Advertisement

Orexinergic system in the locus coeruleus modulates the CO2 ventilatory response

  • Mariane C. Vicente
  • Mirela B. Dias
  • Elisa M. Fonseca
  • Kênia C. Bícego
  • Luciane H. Gargaglioni
Integrative physiology

Abstract

The orexins are hypothalamic neuropeptides involved in an array of functions such as regulation of sleep/wake states and chemoreception to CO2/pH. The locus coeruleus (LC) is a chemosensitive site and expresses an extensive population of orexin receptor 1 (OX1R). We tested the hypothesis that OX1Rs located in the LC participate in the ventilatory response to hypercapnia in a vigilance state and diurnal cycle-dependent manner. For this, we performed unilateral injections of SB-334867 (OX1R antagonist, 5 mM) into the LC of male Wistar rats and evaluated the ventilatory response to 7 % CO2 during wakefulness and sleep in the dark and light phases of the diurnal cycle. Hypercapnia induced an increase in ventilation (V E) in all groups compared to normocapnic values. However, during the dark phase, but not in the light phase, SB-334867 injection promoted an attenuation of the hypercapnic chemoreflex during wakefulness (V E: vehicle, 1502.6 ± 100 mL kg−1 min−1 vs SB-334867, 1200.3 ± 70.0 mL kg−1 min−1) but not during sleep (V E: vehicle, 1383.0 ± 113.9 vs SB-334687, 1287.6 ± 92.1 mL kg−1 min−1), due to changes in tidal volume (V T). We suggest that projections of orexin-containing neurons to the LC contribute, via OX1Rs, to the hypercapnic chemoreflex during wakefulness in the dark phase.

