GO, Lowery RL, Tremblay M‐È, Kelly EA, Lamantia CE, Majewska AK. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun 7: 10905, 2016.
 301.Smith A. Sleep, colds and performance. In: Broughton RJ, Ogilvie RD editors. Sleep, Arousal and Performance. Boston: Birkhauser, 1992, p. 233‐242.
 302.Smith DE, Lipsky BP, Russell C, Ketchem RR, Kirchner J, Hensley K, Huang Y, Friedman WJ, Boissonneault V, Plante M‐M, Rivest S, Sims JE. A central nervous system‐restricted isoform of the interleukin‐1 receptor accessory protein modulates neuronal responses to interleukin‐1. Immunity 30: 817‐831, 2009.
 303.Sousa C, Biber K, Michelucci A. Cellular and molecular characterization of microglia: A unique immune cell population. Front Immunol 8: 198, 2017.
 304.Stenberg D, Litonius E, Halldner L, Johansson B, Fredholm BB, Porkka‐Heiskanen T. Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor. J Sleep Res 12: 283‐290, 2003.
 305.Stender J, Mortensen KN, Thibaut A, Darkner S, Laureys S, Gjedde A, Kupers R. The minimal energetic requirement of sustained awareness after brain injury. Curr Biol 26: 1494‐1499, 2016.
 306.Sterr A, Herron K, Dijk D‐J, Ellis J. Time to wake‐up: Sleep problems and daytime sleepiness in long‐term stroke survivors. Brain Inj 22: 575‐579, 2008.
 307.Stowell RD, Sipe GO, Dawes RP, Batchelor HN, Lordy KA, Whitelaw BS, Stoessel MB, Bidlack JM, Brown E, Sur M, Majewska AK. Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Nat Neurosci. DOI: 10.1038/s41593‐019‐0514‐0.
 308.Susić V, Totić S. “Recovery” function of sleep: Effects of purified human interleukin‐1 on the sleep and febrile response of cats. Metab Brain Dis 4: 73‐80, 1989.
 309.Szabó Z, Héja L, Szalay G, Kékesi O, Füredi A, Szebényi K, Dobolyi Á, Orbán TI, Kolacsek O, Tompa T, Miskolczy Z, Biczók L, Rózsa B, Sarkadi B, Kardos J. Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo. Sci Rep 7: 6018, 2017.
 310.Taishi P, Bredow S, Guha‐Thakurta N, Obál F, Krueger JM. Diurnal variations of interleukin‐1 beta mRNA and beta‐actin mRNA in rat brain. J Neuroimmunol 75: 69‐74, 1997.
 311.Taishi P, Chen Z, Obál F, Hansen MK, Zhang J, Fang J, Krueger JM. Sleep‐associated changes in interleukin‐1beta mRNA in the brain. J Interferon Cytokine Res Off J Int Soc Interferon Cytokine Res 18: 793‐798, 1998.
 312.Taishi P, De A, Alt J, Gardi J, Obal F, Krueger JM. Interleukin‐1beta stimulates growth hormone‐releasing hormone receptor mRNA expression in the rat hypothalamus in vitro and in vivo. J Neuroendocrinol 16: 113‐118, 2004.
 313.Takahashi S, Fang J, Kapás L, Wang Y, Krueger JM. Inhibition of brain interleukin‐1 attenuates sleep rebound after sleep deprivation in rabbits. Am J Physiol 273: R677‐R682, 1997.
 314.Tay TL, Savage JC, Hui CW, Bisht K, Tremblay M‐È. Microglia across the lifespan: From origin to function in brain development, plasticity and cognition. J Physiol 595: 1929‐1945, 2017.
 315.Terao A, Matsumura H, Saito M. Interleukin‐1 induces slow‐wave sleep at the prostaglandin D2‐sensitive sleep‐promoting zone in the rat brain. J Neurosci Off J Soc Neurosci 18: 6599‐6607, 1998.
 316.Terao A, Matsumura H, Yoneda H, Saito M. Enhancement of slow‐wave sleep by tumor necrosis factor‐alpha is mediated by cyclooxygenase‐2 in rats. Neuroreport 9: 3791‐3796, 1998.
 317.Thannickal TC, Lai Y‐Y, Siegel JM. Hypocretin (orexin) cell loss in Parkinson's disease. Brain J Neurol 130: 1586‐1595, 2007.
 318.Tononi G, Cirelli C. Sleep and synaptic homeostasis: A hypothesis. Brain Res Bull 62: 143‐150, 2003.
 319.Tononi G, Cirelli C, Dash MB. Extracellular levels of lactate, but not oxygen, reflect sleep homeostasis in the rat cerebral cortex. Sleep 35: 909‐919, 2012.
 320.Toth LA, Krueger JM. Alteration of sleep in rabbits by Staphylococcus aureus infection. Infect Immun 56: 1785‐1791, 1988.
 321.Toth LA, Krueger JM. Effects of microbial challenge on sleep in rabbits. FASEB J Off Publ Fed Am Soc Exp Biol 3: 2062‐2066, 1989.
 322.Toth LA, Krueger JM. Somnogenic, pyrogenic, and hematologic effects of experimental pasteurellosis in rabbits. Am J Physiol 258: R536‐R542, 1990.
 323.Toth LA, Krueger JM. Lighting conditions alter Candida albicans‐induced sleep responses in rabbits. Am J Physiol 269: R1441‐R1447, 1995.
 324.Toth LA, Rehg JE, Webster RG. Strain differences in sleep and other pathophysiological sequelae of influenza virus infection in naive and immunized mice. J Neuroimmunol 58: 89‐99, 1995.
 325.Toth LA, Tolley EA, Broady R, Blakely B, Krueger JM. Sleep during experimental trypanosomiasis in rabbits. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N 205: 174‐181, 1994.
 326.Toth LA, Tolley EA, Krueger JM. Sleep as a prognostic indicator during infectious disease in rabbits. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N 203: 179‐192, 1993.
 327.Touret M, Sallanon‐Moulin M, Fages C, Roudier V, Didier‐Bazes M, Roussel B, Tardy M, Jouvet M. Effects of modafinil‐induced wakefulness on glutamine synthetase regulation in the rat brain. Mol Brain Res 26: 123‐128, 1994.
 328.Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori M‐A, Werts C, Boneca IG. Toll‐like receptor 2‐dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 5: 1000‐1006, 2004.
 329.Tremblay M‐E, Cookson MR, Civiero L. Glial phagocytic clearance in Parkinson's disease. Mol Neurodegener 14: 16, 2019.
 330.Tremblay M‐È, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8: e1000527, 2010.
 331.Tremblay M‐È, Majewska AK. A role for microglia in synaptic plasticity? Commun Integr Biol 4: 220‐222, 2011.
 332.van Calker D, Biber K. The role of glial adenosine receptors in neural resilience and the neurobiology of mood disorders. Neurochem Res 30: 1205‐1217, 2005.
