Chronic Intermittent Hypoxia Blunts the Expression of Ventilatory Long Term Facilitation in Sleeping Rats

  • Deirdre EdgeEmail author
  • Ken D. O’Halloran
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 860)


We have previously reported that chronic intermittent hypoxia (CIH), a central feature of human sleep-disordered breathing, causes respiratory instability in sleeping rats (Edge D, Bradford A, O’halloran KD. Adv Exp Med Biol 758:359–363, 2012). Long term facilitation (LTF) of respiratory motor outputs following exposure to episodic, but not sustained, hypoxia has been described. We hypothesized that CIH would enhance ventilatory LTF during sleep. We examined the effects of 3 and 7 days of CIH exposure on the expression of ventilatory LTF in sleeping rats. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5 % O2 at nadir; SaO2 ~ 80 %) per hour, 8 h per day for 3 or 7 consecutive days (CIH, N = 7 per group). Corresponding sham groups (N = 7 per group) were subjected to alternating cycles of air under identical experimental conditions in parallel. Following gas exposures, breathing during sleep was assessed in unrestrained, unanaesthetized animals using the technique of whole-body plethysmography. Rats were exposed to room air (baseline) and then to an acute IH (AIH) protocol consisting of alternating periods of normoxia (7 min) and hypoxia (FiO2 0.1, 5 min) for 10 cycles. Breathing was monitored during the AIH exposure and for 1 h in normoxia following AIH exposure. Baseline ventilation was elevated after 3 but not 7 days of CIH exposure. The hypoxic ventilatory response was equivalent in sham and CIH animals after 3 days but ventilatory responses to repeated hypoxic challenges were significantly blunted following 7 days of CIH. Minute ventilation was significantly elevated following AIH exposure compared to baseline in sham but not in CIH exposed animals. LTF, determined as the % increase in minute ventilation from baseline following AIH exposure, was significantly blunted in CIH exposed rats. In summary, CIH leads to impaired ventilatory responsiveness to AIH. Moreover, CIH blunts ventilatory LTF. The physiological significance of ventilatory LTF is context-dependent but it is reasonable to consider that it can potentially destabilize respiratory control, in view of the potential for LTF to give rise to hypocapnia. CIH-induced blunting of LTF may represent a compensatory mechanism subserving respiratory homeostasis. Our results suggest that CIH-induced increase in apnoea index (Edge D, Bradford A, O’halloran KD. Adv Exp Med Biol 758:359–363, 2012) is not related to enhanced ventilatory LTF. We conclude that the mature adult respiratory system exhibits plasticity and metaplasticity with potential consequences for the control of respiratory homeostasis. Our results may have implications for human sleep apnoea.


Long term facilitation Chronic intermittent hypoxia Ventilation Obstructive sleep apnoea Hypoxia 



Supported by the Health Research Board, Ireland (RP/2007/29).