Keywords

Awake Chemoreception Orexin Hypercapnia Sleep Ventilation 

Notes

Acknowledgments

This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP - 2012/19966-0), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - 442560/2014-1). The authors thank Euclides Seccato for his technical assistance and Luis Gustavo Patrone for helping with the statistics.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Almeida MC, Steiner AA, Coimbra NC, Branco LG (2004) Thermoeffector neuronal pathways in fever: role of the locus coeruleus. J Physiol 558:283–294CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Aston-Jones G (2005) Brain structures and receptors involved in alertness. Sleep Med Suppl 1:S3-7Google Scholar
  3. 3.
    Aston-Jones G, Bloom FE (1981) Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 8:876–886Google Scholar
  4. 4.
    Bartlett D, Tenney SM (1970) Control of breathing in experimental anemia. Respir Physiol 10:384–395CrossRefPubMedGoogle Scholar
  5. 5.
    Barros RCH, Branco LGS, Carnio EC (2004) Evidence for thermoregulation by dopamine D1 and D2 receptors in the anteroventral preoptic region during normoxia and hypoxia. Brain Res 1030(2):165–171CrossRefPubMedGoogle Scholar
  6. 6.
    Biancardi V, Bícego KC, Almeida MC, Gargaglioni LH (2008) Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflugers Arch 455(6):1119–1128CrossRefPubMedGoogle Scholar
  7. 7.
    Biancardi V, Bícego KC, Gargaglioni LH (2014) ATP in the locus coeruleus as a modulator of cardiorespiratory control in unanaesthetized male rats. Exp Physiol 99(1):232–247CrossRefPubMedGoogle Scholar
  8. 8.
    Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13(2):150–155CrossRefPubMedGoogle Scholar
  9. 9.
    Bourgin P, Huitrón-Résendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20(20):7760–7765PubMedGoogle Scholar
  10. 10.
    Burlet S, Tyler CJ, Leonard CS (2002) Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy. J Neurosci 22(7):2862–2872PubMedGoogle Scholar
  11. 11.
    De Carvalho D, Bícego KC, Castro OW, Da Silva GSF, Cairasco NG, Gargaglioni LH (2010) Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia. Respir Physiol Neurobiol 172:24–31CrossRefPubMedGoogle Scholar
  12. 12.
    de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1996) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 5:322–327Google Scholar
  13. 13.
    Dejours P (1981) Principle of comparative respiratory physiology, 2nd edn. Elsevier, New YorkGoogle Scholar
  14. 14.
    Del Cid-Pellitero E, Garzón M (2011) Hypocretin1/OrexinA-containing axons innervate locus coeruleus neurons that project to the rat medial prefrontal cortex. Implication in the sleep-wakefulness cycle and cortical activation. Synapse 65(9):843–857CrossRefPubMedGoogle Scholar
  15. 15.
    Deng BS, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T (2007) Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol 103(5):1772–1779CrossRefPubMedGoogle Scholar
  16. 16.
    Desarnaud F, Murillo-Rodriguez E, Lin L, Xu M, Gerashchenko D, Shiromani SN, Nishino S, Mignot E, Shiromani PJ (2004) The diurnal rhythm of hypocretin in young and old F344 rats. Sleep 27(5):851–856PubMedPubMedCentralGoogle Scholar
  17. 17.
    Dias MB, Li A, Nattie EE (2009) Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol 587(9):2059–2067CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dias MB, Li A, Nattie EE (2010) The orexin receptor 1 (OX1R) in the rostral medullary raphe contributes to the hypercapnic chemoreflex in wakefulness, during the active period of the diurnal cycle. Respir Physiol Neurobiol 170(1):96–102CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dimicco JA, Zaretsky DV (2007) The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol 292(1):47–63CrossRefGoogle Scholar
  20. 20.
    Eggermann E, Serafin M, Bayer L, Machard D, Saint-Mleux B, Jones BE, Mühlethaler M (2001) Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience 108(2):177–181CrossRefPubMedGoogle Scholar
  21. 21.
    Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE (2001) Fos expression in orexin neurons varies with behavioral state. J Neurosci 21(5):1656–1662PubMedGoogle Scholar
  22. 22.
    España RA, Reis KM, Valentino RJ, Berridge CW (2005) Organization of hypocretin/orexin efferents to locus coeruleus and basal forebrain arousal-related structures. J Comp Neurol 481(2):160–178CrossRefPubMedGoogle Scholar
  23. 23.
