Dynamics of the Inferior Olive Oscillator and Cerebellar Function

  • Alexandre Mathy
  • Beverley A. Clark
Reference work entry


The inferior olive gives rise to the climbing fiber input to cerebellar Purkinje cells and is therefore the source of one of the most powerful synapses in the brain, generating a large burst of Purkinje cell activity referred to as the complex spike. The timing of complex spikes plays a key role in theories of cerebellar function and the determinants of the temporal output structure of neurons of the inferior olive are thus of critical importance. Olivary neurons display spontaneous subthreshold oscillations (STOs) that are generated by the interplay of intrinsic voltage- and calcium-gated conductances and electrotonic coupling between groups of neurons that consequently oscillate in synchrony. Olivary action potentials are also complex, consisting of an initial spike followed by a plateau potential that drives a burst of axonal action potentials. The STOs can influence the timing of spike output and the number of spikes in this burst, implicating them in important downstream effects in the cerebellar cortex, such as complex spike timing and synchrony, and synaptic plasticity. STOs and the coupling between olivary neurons can be modified by extrinsic input, a key candidate being the afferent inhibitory connections forming the descending limb of the olivocerebellar loop. This may result in an olivary network with dynamic properties, which has led to theories of the olivocerebellar system as a generator of spatiotemporal patterns of firing. This chapter discusses evidence for these and competing models, as well as their implications for the production of motor rhythms.


Purkinje Cell Cerebellar Cortex Inferior Olivary Climbing Fiber Deep Cerebellar Nucleus 
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  1. Albus J (1971) A theory of cerebellar function. Mathematical Biosciences 10:25–61CrossRefGoogle Scholar
  2. Apps R, Garwicz M (2005) Anatomical and physiological foundations of cerebellar information processing. Nat Rev Neurosci 6(4):297–311PubMedCrossRefGoogle Scholar
  3. Armstrong DM (1974) Functional significance of connections of the inferior olive. Physiol Rev 54(2):358–417PubMedGoogle Scholar
  4. Armstrong DM, Rawson JA (1979) Activity patterns of cerebellar cortical neurones and climbing fibre afferents in the awake cat. J Physiol 289:425–448PubMedGoogle Scholar
  5. Armstrong DM, Edgley SA et al (1988) Complex spikes in Purkinje cells of the paravermal part of the anterior lobe of the cat cerebellum during locomotion. J Physiol 400:405–414PubMedGoogle Scholar
  6. Bal T, McCormick DA (1997) Synchronized oscillations in the inferior olive are controlled by the hyperpolarization-activated cation current I(h). J Neurophysiol 77(6):3145–3156PubMedGoogle Scholar
  7. Bell CC, Kawasaki T (1972) Relations among climbing fiber responses of nearby Purkinje cells. J Neurophysiol 35(2):155–169PubMedGoogle Scholar
  8. Benardo LS, Foster RE (1986) Oscillatory behavior in inferior olive neurons: mechanism, modulation, cell aggregates. Brain Res Bull 17(6):773–784PubMedCrossRefGoogle Scholar
  9. Best AR, Regehr WG (2008) Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses. J Neurosci 28(25):6508–6515PubMedCrossRefGoogle Scholar
  10. Bishop GA, Ho RH (1984) Substance P and serotonin immunoreactivity in the rat inferior olive. Brain Res Bull 12(1):105–113PubMedCrossRefGoogle Scholar
  11. Bishop GA, Ho RH (1986) Cell bodies of origin of serotonin-immunoreactive afferents to the inferior olivary complex of the rat. Brain Res 399(2):369–373PubMedCrossRefGoogle Scholar
  12. Bleasel AF, Pettigrew AG (1992) Development and properties of spontaneous oscillations of the membrane potential in inferior olivary neurons in the rat. Brain Res Dev Brain Res 65(1):43–50PubMedCrossRefGoogle Scholar
