Inferior Olive: All Ins and Outs

  • S. Loyola
  • L. W. J. BosmanEmail author
  • J. R. De Gruijl
  • M. T. G. De Jeu
  • M. Negrello
  • T. M. HooglandEmail author
  • C. I. De Zeeuw
Living reference work entry


The inferior olive in the ventral medulla oblongata provides climbing fibers to Purkinje cells in the cerebellar cortex as well as collaterals to the cerebellar nuclei and thereby exerts a strong impact on cerebellar output. As a consequence, the intrinsic properties of olivary neurons and the synaptic inputs that modify their output are critical for cerebellar function. In this chapter, all major issues relevant for the ultimate function of the olivocerebellar system are addressed. First, developmental aspects including the origin and migratory routes of the cell bodies of the inferior olivary neurons are described, followed by the organization of the olivary neurons into subnuclei, as well as the outgrowth of their axons into climbing fibers innervating Purkinje cells. Subsequently, a detailed description is provided of the ultrastructure of the olivary neuropil, which is characterized by the presence of dendrodendritic gap junctions located in glomeruli and by the ubiquitously combined excitatory and inhibitory synaptic inputs of their coupled spines. Furthermore, we describe the main electrophysiological properties of the olivary neurons, highlighting their propensity to oscillate and fire in synchrony at relatively low and stable frequencies. Finally, we review the most recent cellular and network models of the inferior olive, which indicate that this unique nucleus is well designed to control patterns of both rate coding and spatiotemporal coding, albeit for short durations. As a consequence, the abnormalities in their firing properties can contribute to syndromes such as tremor, palatomyoclonus, dystonia, ataxia, respiratory deficits, and possibly also autism.


Gap junction Connexin36 Electrical synapse Coupling Synchrony Olivary glomeruli Subthreshold oscillation Climbing fiber Error signal Action potential After depolarizing potential After hyperpolarizing potential Wavelet Burst firing Motor performance Motor learning Harmaline Tremor 3-AP Inferior olive Medial accessory olive Dorsal accessory olive Principal olive Dorsal cap of Kooy Beta-nucleus Ventrolateral outgrowth Dorsomedial cell column Cerebellar nucleus Mesodiencephalic junction Trigeminal nucleus Dorsal column nucleus Pretectal complexes Red nucleus Development rhombomeres Hox genes Retinoic acid Isthmic organizer Rhombic lip Ptf1a Migration Submarginal strand Slit Nephrin Robo3 Ephrin Wnt1 Fgf8 Olig3 Otx2 Gbx2 Lmx1b Pax2 Midline Neural tube Axonal competition Palatomyoclonus Autism Dendritic lamellar bodies Purkinje cells 


  1. Acampora D, Mazan S, Lallemand Y, Avantaggiato V, Maury M, Simeone A, Brûlet P (1995) Forebrain and midbrain regions are deleted in Otx2−/− mutants due to a defective anterior neuroectoderm specification during gastrulation. Development 121:3279–3290PubMedPubMedCentralGoogle Scholar
  2. Adams KA, Maida JM, Golden JA, Riddle RD (2000) The transcription factor Lmx1b maintains Wnt1 expression within the isthmic organizer. Development 127:1857–1867PubMedPubMedCentralGoogle Scholar
  3. Aizenman CD, Linden DJ (1999) Regulation of the rebound depolarization and spontaneous firing patterns of deep nuclear neurons in slices of rat cerebellum. J Neurophysiol 82:1697–1709. Scholar
  4. Aizenman CD, Manis PB, Linden DJ (1998) Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse. Neuron 21:827–835CrossRefGoogle Scholar