  1. Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126–130PubMedCrossRefGoogle Scholar
  2. Bach KB, Mitchell GS (1996) Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respir Physiol 104:251–260PubMedCrossRefGoogle Scholar
  3. Baker TL, Mitchell GS (2000) Episodic but not continuous hypoxia elicits long-term facilitation of phrenic motor output in rats. J Physiol 529(Pt 1):215–219PubMedCrossRefPubMedCentralGoogle Scholar
  4. Baker TL, Fuller DD, Zabka AG, Mitchell GS (2001) Respiratory plasticity: differential actions of continuous and episodic hypoxia and hypercapnia. Respir Physiol 129:25–35PubMedCrossRefGoogle Scholar
  5. Baker-Herman TL, Mitchell GS (2002) Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J Neurosci 22:6239–6246PubMedGoogle Scholar
  6. Baker-Herman TL, Mitchell GS (2008) Determinants of frequency long-term facilitation following acute intermittent hypoxia in vagotomized rats. Respir Physiol Neurobiol 162:8–17PubMedCrossRefPubMedCentralGoogle Scholar
  7. Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, Mitchell GS (2004) BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7:48–55PubMedCrossRefGoogle Scholar
  8. Baker-Herman TL, Bavis RW, Dahlberg JM, Mitchell AZ, Wilkerson JE, Golder FJ, Macfarlane PM, Watters JJ, Behan M, Mitchell GS (2010) Differential expression of respiratory long-term facilitation among inbred rat strains. Respir Physiol Neurobiol 170:260–267PubMedCrossRefPubMedCentralGoogle Scholar
  9. Cao KY, Zwillich CW, Berthon-Jones M, Sullivan CE (1992) Increased normoxic ventilation induced by repetitive hypoxia in conscious dogs. J Appl Physiol 73:2083–2088PubMedGoogle Scholar
  10. Cao Y, Liu C, Ling L (2010) Glossopharyngeal long-term facilitation requires serotonin 5-HT2 and NMDA receptors in rats. Respir Physiol Neurobiol 170:164–172PubMedCrossRefPubMedCentralGoogle Scholar
  11. Dale-Nagle EA, Hoffman MS, Macfarlane PM, Mitchell GS (2010a) Multiple pathways to long-lasting phrenic motor facilitation. Adv Exp Med Biol 669:225–230PubMedCrossRefPubMedCentralGoogle Scholar
  12. Dale-Nagle EA, Hoffman MS, Macfarlane PM, Satriotomo I, Lovett-Barr MR, Vinit S, Mitchell GS (2010b) Spinal plasticity following intermittent hypoxia: implications for spinal injury. Ann N Y Acad Sci 1198:252–259PubMedCrossRefPubMedCentralGoogle Scholar
  13. Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW (1982a) Respiration during sleep in normal man. Thorax 37:840–844PubMedCrossRefPubMedCentralGoogle Scholar
  14. Douglas NJ, White DP, Weil JV, Pickett CK, Martin RJ, Hudgel DW, Zwillich CW (1982b) Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 125:286–289PubMedGoogle Scholar
  15. Douglas NJ, White DP, Weil JV, Pickett CK, Zwillich CW (1982c) Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 126:758–762PubMedGoogle Scholar
  16. Edge D, Bradford A, O’Halloran KD (2012) Chronic intermittent hypoxia increases apnoea index in sleeping rats. Adv Exp Med Biol 758:359–363Google Scholar
  17. Fregosi RF, Mitchell GS (1994) Long-term facilitation of inspiratory intercostal nerve activity following carotid sinus nerve stimulation in cats. J Physiol 477(Pt 3):469–479PubMedCrossRefPubMedCentralGoogle Scholar
  18. Fuller DD, Bach KB, Baker TL, Kinkead R, Mitchell GS (2000) Long term facilitation of phrenic motor output. Respir Physiol 121:135–146PubMedCrossRefGoogle Scholar
  19. Fuller DD, Baker TL, Behan M, Mitchell GS (2001a) Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat. Physiol Genomics 4:175–181PubMedGoogle Scholar
  20. Fuller DD, Zabka AG, Baker TL, Mitchell GS (2001b) Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J Appl Physiol 90:2001–2006; Discussion 2000PubMedGoogle Scholar
  21. Fuller DD, Johnson SM, Olson EB Jr, Mitchell GS (2003) Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J Neurosci 23:2993–3000PubMedGoogle Scholar
