Abstract
Astrocytes occupy a strategic position in the brain where they can act as an interface between neurones and blood vessels, and neurones and the cerebro-spinal fluid. This location is ideal for functioning as interoceptors, as they may sense changes in brain microenvironment and contribute to the adaptive homeostatic responses coordinated by neuronal networks. Here we briefly review some of the recent evidence, which implicates the involvement of astrocytes in the central nervous control of breathing, sympathetic tone and blood glucose levels. L-lactate appears a potentially crucial signaling molecule in the communication between astrocytes and neurones. Based on the available evidence, we conclude that astrocytes contribute to the homeostasis by playing a significant role in the brain’s interoceptive mechanisms.
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Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58:1094–1103
Agulhon C, Fiacco TA, McCarthy KD (2010) Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science 327:1250–1254
Schipke CG, Kettenmann H (2004) Astrocyte responses to neuronal activity. Glia 47:226–232
Perea G, Yang A, Boyden ES, Sur M (2014) Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo. Nat Commun 5:3262
Schummers J, Yu H, Sur M (2008) Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320:1638–1643
Ding F, O’Donnell J, Thrane AS et al (2013) α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54:387–394
Bekar LK, He W, Nedergaard M (2008) Locus coeruleus alpha-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb Cortex 18:2789–2795
Bekar LK, Wei HS, Nedergaard M (2012) The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand. J Cereb Blood Flow Metab 32:2135–2145
Heeringa J, Berkenbosch A, de GJ, Olievier CN (1979) Relative contribution of central and peripheral chemoreceptors to the ventilatory response to CO2 during hyperoxia. Respir Physiol 37:365–379
Erlichman JS, Li A, Nattie EE (1998) Ventilatory effects of glial dysfunction in a rat brain stem chemoreceptor region. J Appl Physiol 85:1599–1604
Holleran J, Babbie M, Erlichman JS (2001) Ventilatory effects of impaired glial function in a brain stem chemoreceptor region in the conscious rat. J Appl Physiol 90:1539–1547
Gourine AV, Llaudet E, Dale N, Spyer KM (2005) ATP is a mediator of chemosensory transduction in the central nervous system. Nature 436:108–111
Gourine AV, Kasymov V, Marina N et al (2010) Astrocytes control breathing through pH-dependent release of ATP. Science 329:571–575
Kasymov V, Larina O, Castaldo C et al (2013) Differential sensitivity of brainstem versus cortical astrocytes to changes in pH reveals functional regional specialization of astroglia. J Neurosci 33:435–441
Liu B, Paton JF, Kasparov S (2008) Viral vectors based on bidirectional cell-specific mammalian promoters and transcriptional amplification strategy for use in vitro and in vivo. BMC Biotechnol 8:49
Yamashita A, Hamada A, Suhara Y et al (2014) Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. Synapse 68:235–247
Marina N, Tang F, Figueiredo M et al (2013) Purinergic signalling in the rostral ventro-lateral medulla controls sympathetic drive and contributes to the progression of heart failure following myocardial infarction in rats. Basic Res Cardiol 108:317
Sasaki T, Beppu K, Tanaka KF, Fukazawa Y, Shigemoto R, Matsui K (2012) Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation. Proc Natl Acad Sci USA 109:20720–20725
Wenker IC, Sobrinho CR, Takakura AC, Moreira TS, Mulkey DK (2012) Regulation of ventral surface CO2/H+-sensitive neurons by purinergic signalling. J Physiol 590:2137–2150
Huckstepp RT, **Bihi id R, Eason R et al (2010) Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity. J Physiol 588:3901–3920
Huda R, McCrimmon DR, Martina M (2013) pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract. J Neurophysiol 110:368–377
Konig SA, Offner B, Czachurski J, Seller H (1995) Changes in medullary extracellular pH, sympathetic and phrenic nerve activity during brainstem perfusion with CO2 enriched solutions. J Auton Nerv Syst 51:67–75
Kaye D, Esler M (2005) Sympathetic neuronal regulation of the heart in aging and heart failure. Cardiovasc Res 66:256–264
Bradley TD, Floras JS (2003) Sleep apnea and heart failure: Part I: obstructive sleep apnea. Circulation 107:1671–1678
Bradley TD, Floras JS (2003) Sleep apnea and heart failure: Part II: central sleep apnea. Circulation 107:1822–1826
Sun MK, Wahlestedt C, Reis DJ (1992) Action of externally applied ATP on rat reticulospinal vasomotor neurons. Eur J Pharmacol 224:93–96
Horiuchi J, Potts PD, Tagawa T, Dampney RAL (1999) Effects of activation and blockade of P(2x) receptors in the ventrolateral medulla on arterial pressure and sympathetic activity. J Auton Nerv Syst 76:118–126
Ralevic V, Thomas T, Burnstock G, Spyer KM (1999) Characterization of P2 receptors modulating neural activity in rat rostral ventrolateral medulla. Neuroscience 94:867–878
Wenker IC, Sobrinho CR, Takakura AC, Mulkey DK, Moreira TS (2013) P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure. Hypertension 62:263–273