  5. Albus JS (1971) A theory of cerebellar function. Math Biosci 10:25–61CrossRefGoogle Scholar
  6. Albus JS (1975) New approach to manipulator control: the cerebellar model articulation controller (CMAC). Trans ASME J Dyn Syst Meas Control 97:220–227CrossRefGoogle Scholar
  7. Alexander T, Nolte C, Krumlauf R (2009) Hox genes and segmentation of the hindbrain and axial skeleton. Annu Rev Cell Dev Biol 25:431–456. Scholar
  8. Altman J (1972) Postnatal development of the cerebellar cortex in the rat. II. Phases in the maturation of Purkinje cells and of the molecular layer. J Comp Neurol 145:399–463. Scholar
  9. Altman J, Anderson WJ (1972) Experimental reorganization of the cerebellar cortex. I. Morphological effects of elimination of all microneurons with prolonged x-irradiation started at birth. J Comp Neurol 146:355–406PubMedCrossRefPubMedCentralGoogle Scholar
  10. Altman J, Bayer SA (1978a) Prenatal development of the cerebellar system in the rat. I. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J Comp Neurol 179:23–48. Scholar
  11. Altman J, Bayer SA (1978b) Prenatal development of the cerebellar system in the rat. II. Cytogenesis and histogenesis of the inferior olive, pontine gray, and the precerebellar reticular nuclei. J Comp Neurol 179:49–75. Scholar
  12. Altman J, Bayer SA (1987) Development of the precerebellar nuclei in the rat: II. The intramural olivary migratory stream and the neurogenetic organization of the inferior olive. J Comp Neurol 257:490–512. Scholar
  13. Ambrosiani J, Armengol JA, Martinez S, Puelles L (1996) The avian inferior olive derives from the alar neuroepithelium of the rhombomeres 7 and 8: an analysis by using chick-quail chimeric embryos. Neuroreport 7:1285–1288PubMedPubMedCentralCrossRefGoogle Scholar
  14. Amoyel M, Cheng YC, Jiang YJ, Wilkinson DG (2005) Wnt1 regulates neurogenesis and mediates lateral inhibition of boundary cell specification in the zebrafish hindbrain. Development 132:775–785. Scholar
  15. Anderson BJ, Steinmetz JE (1994) Cerebellar and brainstem circuits involved in classical eyeblink conditioning. Rev Neurosci 5:251–273PubMedCrossRefPubMedCentralGoogle Scholar
  16. Aragón F et al (2005) vHnf1 regulates specification of caudal rhombomere identity in the chick hindbrain. Dev Dyn 234:567–576. Scholar
  17. Armstrong DM (1974) Functional significance of connections of the inferior olive. Physiol Rev 54:358–417PubMedCrossRefPubMedCentralGoogle Scholar
  18. Armstrong DM, Eccles JC, Harvey RJ, Matthews PBC (1968) Responses in the dorsal accessory olive of the cat to stimulation of hind limb afferents. J Physiol 194:125–145PubMedPubMedCentralCrossRefGoogle Scholar
  19. Avanzino L, Bove M, Tacchino A, Ruggeri P, Giannini A, Trompetto C, Abbruzzese G (2009) Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor. Eur J Neurosci 30:1971–1979. EJN6984 [pii].
  20. Ayuso Blanco T, Urriza Mena J, Caballero Martinez C, Iriarte Franco J, Munoz R, Garcia-Bragado F (2006) Insomnio letal familiar: Estudio clínico, neurofisiológico e histopatológico de dos casos. Neurologia 21:414–420. 61090815 [pii], ISSN 0213-4853, ISSN-e 1578–1968PubMedPubMedCentralGoogle Scholar
  21. Badura A, De Zeeuw CI (2017) Cerebellar granule cells: dense, rich and evolving representations. Curr Biol 27:R415–R418. Scholar
  22. Badura A et al (2013) Climbing fiber input shapes reciprocity of Purkinje cell firing. Neuron 78:700–713. Scholar
  23. Bailey A et al (1998) A clinicopathological study of autism. Brain 121:889–905PubMedCrossRefPubMedCentralGoogle Scholar