  13. Blenkinsop TA, Lang EJ (2006) Block of inferior olive gap junctional coupling decreases Purkinje cell complex spike synchrony and rhythmicity. J Neurosci 26(6):1739–1748PubMedCrossRefGoogle Scholar
  14. Bloedel JR, Ebner TJ (1984) Rhythmic discharge of climbing fibre afferents in response to natural peripheral stimuli in the cat. J Physiol 352:129–146PubMedGoogle Scholar
  15. Buzsaki G, Draguhn A (2004) Neuronal oscillations in cortical networks. Science 304(5679):1926–1929PubMedCrossRefGoogle Scholar
  16. Choi S, Yu E et al (2010) Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q- and T-type calcium channels: a study in mutant mice. J Physiol 588(Pt 16):3031–3043PubMedCrossRefGoogle Scholar
  17. Chorev E, Yarom Y et al (2007) Rhythmic episodes of subthreshold membrane potential oscillations in the rat inferior olive nuclei in vivo. J Neurosci 27(19):5043–5052PubMedCrossRefGoogle Scholar
  18. Connors BW, Long MA (2004) Electrical synapses in the mammalian brain. Annu Rev Neurosci 27:393–418PubMedCrossRefGoogle Scholar
  19. Crill WE (1970) Unitary multiple-spiked responses in cat inferior olive nucleus. J Neurophysiol 33(2):199–209PubMedGoogle Scholar
  20. Davie JT, Clark BA et al (2008) The origin of the complex spike in cerebellar Purkinje cells. J Neurosci 28(30):7599–7609PubMedCrossRefGoogle Scholar
  21. de Montigny C, Lamarre Y (1973) Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat. Brain Res 53(1):81–95PubMedCrossRefGoogle Scholar
  22. De Montigny C, Lamarre Y (1974) Activity in the olivo-cerebello-bulbar system of the cat during ibogaline- and oxotremorine-induced tremor. Brain Res 82(2):369–373PubMedCrossRefGoogle Scholar
  23. De Zeeuw CI, Holstege JC et al (1989) Ultrastructural study of the GABAergic, cerebellar, and mesodiencephalic innervation of the cat medial accessory olive: anterograde tracing combined with immunocytochemistry. J Comp Neurol 284(1):12–35PubMedCrossRefGoogle Scholar
  24. De Zeeuw CI, Wylie DR et al. (1995) Phase relations of Purkinje cells in the rabbit flocculus during compensatory eye movements. J Neurophysiol 74:2051–2064PubMedGoogle Scholar
  25. De Zeeuw CI, Lang EJ et al (1996) Morphological correlates of bilateral synchrony in the rat cerebellar cortex. J Neurosci 16(10):3412–3426PubMedGoogle Scholar
  26. De Zeeuw CI, Van Alphen AM et al (1997) Climbing fibre collaterals contact neurons in the cerebellar nuclei that provide a GABAergic feedback to the inferior olive. Neuroscience 80(4):981–986PubMedCrossRefGoogle Scholar
  27. De Zeeuw CI, Simpson JI et al (1998) Microcircuitry and function of the inferior olive. Trends Neurosci 21(9):391–400PubMedCrossRefGoogle Scholar
  28. De Zeeuw CI, Chorev E et al (2003) Deformation of network connectivity in the inferior olive of connexin 36-deficient mice is compensated by morphological and electrophysiological changes at the single neuron level. J Neurosci 23(11):4700–4711PubMedGoogle Scholar
  29. De Zeeuw CI, Hoebeek FE et al (2011) Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci 12(6):327–344PubMedCrossRefGoogle Scholar
  30. Dean P, Porrill J et al (2010) The cerebellar microcircuit as an adaptive filter: experimental and computational evidence. Nat Rev Neurosci 11(1):30–43PubMedCrossRefGoogle Scholar
  31. Devor A (2002) The great gate: control of sensory information flow to the cerebellum. Cerebellum 1(1):27–34PubMedCrossRefGoogle Scholar
  32. Devor A, Yarom Y (2000) GABAergic modulation of olivary oscillations. Prog Brain Res 124:213–220PubMedCrossRefGoogle Scholar
  33. Devor A, Yarom Y (2002a) Coherence of subthreshold activity in coupled inferior olivary neurons. Ann N Y Acad Sci 978:508PubMedCrossRefGoogle Scholar
  34. Devor A, Yarom Y (2002b) Generation and propagation of subthreshold waves in a network of inferior olivary neurons. J Neurophysiol 87(6):3059–3069PubMedGoogle Scholar
  35. Eccles JC, Llinas R, Sasaki K (1966) The excitatory synaptic action of climbing fibres on the purkinje cells of the cerebellum. J Physiol 182:268–296PubMedGoogle Scholar