 333.van den Munckhof B, de Vries EE, Braun KPJ, Boss HM, Willemsen MA, van Royen‐Kerkhof A, de Jager W, Jansen FE. Serum inflammatory mediators correlate with disease activity in electrical status epilepticus in sleep (ESES) syndrome. Epilepsia 57: e45‐e50, 2016.
 334.Ventura R, Harris KM. Three‐dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 19: 6897‐6906, 1999.
 335.Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev 98: 239‐389, 2018.
 336.Vermeulen MW, Gray GR. Processing of Bacillus subtilis peptidoglycan by a mouse macrophage cell line. Infect Immun 46: 476‐483, 1984.
 337.Vincent C, Siddiqui TA, Schlichter LC. Podosomes in migrating microglia: Components and matrix degradation. J Neuroinflammation 9: 190, 2012.
 338.Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med 11: e10248, 2019.
 339.Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: The revolution continues. Nat Rev Neurosci 6: 626‐640, 2005.
 340.Vorster AP, Born J. Sleep and memory in mammals, birds and invertebrates. Neurosci Biobehav Rev 50: 103‐119, 2015.
 341.Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OFX, Sousa N, Sotiropoulos I. Chronic stress and glucocorticoids: From neuronal plasticity to neurodegeneration. Neural Plast 2016: 6391686, 2016.
 342.Wada H, Inagaki N, Itowi N, Yamatodani A. Histaminergic neuron system in the brain: Distribution and possible functions. Brain Res Bull 27: 367‐370, 1991.
 343.Wadhwa M, Chauhan G, Roy K, Sahu S, Deep S, Jain V, Kishore K, Ray K, Thakur L, Panjwani U. Caffeine and modafinil ameliorate the neuroinflammation and anxious behavior in rats during sleep deprivation by inhibiting the microglia activation. Front Cell Neurosci 12: 49, 2018.
 344.Wagner RR, Bennett IL, LeQUIRE VS. The production of fever by influenzal viruses; factors influencing the febrile response to single injections of virus. J Exp Med 90: 321‐334, 1949.
 345.Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci 15: 84‐97, 2014.
 346.Willette AA, Bendlin BB, Starks EJ, Birdsill AC, Johnson SC, Christian BT, Okonkwo OC, La Rue A, Hermann BP, Koscik RL, Jonaitis EM, Sager MA, Asthana S. Association of insulin resistance with cerebral glucose uptake in late middle‐aged adults at risk for alzheimer disease. JAMA Neurol 72: 1013‐1020, 2015.
 347.Winn P. How best to consider the structure and function of the pedunculopontine tegmental nucleus: Evidence from animal studies. J Neurol Sci 248: 234‐250, 2006.
 348.Wisor JP, Clegern WC, Schmidt MA. Toll‐like receptor 4 is a regulator of monocyte and electroencephalographic responses to sleep loss. Sleep 34: 1335‐1345, 2011.
 349.Wisor JP, Schmidt MA, Clegern WC. Evidence for neuroinflammatory and microglial changes in the cerebral response to sleep loss. Sleep 34: 261‐272, 2011.
 350.Wodarski R, Schuh‐Hofer S, Yurek DA, Wafford KA, Gilmour G, Treede R‐D, Kennedy JD. Development and pharmacological characterization of a model of sleep disruption‐induced hypersensitivity in the rat. Eur J Pain 19: 554‐566, 2015.
 351.Wolf SA, Boddeke HWGM, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol 79: 619‐643, 2017.
 352.Xia M, Li X, Yang L, Ren J, Sun G, Qi S, Verkhratsky A, Li B. The ameliorative effect of fluoxetine on neuroinflammation induced by sleep deprivation. J Neurochem. DOI: 10.1111/jnc.14272.
 353.Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science 342: 373‐377, 2013.
 354.Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25: 181‐213, 2011.
 355.Yoshida H, Kubota T, Krueger JM. A cyclooxygenase‐2 inhibitor attenuates spontaneous and TNF‐alpha‐induced non‐rapid eye movement sleep in rabbits. Am J Physiol Regul Integr Comp Physiol 285: R99‐R109, 2003.
 356.Yuan X‐S, Wang L, Dong H, Qu W‐M, Yang S‐R, Cherasse Y, Lazarus M, Schiffmann SN, de Kerchove d'Exaerde A, Li R‐X, Huang Z‐L. Striatal adenosine A2A receptor neurons control active‐period sleep via parvalbumin neurons in external globus pallidus. eLife 6: e29055, 2017.
 357.Zeitzer JM, Morales‐Villagran A, Maidment NT, Behnke EJ, Ackerson LC, Lopez‐Rodriguez F, Fried I, Engel J, Wilson CL. Extracellular adenosine in the human brain during sleep and sleep deprivation: An in vivo microdialysis study. Sleep 29: 455‐461, 2006.
 358.Zhang J, Wang H, Ye C, Ge W, Chen Y, Jiang Z, Wu C, Poo M, Duan S. ATP released by astrocytes mediates glutamatergic activity‐dependent heterosynaptic suppression. Neuron 40: 971‐982, 2003.
 359.Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong J‐S, Zhang J. Aggregated alpha‐synuclein activates microglia: A process leading to disease progression in Parkinson's disease. FASEB J Off Publ Fed Am Soc Exp Biol 19: 533‐542, 2005.
 360.Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. An RNA‐sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci Off J Soc Neurosci 34: 11929‐11947, 2014.
 361.Zhou X, Oishi Y, Cherasse Y, Korkutata M, Fujii S, Lee C‐Y, Lazarus M. Extracellular adenosine and slow‐wave sleep are increased after ablation of nucleus accumbens core astrocytes and neurons in mice. Neurochem Int 124: 256‐263, 2019.
 362.Zhu B, Dong Y, Xu Z, Gompf HS, Ward SAP, Xue Z, Miao C, Zhang Y, Chamberlin NL, Xie Z. Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis 48: 348‐355, 2012.
 363.Zielinski MR, Gerashchenko D, Karpova SA, Konanki V, McCarley RW, Sutterwala FS, Strecker RE, Basheer R. The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide. Brain Behav Immun 62: 137‐150, 2017.
 364.Zielinski MR, Krueger JM. Sleep and innate immunity. Front Biosci Sch Ed 3: 632‐642, 2011.
 365.Zielinski MR, Taishi P, Clinton JM, Krueger JM. 5′‐Ectonucleotidase‐knockout mice lack non‐REM sleep responses to sleep deprivation. Eur J Neurosci 35: 1789‐1798, 2012.