  24. Bal T, McCormick DA (1997) Synchronized oscillations in the inferior olive are controlled by the hyperpolarization-activated cation current I(h). J Neurophysiol 77:3145–3156PubMedCrossRefPubMedCentralGoogle Scholar
  25. Barragan LA, Galindo-Morales JA, Delhaye-Bouchaud N (1983) The microiontophoretic sensitivity of the inferior olivary nucleus to serotonin and related drugs. Proc West Pharmacol Soc 26:151–154PubMedPubMedCentralGoogle Scholar
  26. Bazzigaluppi P, De Gruijl JR, van der Giessen RS, Khosrovani S, De Zeeuw CI, de Jeu MTG (2012a) Olivary subthreshold oscillations and burst activity revisited. Front Neural Circuits 6:91. Scholar
  27. Bazzigaluppi P, de Jeu MTG (2016) Heterogeneous expression of T-type Ca2+ channels defines different neuronal populations in the inferior olive of the mouse. Front Cell Neurosci 10:192. Scholar
  28. Bazzigaluppi P, Isenia SC, Haasdijk ED, Elgersma Y, De Zeeuw CI, van der Giessen RS, de Jeu MTG (2017) Modulation of murine olivary connexin 36 gap junctions by PKA and CaMKII. Front Cell Neurosci 11:397. Scholar
  29. Bazzigaluppi P, Ruigrok T, Saisan P, De Zeeuw CI, de Jeu M (2012b) Properties of the nucleo-olivary pathway: an in vivo whole-cell patch clamp study. PLoS One 7:e46360. Scholar
  30. Becker N et al (1994) Several receptor tyrosine kinase genes of the Eph family are segmentally expressed in the developing hindbrain. Mech Dev 47:3–17. Scholar
  31. Bell CC, Grimm RJ (1969) Discharge properties of Purkinje cells recorded on single and double microelectrodes. J Neurophysiol 32:1044–1055PubMedCrossRefPubMedCentralGoogle Scholar
  32. Bell CC, Kawasaki T (1972) Relations among climbing fiber responses of nearby Purkinje cells. J Neurophysiol 35:155–169PubMedCrossRefPubMedCentralGoogle Scholar
  33. Benardo LS, Foster RE (1986) Oscillatory behavior in inferior olive neurons: mechanism, modulation, cell aggregates. Brain Res Bull 17:773–784PubMedCrossRefPubMedCentralGoogle Scholar
  34. Bengtsson F, Jirenhed DA, Svensson P, Hesslow G (2007) Extinction of conditioned blink responses by cerebello-olivary pathway stimulation. Neuroreport 18:1479–1482PubMedCrossRefPubMedCentralGoogle Scholar
  35. Bergemann AD, Cheng HJ, Brambilla R, Klein R, Flanagan JG (1995) ELF-2, a new member of the Eph ligand family, is segmentally expressed in mouse embryos in the region of the hindbrain and newly forming somites. Mol Cell Biol 15:4921–4929PubMedPubMedCentralCrossRefGoogle Scholar
  36. Bernard JF, Buisseret-Delmas C, Compoint C, Laplante S (1984) Harmaline induced tremor. III. A combined simple units, horseradish peroxidase, and 2-deoxyglucose study of the olivocerebellar system in the rat. Exp Brain Res 57:128–137PubMedCrossRefPubMedCentralGoogle Scholar
  37. Bishop GA, Ho RH (1984) Substance P and serotonin immunoreactivity in the rat inferior olive. Brain Res Bull 12:105–113PubMedCrossRefPubMedCentralGoogle Scholar
  38. 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 65:43–50PubMedCrossRefPubMedCentralGoogle Scholar
  39. Bleckert A, Wong ROL (2011) Identifying roles for neurotransmission in circuit assembly: insights gained from multiple model systems and experimental approaches. BioEssays 33:61–72. Scholar
  40. Blenkinsop TA, Lang EJ (2006) Block of inferior olive gap junctional coupling decreases Purkinje cell complex spike synchrony and rhythmicity. J Neurosci 26:1739–1748. 26/6/1739 [pii]. Scholar
  41. Bloch-Gallego E, Ezan F, Tessier-Lavigne M, Sotelo C (1999) Floor plate and netrin-1 are involved in the migration and survival of inferior olivary neurons. J Neurosci 19:4407–4420PubMedPubMedCentralCrossRefGoogle Scholar