Mazza E Jr, Edelman NH, Neubauer JA (1985) Hypoxic excitation in neurons cultured from the rostral ventrolateral medulla of the neonatal rat. J Appl Physiol 88(2000):2319–2329
Aley PK, Murray HJ, Boyle JP, Pearson HA, Peers C (2006) Hypoxia stimulates Ca2+ release from intracellular stores in astrocytes via cyclic ADP ribose-mediated activation of ryanodine receptors. Cell Calcium 39:95–100
Bowser DN, Khakh BS (2007) Vesicular ATP is the predominant cause of intercellular calcium waves in astrocytes. J Gen Physiol 129:485–491
Burcelin R, Thorens B (2001) Evidence that extrapancreatic GLUT2-dependent glucose sensors control glucagon secretion. Diabetes 50:1282–1289
Marty N, Dallaporta M, Foretz M et al (2005) Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J Clin Investig 115:3545–3553
McDougal DH, Hermann GE, Rogers RC (2013) Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis. Front Neurosci 7:249
McDougal DH, Viard E, Hermann GE, Rogers RC (2013) Astrocytes in the hindbrain detect glucoprivation and regulate gastric motility. Auton Neurosci 175:61–69
Hermann GE, Viard E, Rogers RC (2014) Hindbrain glucoprivation effects on gastric vagal reflex circuits and gastric motility in the rat are suppressed by the astrocyte inhibitor fluorocitrate. J Neurosci 34:10488–10496
Fonnum F, Johnsen A, Hassel B (1997) Use of fluorocitrate and fluoroacetate in the study of brain metabolism. Glia 21:106–113
Dienel GA (2012) Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 32:1107–1138
Dienel GA (2012) Fueling and imaging brain activation. ASN Neuro 4(5):e00093. doi:10.1042/AN20120021
Gandhi GK, Cruz NF, Ball KK, Dienel GA (2009) Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem 111:522–536
Dienel GA, Schmidt KC, Cruz NF (2007) Astrocyte activation in vivo during graded photic stimulation. J Neurochem 103:1506–1522
Pellerin L, Magistretti PJ (1996) Excitatory amino acids stimulate aerobic glycolysis in astrocytes via an activation of the Na+/K+ ATPase. Dev Neurosci 18:336–342
Suzuki A, Stern SA, Bozdagi O et al (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144:810–823
Magistretti PJ (2006) Neuron-glia metabolic coupling and plasticity. J Exp Biol 209:2304–2311
Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME (2010) Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci USA 107:17757–17762
Demestre M, Boutelle M, Fillenz M (1997) Stimulated release of lactate in freely moving rats is dependent on the uptake of glutamate. J Physiol 499(Pt 3):825–832
Kuhr WG, Korf J (1988) Extracellular lactic acid as an indicator of brain metabolism: continuous on-line measurement in conscious, freely moving rats with intrastriatal dialysis. J Cereb Blood Flow Metab 8:130–137
Dienel GA, Ball KK, Cruz NF (2007) A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover. J Neurochem 102:466–478
Cruz NF, Dienel GA (2002) High glycogen levels in brains of rats with minimal environmental stimuli: implications for metabolic contributions of working astrocytes. J Cereb Blood Flow Metab 22:1476–1489
Matsui T, Ishikawa T, Ito H et al (2012) Brain glycogen supercompensation following exhaustive exercise. J Physiol 590:607–616
de Lecea L, Jones BE, Boutrel B et al (2006) Addiction and arousal: alternative roles of hypothalamic peptides. J Neurosci 26:10372–10375
Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G (2010) Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100:419–428
Naslund E, Hellstrom PM (2007) Appetite signaling: from gut peptides and enteric nerves to brain. Physiol Behav 92:256–262
Gonzalez JA, Jensen LT, Fugger L, Burdakov D (2008) Metabolism-independent sugar sensing in central orexin neurons. Diabetes 57:2569–2576
Parsons MP, Hirasawa M (2010) ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal. J Neurosci 30:8061–8070
Ashcroft FM (2005) ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Investig 115:2047–2058
Ahmed K, Tunaru S, Offermanns S (2009) GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors. Trends Pharmacol Sci 30:557–562
Liu C, Wu J, Zhu J et al (2009) Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem 284:2811–2822
Cai TQ, Ren N, Jin L et al (2008) Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun 377:987–991
Lauritzen KH, Morland C, Puchades M et al (2014) Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24(10):2784–2795
Bozzo L, Puyal J, Chatton JY (2013) Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway. PLoS One 8:e71721
Tang F, Lane S, Korsak A et al (2014) Lactate-mediated glia-neuronal signalling in the mammalian brain. Nat Commun 5:3284
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Special Issue: In Honor of Dr. Gerald Dienel.
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Teschemacher, A.G., Gourine, A.V. & Kasparov, S. A Role for Astrocytes in Sensing the Brain Microenvironment and Neuro-Metabolic Integration. Neurochem Res 40, 2386–2393 (2015). https://doi.org/10.1007/s11064-015-1562-9
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DOI: https://doi.org/10.1007/s11064-015-1562-9