  22. Fuller DD, Baker-Herman TL, Golder FJ, Doperalski NJ, Watters JJ, Mitchell GS (2005) Cervical spinal cord injury upregulates ventral spinal 5-HT2A receptors. J Neurotrauma 22:203–213PubMedCrossRefGoogle Scholar
  23. Gerst DG 3rd, Yokhana SS, Carney LM, Lee DS, Badr MS, Qureshi T, Anthouard MN, Mateika JH (2011) The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. J Appl Physiol 110:15–28PubMedCrossRefPubMedCentralGoogle Scholar
  24. Golder FJ, Zabka AG, Bavis RW, Baker-Herman T, Fuller DD, Mitchell GS (2005) Differences in time-dependent hypoxic phrenic responses among inbred rat strains. J Appl Physiol 98:838–844PubMedCrossRefGoogle Scholar
  25. Golder FJ, Ranganathan L, Satriotomo I, Hoffman M, Lovett-Barr MR, Watters JJ, Baker-Herman TL, Mitchell GS (2008) Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation. J Neurosci 28:2033–2042PubMedCrossRefGoogle Scholar
  26. Harris DP, Balasubramaniam A, Badr MS, Mateika JH (2006) Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans. Am J Physiol Regul Integr Comp Physiol 291:R1111–R1119PubMedCrossRefGoogle Scholar
  27. Hoffman MS, Mitchell GS (2011) Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. J Physiol 589:1397–1407PubMedCrossRefPubMedCentralGoogle Scholar
  28. Hoffman MS, Golder FJ, Mahamed S, Mitchell GS (2010) Spinal adenosine A2(A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia. J Physiol 588:255–266PubMedCrossRefPubMedCentralGoogle Scholar
  29. Iturriaga R, Rey S, Alcayaga J, Del Rio R (2006) Chronic intermittent hypoxia enhances carotid body chemosensory responses to acute hypoxia. Adv Exp Med Biol 580:227–232; Discussion 351–9PubMedCrossRefGoogle Scholar
  30. Johnson SM, Mitchell GS (2002) Activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons. Respir Physiol Neurobiol 131:79–90PubMedCrossRefGoogle Scholar
  31. Kinkead R, Bach KB, Johnson SM, Hodgeman BA, Mitchell GS (2001) Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergic and noradrenergic modulatory systems. Comp Biochem Physiol A Mol Integr Physiol 130:207–218PubMedCrossRefGoogle Scholar
  32. Ling L, Fuller DD, Bach KB, Kinkead R, Olson EB Jr, Mitchell GS (2001) Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing. J Neurosci 21:5381–5388PubMedGoogle Scholar
  33. Lovett-Barr MR, Satriotomo I, Muir GD, Wilkerson JE, Hoffman MS, Vinit S, Mitchell GS (2012) Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury. J Neurosci 32:3591–3600PubMedCrossRefPubMedCentralGoogle Scholar
  34. Macfarlane PM, Mitchell GS (2008) Respiratory long-term facilitation following intermittent hypoxia requires reactive oxygen species formation. Neuroscience 152:189–197PubMedCrossRefPubMedCentralGoogle Scholar
  35. Macfarlane PM, Wilkerson JE, Lovett-Barr MR, Mitchell GS (2008) Reactive oxygen species and respiratory plasticity following intermittent hypoxia. Respir Physiol Neurobiol 164:263–271PubMedCrossRefPubMedCentralGoogle Scholar
  36. Macfarlane PM, Satriotomo I, Windelborn JA, Mitchell GS (2009) NADPH oxidase activity is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. J Physiol 587:1931–1942PubMedCrossRefPubMedCentralGoogle Scholar
  37. Macfarlane PM, Vinit S, Mitchell GS (2011) Serotonin 2A and 2B receptor-induced phrenic motor facilitation: differential requirement for spinal NADPH oxidase activity. Neuroscience 178:45–55PubMedCrossRefPubMedCentralGoogle Scholar
  38. Mahamed S, Mitchell GS (2007) Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol 92:27–37PubMedCrossRefGoogle Scholar
  39. Mahamed S, Mitchell GS (2008a) Respiratory long-term facilitation: too much or too little of a good thing? Adv Exp Med Biol 605:224–227PubMedCrossRefGoogle Scholar
  40. Mahamed S, Mitchell GS (2008b) Simulated apnoeas induce serotonin-dependent respiratory long-term facilitation in rats. J Physiol 586:2171–2181PubMedCrossRefPubMedCentralGoogle Scholar