  42. Boele HJ, Peter S, Ten Brinke MM, Verdonschot L, IJpelaar ACH, Rizopoulos D, Gao Z, Koekkoek SKE, Zeeuw CID (2018) Impact of parallel fiber to Purkinje cell long-term depression is unmasked in absence of inhibitory input Science Advances, vol 4, no 10. Scholar
  43. Bosman LWJ, Hartmann J, Barski JJ, Lepier A, Noll-Hussong M, Reichardt LF, Konnerth A (2006) Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells. Brain Cell Biol 35:87–101. Scholar
  44. Bosman LWJ et al (2010) Encoding of whisker input by cerebellar Purkinje cells. J Physiol 588:3757–3783. Scholar
  45. Bosman LWJ, Konnerth A (2009) Activity-dependent plasticity of developing climbing fiber-Purkinje cell synapses. Neuroscience 162:612–623. S0306-4522(09)00038-4 [pii]. Scholar
  46. Bosman LWJ, Takechi H, Hartmann J, Eilers J, Konnerth A (2008) Homosynaptic LTP of the “winner” climbing fiber synapse in developing Purkinje cells. J Neurosci 28:798–807PubMedCrossRefPubMedCentralGoogle Scholar
  47. Bourrat F, Sotelo C (1988) Migratory pathways and neuritic differentiation of inferior olivary neurons in the rat embryo. Axonal tracing study using the in vitro slab technique. Brain Res Dev Brain Res 39:19–37CrossRefGoogle Scholar
  48. Bowman JP, Sladek JR Jr (1973) Morphology of the inferior olivary complex of the rhesus monkey (Macaca mulatta). J Comp Neurol 152:299–316. Scholar
  49. Bright FM, Vink R, Byard RW, Duncan JR, Krous HF, Paterson DS (2017) Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex. PLoS One 12:e0184958. Scholar
  50. Broccoli V, Boncinelli E, Wurst W (1999) The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401:164–168. Scholar
  51. Carpenter EM, Goddard JM, Chisaka O, Manley NR, Capecchi MR (1993) Loss of Hox-A1 (Hox-1.6) function results in the reorganization of the murine hindbrain. Development 118:1063–1075PubMedPubMedCentralGoogle Scholar
  52. Cesa R, Morando L, Strata P (2005) Purkinje cell spinogenesis during architectural rewiring in the mature cerebellum. Eur J Neurosci 22:579–586PubMedCrossRefPubMedCentralGoogle Scholar
  53. Cesa R, Scelfo B, Strata P (2007) Activity-dependent presynaptic and postsynaptic structural plasticity in the mature cerebellum. J Neurosci 27:4603–4611. 27/17/4603 [pii]. Scholar
  54. Chan-Palay V, Palay SL (1971) Tendril and glomerular collaterals of climbing fibers in the granular layer of the rat’s cerebellar cortex. Z Anat Entwicklungsgesch 133:247–273PubMedCrossRefPubMedCentralGoogle Scholar
  55. Chédotal A, Sotelo C (1992) Early development of olivocerebellar projections in the fetal rat ssing CGRP immunocytochemistry. Eur J Neurosci 4:1159–1179CrossRefGoogle Scholar
  56. Chédotal A, Sotelo C (1993) The ‘creeper stage’ in cerebellar climbing fiber synaptogenesis precedes the ‘pericellular nest’–ultrastructural evidence with parvalbumin immunocytochemistry. Brain Res Dev Brain Res 76:207–220PubMedCrossRefPubMedCentralGoogle Scholar
  57. Chi CL, Martinez S, Wurst W, Martin GR (2003) The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum. Development 130:2633–2644PubMedCrossRefPubMedCentralGoogle Scholar
  58. Chizhikov VV et al (2010) Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem. Proc Natl Acad Sci U S A 107:10725–10730. 0910786107 [pii]. Scholar
  59. Choi S, Yu E, Kim D, Urbano FJ, Makarenko V, Shin HS, Llinás RR (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 588:3031–3043. Scholar
  60. Choo M et al (2017) Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. Nat Commun 8:195. Scholar
  61. Ciani L, Salinas PC (2005) WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6:351–U317. Scholar
  62. Coesmans M, Weber JT, De Zeeuw CI, Hansel C (2004) Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron 44:691–700PubMedCrossRefPubMedCentralGoogle Scholar