    Fabris G, Steiner AA, Anselmo-Franci JA, Branco LG (2000) Role of nitric oxide in rat locus coeruleus in hypoxia-induced hyperventilation and hypothermia. Neuroreport 11(13):2991–2995CrossRefPubMedGoogle Scholar
  24. 24.
    Farkas M, Donhoffer S (1975) The effect of hypercapnia on heat production and body temperature in the new-born guinea pig. Acta Physiol Acad Sci Hung 46(3):201–217PubMedGoogle Scholar
  25. 25.
    Gargaglioni LH, Hartzler LK, Putnam RW (2010) The locus coeruleus and central chemosensitivity. Respir Physiol Neurobiol 173(3):264–273CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gautvik KM, de Lecea L, Gautvik VT, Danielson PE, Tranque P, Dopazo A, Bloom FE, Sutcliffe JG (1996) Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. Proc Natl Acad Sci U S A 93(16):8733–8738CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gestreau C, Bevengut M, Dutschmann M (2008) The dual role of the orexin/hypocretin system in modulating wakefulness and respiratory drive. Curr Opin Pulm Med 14(6):512–518CrossRefPubMedGoogle Scholar
  28. 28.
    Greco MA, Shiromani PJ (2001) Hypocretin receptor protein and mRNA expression in the dorsolateral pons of rats. Brain Res Mol Brain Res 88:176–182CrossRefPubMedGoogle Scholar
  29. 29.
    Grimaldi D, Silvani A, Benarroch EE, Cortelli P (2014) Orexin/hypocretin system and autonomic control: new insights and clinical correlations. Neurology 82(3):271–278CrossRefPubMedGoogle Scholar
  30. 30.
    Gottesmann C (2008) Noradrenaline involvement in basic and higher integrated REM sleep processes. Neurobiol 82:237–272Google Scholar
  31. 31.
    Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103(3):777–797CrossRefPubMedGoogle Scholar
  32. 32.
    Hobson JA, McCarley RW, Wyzinski PW (1975) Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science 189:55–58CrossRefPubMedGoogle Scholar
  33. 33.
    Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415(2):145–159CrossRefPubMedGoogle Scholar
  34. 34.
    Kuwaki T (2011) Orexin links emotional stress to autonomic functions. Auton Neurosci 161:20–27CrossRefPubMedGoogle Scholar
  35. 35.
    Lai YL, Lamm JE, Hildebrandt J (1981) Ventilation during prolonged hypercapnia in the rat. J Appl Physiol Respir Environ Exerc Physiol 51(1):78–83PubMedGoogle Scholar
  36. 36.
    Lee MG, Hassani OK, Jones BE (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25(28):6716–6720CrossRefPubMedGoogle Scholar
  37. 37.
    Li A, Nattie E (2010) Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol 588(15):2935–2944CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Li N, Li A, Nattie E (2013) Focal microdialysis of CO2 in the perifornical-hypothalamic area increases ventilation during wakefulness but not NREM sleep. Respir Physiol Neurobiol 185:349–355CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    McCarley WR, Christopher MS (2004) Neurophysiological mechanisms of sleep and wakefulness: a question of balance. Semin Neurol 24(3):211–223CrossRefPubMedGoogle Scholar
  40. 40.
    Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435(1):6–25CrossRefPubMedGoogle Scholar
  41. 41.
    Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46(5):787–798CrossRefPubMedGoogle Scholar
  42. 42.
    Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T (2007) Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102:241–248CrossRefPubMedGoogle Scholar
  43. 43.
    Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260CrossRefPubMedGoogle Scholar
  44. 44.
    Nattie EE, Li A (2002) CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness. J Appl Physiol 92:2119–2130CrossRefPubMedGoogle Scholar
  45. 45.
    Nattie E, Li A (2010) Central chemoreception in wakefulness and sleep: evidence for a distributed network and a role for orexin. J Appl Physiol 108(5):1417–1424CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nattie EE, Li A (2012) Respiration and autonomic regulation and orexin. Prog Brain Res 198:25–46CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Nixon JP, Smale L (2007) A comparative analysis of the distribution of immunoreactive orexin A and B in the brains of nocturnal and diurnal rodents. Behav Brain Funct 3:28CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Novak CM, Albers HE (2002) Localization of hypocretin-like immunoreactivity in the brain of the diurnal rodent, Arvicanthis niloticus. J Chem Neuroanat 23(1):49–58CrossRefPubMedGoogle Scholar
  49. 49.