  36. Gellman R, Houk JC et al (1983) Somatosensory properties of the inferior olive of the cat. J Comp Neurol 215(2):228–243PubMedCrossRefGoogle Scholar
  37. Gellman R, Gibson AR et al (1985) Inferior olivary neurons in the awake cat: detection of contact and passive body displacement. J Neurophysiol 54(1):40–60PubMedGoogle Scholar
  38. Headley PM, Lodge D et al (1976) Drug-induced rhythmical activity in the inferior olivary complex of the rat. Brain Res 101(3):461–478PubMedCrossRefGoogle Scholar
  39. Hoebeek FE, Witter L et al (2010) Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei. Proc Natl Acad Sci USA 107(18):8410–8415PubMedCrossRefGoogle Scholar
  40. Hoge G, Davidson KG et al (2010) The extent and strength of electrical coupling between inferior olivary neurons is heterogeneous. J Neurophysiol 105:1089–1101PubMedCrossRefGoogle Scholar
  41. Ito M (1970) Neurophysiological aspects of the cerebellar motor control system. Int J Neurol 7(2):162–176PubMedGoogle Scholar
  42. Ito M (2001) Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev 81:1143–1195PubMedGoogle Scholar
  43. Jacobson GA, Rokni D et al (2008) A model of the olivo-cerebellar system as a temporal pattern generator. Trends Neurosci 31(12):617–625PubMedCrossRefGoogle Scholar
  44. Jacobson GA, Lev I et al (2009) Invariant phase structure of olivo-cerebellar oscillations and its putative role in temporal pattern generation. Proc Natl Acad Sci USA 106(9):3579–3584PubMedCrossRefGoogle Scholar
  45. Keating JG, Thach WT (1995) Nonclock behavior of inferior olive neurons: interspike interval of Purkinje cell complex spike discharge in the awake behaving monkey is random. J Neurophysiol 73(4):1329–1340PubMedGoogle Scholar
  46. Keating JG, Thach WT (1997) No clock signal in the discharge of neurons in the deep cerebellar nuclei. J Neurophysiol 77(4):2232–2234PubMedGoogle Scholar
  47. Keller R (1901) Ueber die Folgen von Verletzungen in der Gegend der unteren Olive bei der Katze. Arch f Ana. u Physiol Anat Abth 17:177–249Google Scholar
  48. Khosrovani S, Van Der Giessen RS et al (2007) In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns. Proc Natl Acad Sci USA 104(40):15911–15916PubMedCrossRefGoogle Scholar
  49. Kim JJ, Krupa DJ, Thompson RF (1998) Inhibitory cerebello-olivary projections and blocking effect in classical conditioning. Science 279:570–573PubMedCrossRefGoogle Scholar
  50. Kistler WM, De Jeu MT et al (2002) Analysis of Cx36 knockout does not support tenet that olivary gap junctions are required for complex spike synchronization and normal motor performance. Ann N Y Acad Sci 978:391–404PubMedCrossRefGoogle Scholar
  51. Kitazawa S, Wolpert DM (2005) Rhythmicity, randomness and synchrony in climbing fiber signals. Trends Neurosci 28(11):611–619PubMedCrossRefGoogle Scholar
  52. Klimoff J (1899) Ueber die Leitungsbahnen des Kleinhirns. Arch f Anat u Physiol Anat Abth 1078:11–27Google Scholar
  53. Lampl I, Yarom Y (1993) Subthreshold oscillations of the membrane potential: a functional synchronizing and timing device. J Neurophysiol 70(5):2181–2186PubMedGoogle Scholar
  54. Lampl I, Yarom Y (1997) Subthreshold oscillations and resonant behavior: two manifestations of the same mechanism. Neuroscience 78(2):325–341PubMedCrossRefGoogle Scholar
  55. Landisman CE, Connors BW (2005) Long-term modulation of electrical synapses in the mammalian thalamus. Science 310(5755):1809–1813PubMedCrossRefGoogle Scholar
  56. Lang EJ (2001) Organization of olivocerebellar activity in the absence of excitatory glutamatergic input. J Neurosci 21(5):1663–1675PubMedGoogle Scholar
  57. Lang EJ (2002) GABAergic and glutamatergic modulation of spontaneous and motor-cortex-evoked complex spike activity. J Neurophysiol 87(4):1993–2008PubMedGoogle Scholar