  63. Condorelli DF, Parenti R, Spinella F, Trovato Salinaro A, Belluardo N, Cardile V, Cicirata F (1998) Cloning of a new gap junction gene (Cx36) highly expressed in mammalian brain neurons. Eur J Neurosci 10:1202–1208PubMedCrossRefPubMedCentralGoogle Scholar
  64. Cozzi B, Huggenberger S, Oelschläger H (2016) Anatomy of dolphins. Academic Press, LondonCrossRefGoogle Scholar
  65. Crepel F (1971) Maturation of climbing fiber responses in the rat. Brain Res 35:272–276. Scholar
  66. Crepel F (1982) Regression of functional synapses in the immature mammalian cerebellum. Trends Neurosci 5:266–269CrossRefGoogle Scholar
  67. Crepel F, Delhaye-Bouchaud N, Dupont JL (1981) Fate of the multiple innervation of cerebellar Purkinje cells by climbing fibers in immature control, x-irradiated and hypothyroid rats. Brain Res Dev Brain Res 1:59–71CrossRefGoogle Scholar
  68. Crill WE (1970) Unitary multiple-spiked responses in cat inferior olive nucleus. J Neurophysiol 33:199–209PubMedCrossRefPubMedCentralGoogle Scholar
  69. Crill WE, Kennedy TT (1967) Inferior olive of the cat: intracellular recording. Science (New York, NY) 157:716–718CrossRefGoogle Scholar
  70. Cunningham TJ, Duester G (2015) Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nature Reviews Molecular and Cellular Biology 16:110–123. Scholar
  71. Czubayko U, Sultan F, Thier P, Schwarz C (2001) Two types of neurons in the rat cerebellar nuclei as distinguished by membrane potentials and intracellular fillings. J Neurophysiol 85:2017–2029. Scholar
  72. Dahmann C, Oates AC, Brand M (2011) Boundary formation and maintenance in tissue development. Nat Rev Genet 12:43–55. nrg2902 [pii]. Scholar
  73. Davies RR, Hodges JR, Kril JJ, Patterson K, Halliday GM, Xuereb JH (2005) The pathological basis of semantic dementia. Brain 128:1984–1995. awh582 [pii]. Scholar
  74. De Gruijl J, Sokol P, Negrello M, De Zeeuw CI (2016) Calcium dependent gap junction plasticity: modulation of electrotonic coupling in the inferior olive glomerulus. bioRxiv:072041.
  75. De Gruijl JR, Bazzigaluppi P, de Jeu MTG, De Zeeuw CI (2012) Climbing fiber burst size and olivary sub-threshold oscillations in a network setting. PLoS Comput Biol 8:e1002814. Scholar
  76. De Gruijl JR, Hoogland TM, De Zeeuw CI (2014a) Behavioral correlates of complex spike synchrony in cerebellar microzones. J Neurosci 34:8937–8944. Scholar
  77. De Gruijl JR, Sokol PA, Negrello M, De Zeeuw CI (2014b) Modulation of electrotonic coupling in the inferior olive by inhibitory and excitatory inputs: integration in the glomerulus. Neuron 81:1215–1217. Scholar
  78. De Zeeuw C (1990) Ultrastructure of the cat inferior olive. Erasmus, RotterdamGoogle Scholar
  79. De Zeeuw CI 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 23:4700–4711PubMedCrossRefPubMedCentralGoogle Scholar
  80. De Zeeuw CI, Gerrits NM, Voogd J, Leonard CS, Simpson JI (1994) The rostral dorsal cap and ventrolateral outgrowth of the rabbit inferior olive receive a GABAergic input from dorsal group Y and the ventral dentate nucleus. J Comp Neurol 341:420–432PubMedCrossRefPubMedCentralGoogle Scholar
  81. De Zeeuw CI, Hertzberg EL, Mugnaini E (1995) The dendritic lamellar body: a new neuronal organelle putatively associated with dendrodendritic gap junctions. J Neurosci 15:1587–1604PubMedCrossRefPubMedCentralGoogle Scholar
  82. De Zeeuw CI, Hoebeek FE, Bosman LWJ, Schonewille M, Witter L, Koekkoek SK (2011) Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci 12:327–344. Scholar