    Pal D, Mallick BN (2007) Neural mechanism of rapid eye movement sleep generation with reference to REM-OFF neurons in locus coeruleus. Indian J Med Res 125(6):721–739PubMedGoogle Scholar
  50. 50.
    Patrone LG, Bicego KC, Hartzler LK, Putnam RW, Gargaglioni LH (2014) Cardiorespiratory effects of gap junction blockade in the locus coeruleus in unanesthetized adult rats. Respir Physiol Neurobiol 190:86–95CrossRefPubMedGoogle Scholar
  51. 51.
    Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
  52. 52.
    Pepelko WE, Dixon GA (1974) Elimination of cold-induced nonshivering thermogenesis by hypercapnia. Am J Physiol 227:264–267PubMedGoogle Scholar
  53. 53.
    Peyron C, Tighe DK, Van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1988) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015Google Scholar
  54. 54.
    Ohno K, Sakurai T (2008) Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuroendocrinol 29:70–87CrossRefPubMedGoogle Scholar
  55. 55.
    Saiki C, Mortola JP (1996) Effect of CO2 on the metabolic and ventilatory responses to ambient temperature in conscious adult and newborn rats. J Physiol 491(1):261–269CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemilli RM, Tanaka H, Clay Williams S, Richardson JA, Kozlowski GP, Wilson S, Arch JRS, Buckingham RE, Haynes AC, Carr SA, Annan RS, Mcnulty DE, Liu WS, Terret JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behaviour. Cell 92:573–585CrossRefPubMedGoogle Scholar
  57. 57.
    Shouse MN, Staba RJ, Saquib SF, Farber PR (2000) Monoamines and sleep: microdialysis findings in pons and amygdala. Brain Res 860(1-2):181–189CrossRefPubMedGoogle Scholar
  58. 58.
    Soffin EM, Evans ML, Gill CH, Harries MH, Benham CD, Davies CH (2002) SB-334867-A antagonises orexin mediated excitation in the locus coeruleus. Neuropharmacology 42(1):127–133CrossRefPubMedGoogle Scholar
  59. 59.
    Souza Moreno V, Bícego KC, Szawka RE, Anselmo-Franci JA, Gargaglioni LH (2010) Serotonergic mechanisms on breathing modulation in the rat Locus coeruleus. Pflugers Arch 459(3):357–368CrossRefPubMedGoogle Scholar
  60. 60.
    Takahashi K, Lin JS, Sakai K (2008) Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience 153(3):860–870CrossRefPubMedGoogle Scholar
  61. 61.
    Tamaki Y, Nakayama T (1987) Effects of air constituents on thermosensitivities of preoptic neurons: hypoxia versus hypercapnia. Pflugers Arch 409:1–6CrossRefPubMedGoogle Scholar
  62. 62.
    Taxini CL, Puga CC, Dias MB, Bícego KC, Gargaglioni LH (2013) Ionotropic but not metabotropic glutamatergic receptors in the locus coeruleus modulate the hypercapnic ventilatory response in unanaesthetized rats. Acta Physiol (Oxf) 208(1):125–135CrossRefGoogle Scholar
  63. 63.
    Thakkar MM, Ramesh V, Strecker RE, McCarley RW (2001) Microdialysis perfusion of orexin-A in the basal forebrain increases wakefulness in freely behaving rats. Arch Ital Biol 139(3):313–328PubMedGoogle Scholar
  64. 64.
    Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LHT, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438(1-2):71–75CrossRefPubMedGoogle Scholar
  65. 65.
    Van den Pol AN, Ghosh PK, Liu RJ, Li Y, Aghajanian GK, Gao XB (2002) Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol 541:169–185CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Williams RH, Burdakov D (2008) Hypothalamic orexins/hypocretins as regulators of breathing. Expert Rev Mol Med 10:e28CrossRefPubMedGoogle Scholar
  67. 67.
    Yamanaka A, Tsujino N, Funahashi H, Honda K, Guan JL, Wang QP, Tominaga M, Goto K, Shioda S, Sakurai T (2002) Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun 290(4):1237–1245CrossRefPubMedGoogle Scholar
  68. 68.
    Young JK, Wu M, Manaye KF, Kc P, Allard JS, MACK SO, Haxhiu MA (2005) Orexin stimulates breathing via medullary and spinal pathways. J Appl Physiol 98(4):1387–1395CrossRefPubMedGoogle Scholar
  69. 69.
    Xi MC, Morales FR, Chase MH (2001) Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res 901(1-2):259–264CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Mariane C. Vicente
    • 1
  • Mirela B. Dias
    • 2
  • Elisa M. Fonseca
    • 1
  • Kênia C. Bícego
    • 1
  • Luciane H. Gargaglioni
    • 1
  1. 1.Department of Animal Morphology and PhysiologySao Paulo State University—UNESP/FCAV at JaboticabalJaboticabalBrazil
  2. 2.Department of Physiology, Institute of BioscienceSão Paulo State University—UNESPBotucatuBrazil

Personalised recommendations