Teaching Material

Stefano Garofalo, Katherine Picard, Cristina Limatola, Agnès Nadjar, Olivier Pascual, and Marie-Ève Tremblay. Role of Glia in the Regulation of Sleep in Health and Disease. Compr Physiol 10 : 2020, 687-712.

Didactic Synopsis

Major Teaching Points:

1. Sleep is a physiological state that involves the activity of glial cells.

2. The two main types of glial cells, astrocytes and microglia, play different roles in the regulation of sleep across health and disease.

3. Astrocytes and microglia both release cytokines that regulate sleep.

4. Astrocytes determine the urge to sleep by regulating extracellular adenosine levels and clearing toxic substances through the glymphatic system.

5. Less is known about the role of microglia during normal physiological conditions.

6. The physiological function of astrocytes and microglia is influenced by neuroinflammation, which modulates sleep.

7. Acute neuroinflammation promotes behaviors such as increased sleep that help to restore the challenged homeostasis.

8. Chronic neuroinflammation can lead to neurodegenerative diseases and other brain diseases, such as pain, epilepsy and cancer, in which sleep disorders are a main comorbidity.

 

9. Studying the involvement of glial cells in sleep disorders might identify new treatments.


Related Articles:

Teaching Material

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Stefano Garofalo, Katherine Picard, Cristina Limatola, Agnès Nadjar, Olivier Pascual, Marie‐Ève Tremblay. Role of Glia in the Regulation of Sleep in Health and Disease. Compr Physiol 2020, 10: 687-712. doi: 10.1002/cphy.c190022