  41. Mateika JH, Narwani G (2009) Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol 94:279–296PubMedCrossRefPubMedCentralGoogle Scholar
  42. Mateika JH, Sandhu KS (2011) Experimental protocols and preparations to study respiratory long term facilitation. Respir Physiol Neurobiol 176:1–11PubMedCrossRefPubMedCentralGoogle Scholar
  43. Mccrimmon DR, Mitchell GS, Alheid GF (2008) Overview: the neurochemistry of respiratory control. Respir Physiol Neurobiol 164:1–2PubMedCrossRefPubMedCentralGoogle Scholar
  44. Mcguire M, Zhang Y, White DP, Ling L (2002) Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats. J Appl Physiol 93:2155–2161PubMedCrossRefGoogle Scholar
  45. Mcguire M, Zhang Y, White DP, Ling L (2003) Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats. J Appl Physiol 95:1499–1508PubMedCrossRefGoogle Scholar
  46. Millhorn DE, Eldridge FL, Waldrop TG (1980) Prolonged stimulation of respiration by a new central neural mechanism. Respir Physiol 41:87–103PubMedCrossRefGoogle Scholar
  47. Mitchell GS, Johnson SM (2003) Neuroplasticity in respiratory motor control. J Appl Physiol 94:358–374PubMedCrossRefGoogle Scholar
  48. Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, Bavis RW, Mack KJ, Olson EB Jr (2001) Invited review: intermittent hypoxia and respiratory plasticity. J Appl Physiol 90:2466–2475PubMedGoogle Scholar
  49. Nakamura A, Olson EB Jr, Terada J, Wenninger JM, Bisgard GE, Mitchell GS (2010) Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats. J Appl Physiol 109:323–331PubMedCrossRefPubMedCentralGoogle Scholar
  50. Olson EB Jr, Bohne CJ, Dwinell MR, Podolsky A, Vidruk EH, Fuller DD, Powell FL, Mitchel GS (2001) Ventilatory long-term facilitation in unanesthetized rats. J Appl Physiol 91:709–716PubMedGoogle Scholar
  51. Peng YJ, Overholt JL, Kline D, Kumar GK, Prabhakar NR (2003) Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci U S A 100:10073–10078PubMedCrossRefPubMedCentralGoogle Scholar
  52. Reeves SR, Gozal D (2006a) Changes in ventilatory adaptations associated with long-term intermittent hypoxia across the Age spectrum in the rat. Respir Physiol Neurobiol 150:135–143PubMedCrossRefGoogle Scholar
  53. Reeves SR, Gozal D (2006b) Respiratory and metabolic responses to early postnatal chronic intermittent hypoxia and sustained hypoxia in the developing rat. Pediatr Res 60:680–686PubMedCrossRefGoogle Scholar
  54. Skelly JR, Edge D, Shortt CM, Jones JF, Bradford A, O’halloran KD (2012) Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia. Am J Respir Cell Mol Biol 46:139–148PubMedCrossRefGoogle Scholar
  55. Terada J, Mitchell GS (2011) Diaphragm long-term facilitation following acute intermittent hypoxia during wakefulness and sleep. J Appl Physiol 110:1299–1310PubMedCrossRefPubMedCentralGoogle Scholar
  56. Turner DL, Mitchell GS (1997) Long-term facilitation of ventilation following repeated hypoxic episodes in awake goats. J Physiol 499(Pt 2):543–550PubMedCrossRefPubMedCentralGoogle Scholar
  57. Vinit S, Lovett-Barr MR, Mitchell GS (2009) Intermittent hypoxia induces functional recovery following cervical spinal injury. Respir Physiol Neurobiol 169:210–217PubMedCrossRefPubMedCentralGoogle Scholar
  58. Wilkerson JE, Mitchell GS (2009) Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation. Exp Neurol 217:116–123PubMedCrossRefPubMedCentralGoogle Scholar
  59. Wilkerson JE, Macfarlane PM, Hoffman MS, Mitchell GS (2007) Respiratory plasticity following intermittent hypoxia: roles of protein phosphatases and reactive oxygen species. Biochem Soc Trans 35:1269–1272PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Physiology, School of MedicineUniversity College CorkCorkIreland

Personalised recommendations