  58. Lang EJ, Sugihara I et al (1997) Differential roles of apamin- and charybdotoxin-sensitive K + conductances in the generation of inferior olive rhythmicity in vivo. J Neurosci 17(8):2825–2838PubMedGoogle Scholar
  59. Lang EJ, Sugihara I et al (1999) Patterns of spontaneous purkinje cell complex spike activity in the awake rat. J Neurosci 19(7):2728–2739PubMedGoogle Scholar
  60. Lang EJ, Llinas R et al (2006a) Isochrony in the olivocerebellar system underlies complex spike synchrony. J Physiol 573(Pt 1):277–279, Author reply 281–272PubMedCrossRefGoogle Scholar
  61. Lang EJ, Sugihara I et al (2006b) Olivocerebellar modulation of motor cortex ability to generate vibrissal movements in rat. J Physiol 571(Pt 1):101–120PubMedGoogle Scholar
  62. Leznik E, Llinas R (2005) Role of gap junctions in synchronized neuronal oscillations in the inferior olive. J Neurophysiol 94(4):2447–2456PubMedCrossRefGoogle Scholar
  63. Leznik E, Makarenko V et al (2002) Electrotonically mediated oscillatory patterns in neuronal ensembles: an in vitro voltage-dependent dye-imaging study in the inferior olive. J Neurosci 22(7):2804–2815PubMedGoogle Scholar
  64. Llinas RR (2009) Inferior olive oscillation as the temporal basis for motricity and oscillatory reset as the basis for motor error correction. Neuroscience 162(3):797–804PubMedCrossRefGoogle Scholar
  65. Llinas R, Sasaki K (1989) The functional organization of the olivo-cerebellar system as examined by multiple Purkinje cell recordings. Eur J Neurosci 1(6):587–602PubMedCrossRefGoogle Scholar
  66. Llinas R, Volkind RA (1973) The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res 18(1):69–87PubMedCrossRefGoogle Scholar
  67. Llinas R, Yarom Y (1981a) Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances. J Physiol 315:549–567PubMedGoogle Scholar
  68. Llinas R, Yarom Y (1981b) Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol 315:569–584PubMedGoogle Scholar
  69. Llinas R, Yarom Y (1986) Oscillatory properties of guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study. J Physiol 376:163–182PubMedGoogle Scholar
  70. Llinas R, Baker R et al (1974) Electrotonic coupling between neurons in cat inferior olive. J Neurophysiol 37(3):560–571PubMedGoogle Scholar
  71. Loewenstein Y, Mahon S et al (2005) Bistability of cerebellar Purkinje cells modulated by sensory stimulation. Nat Neurosci 8(2):202–211PubMedCrossRefGoogle Scholar
  72. Long MA, Deans MR et al (2002) Rhythmicity without synchrony in the electrically uncoupled inferior olive. J Neurosci 22(24):10898–10905PubMedGoogle Scholar
  73. Manor Y, Yarom Y et al (2000) To beat or not to beat: a decision taken at the network level. J Physiol Paris 94(5–6):375–390PubMedCrossRefGoogle Scholar
  74. Marr D (1969) A theory of cerebellar cortex. J Physiol 202(2):437–470PubMedGoogle Scholar
  75. Marshall SP, Lang EJ (2004) Inferior olive oscillations gate transmission of motor cortical activity to the cerebellum. J Neurosci 24(50):11356–11367PubMedCrossRefGoogle Scholar
  76. Marshall SP, Lang EJ (2009) Local changes in the excitability of the cerebellar cortex produce spatially restricted changes in complex spike synchrony. J Neurosci 29(45):14352–14362PubMedCrossRefGoogle Scholar
  77. Maruta J, Hensbroek RA et al (2007) Intraburst and interburst signaling by climbing fibers. J Neurosci 27:11263–11270PubMedCrossRefGoogle Scholar
  78. Mathy A, Ho SS et al (2009) Encoding of oscillations by axonal bursts in inferior olive neurons. Neuron 62(3):388–399PubMedCrossRefGoogle Scholar
  79. Ozden I, Sullivan MR et al (2009) Reliable coding emerges from coactivation of climbing fibers in microbands of cerebellar Purkinje neurons. J Neurosci 29(34):10463–10473PubMedCrossRefGoogle Scholar
  80. Pardoe J, Edgley SA et al (2004) Changes in excitability of ascending and descending inputs to cerebellar climbing fibers during locomotion. J Neurosci 24:2656–2666PubMedCrossRefGoogle Scholar
  81. Park YG, Park HY et al (2010) Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc Natl Acad Sci USA 107:10731–10736PubMedCrossRefGoogle Scholar
  82. Placantonakis D, Welsh J (2001) Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive. J Physiol 534(Pt 1):123–140PubMedCrossRefGoogle Scholar
  83. Placantonakis DG, Schwarz C et al (2000) Serotonin suppresses subthreshold and suprathreshold oscillatory activity of rat inferior olivary neurones in vitro. J Physiol 524(Pt 3):833–851PubMedCrossRefGoogle Scholar
  84. Placantonakis DG, Bukovsky AA et al (2004) Fundamental role of inferior olive connexin 36 in muscle coherence during tremor. Proc Natl Acad Sci USA 101(18):7164–7169PubMedCrossRefGoogle Scholar
  85. Placantonakis DG, Bukovsky AA et al (2006) Continuous electrical oscillations emerge from a coupled network: a study of the inferior olive using lentiviral knockdown of connexin36. J Neurosci 26(19):5008–5016PubMedCrossRefGoogle Scholar
  86. Ramon y Cajal S (1909) Histologie du système nerveux de l’homme et des vertébrés. Maloine, Paris.Google Scholar
  87. Scheibel ME, Scheibel AB (1955) The inferior olive; a golgi study. J Comp Neurol 102(1):77–131PubMedCrossRefGoogle Scholar
  88. Schultz SR, Kitamura K et al (2009) Spatial pattern coding of sensory information by climbing fiber-evoked calcium signals in networks of neighboring cerebellar Purkinje cells. J Neurosci 29(25):8005–8015PubMedCrossRefGoogle Scholar
  89. Schweighofer N, Doya K et al (1999) Electrophysiological properties of inferior olive neurons: a compartmental model. J Neurophysiol 82(2):804–817PubMedGoogle Scholar
  90. Schweighofer N, Doya K et al (2004) Chaos may enhance information transmission in the inferior olive. Proc Natl Acad Sci USA 101(13):4655–4660PubMedCrossRefGoogle Scholar
  91. Smith SS (1998) Step cycle-related oscillatory properties of inferior olivary neurons recorded in ensembles. Neuroscience 82(1):69–81PubMedCrossRefGoogle Scholar
  92. Sotelo C, Llinas R et al (1974) Structural study of inferior olivary nucleus of the cat: morphological correlates of electrotonic coupling. J Neurophysiol 37(3):541–559PubMedGoogle Scholar
  93. Sugihara I, Lang EJ et al (1995) Serotonin modulation of inferior olivary oscillations and synchronicity: a multiple-electrode study in the rat cerebellum. Eur J Neurosci 7(4):521–534PubMedCrossRefGoogle Scholar
  94. Szentagothai J, Rajkovits K (1959) Uber den ursprung der kletterfasern des kleinhirns. Z Anat EntwGesch 121:130–141CrossRefGoogle Scholar
  95. Takeuchi Y, Sano Y (1983) Immunohistochemical demonstration of serotonin-containing nerve fibers in the inferior olivary complex of the rat, cat and monkey. Cell Tissue Res 231:17–28PubMedCrossRefGoogle Scholar
  96. Urbano FJ, Simpson JI et al (2006) Somatomotor and oculomotor inferior olivary neurons have distinct electrophysiological phenotypes. Proc Natl Acad Sci USA 103(44):16550–16555PubMedCrossRefGoogle Scholar
  97. Van Der Giessen RS, Koekkoek SK et al (2008) Role of olivary electrical coupling in cerebellar motor learning. Neuron 58(4):599–612CrossRefGoogle Scholar
  98. van Essen TA, van der Giessen RS et al (2010) Anti-malaria drug mefloquine induces motor learning deficits in humans. Front Neurosci 4:191PubMedCrossRefGoogle Scholar
  99. van Welie I, van Hooft JA et al (2004) Homeostatic scaling of neuronal excitability by synaptic modulation of somatic hyperpolarization-activated Ih channels. Proc Natl Acad Sci USA 101(14):5123–5128PubMedCrossRefGoogle Scholar
  100. Welsh JP, Lang EJ et al (1995) Dynamic organization of motor control within the olivocerebellar system. Nature 374(6521):453–457PubMedCrossRefGoogle Scholar
  101. Welsh JP, Han VZ et al (2011) Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence. Proc Natl Acad Sci USA 25:10314–10319CrossRefGoogle Scholar

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© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK

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