  83. De Zeeuw CI, Holstege JC, Calkoen F, Ruigrok TJ, Voogd J (1988) A new combination of WGA-HRP anterograde tracing and GABA immunocytochemistry applied to afferents of the cat inferior olive at the ultrastructural level. Brain Res 447:369–375PubMedCrossRefPubMedCentralGoogle Scholar
  84. De Zeeuw CI, Holstege JC, Ruigrok TJ, Voogd J (1989a) Ultrastructural study of the GABAergic, cerebellar, and mesodiencephalic innervation of the cat medial accessory olive: anterograde tracing combined with immunocytochemistry. J Comp Neurol 284:12–35. Scholar
  85. De Zeeuw CI, Holstege JC, Ruigrok TJH, Voogd J (1989b) The cerebellar, mesodiencephalic and GABAergic innervation of the glomeruli in the cat inferior olive. A comparison at the ultrastructural level. In: Strata P (ed) The olivocerebellar system in motor control, Experimental brain research series, vol 17. Springer, Berlin/HeidelbergGoogle Scholar
  86. De Zeeuw CI, Holstege JC, Ruigrok TJH, Voogd J (1990a) Mesodiencephalic and cerebellar terminals terminate upon the same dendritic spines in the glomeruli of the cat and rat inferior olive: an ultrastructural study using a combination of [3H]leucine and wheat germ agglutinin coupled horseradish peroxidase anterograde tracing. Neuroscience 34:645–655. Scholar
  87. De Zeeuw CI, Hoogenraad CC, Goedknegt E, Hertzberg E, Neubauer A, Grosveld F, Galjart N (1997a) CLIP-115, a novel brain-specific cytoplasmic linker protein, mediates the localization of dendritic lamellar bodies. Neuron 19:1187–1199PubMedCrossRefPubMedCentralGoogle Scholar
  88. De Zeeuw CI, Koekkoek SKE, Wylie DRW, Simpson JI (1997b) Association between dendritic lamellar bodies and complex spike synchrony in the olivocerebellar system. J Neurophysiol 77:1747–1758PubMedCrossRefPubMedCentralGoogle Scholar
  89. De Zeeuw CI, Lang EJ, Sugihara I, Ruigrok TJH, Eisenman LM, Mugnaini E, Llinás R (1996) Morphological correlates of bilateral synchrony in the rat cerebellar cortex. J Neurosci 16:3412–3426PubMedCrossRefPubMedCentralGoogle Scholar
  90. De Zeeuw CI, Ruigrok TJ (1994) Olivary projecting neurons in the nucleus of Darkschewitsch in the cat receive excitatory monosynaptic input from the cerebellar nuclei. Brain Res 653:345–350PubMedCrossRefPubMedCentralGoogle Scholar
  91. De Zeeuw CI, Ruigrok TJH, Holstege JC, Jansen HG, Voogd J (1990b) Intracellular labeling of neurons in the medial accessory olive of the cat: II. Ultrastructure of dendritic spines and their GABAergic innervation. J Comp Neurol 300:478–494. Scholar
  92. De Zeeuw CI, Ruigrok TJH, Holstege JC, Schalekamp MPA, Voogd J (1990c) Intracellular labeling of neurons in the medial accessory olive of the cat: III. Ultrastructure of axon hillock and initial segment and their GABAergic innervation. J Comp Neurol 300:495–510. Scholar
  93. De Zeeuw CI, Ruigrok TJH, Schalekamp MPA, Boesten AJ, Voogd J (1990d) Ultrastructural study of the cat hypertrophic inferior olive following anterograde tracing, immunocytochemistry, and intracellular labeling. Eur J Morphol 28:240–255PubMedPubMedCentralGoogle Scholar
  94. De Zeeuw CI, Simpson JI, Hoogenraad CC, Galjart N, Koekkoek SKE, Ruigrok TJH (1998) Microcircuitry and function of the inferior olive. Trends Neurosci 21:391–400PubMedCrossRefPubMedCentralGoogle Scholar
  95. De Zeeuw CI, Ten Brinke MM (2015) Motor learning and the cerebellum. Cold Spring Harb Perspect Biol 7:a021683. Scholar
  96. De Zeeuw CI, Wentzel P, Mugnaini E (1993) Fine structure of the dorsal cap of the inferior olive and its GABAergic and non-GABAergic input from the nucleus prepositus hypoglossi in rat and rabbit. J Comp Neurol 327:63–82PubMedCrossRefPubMedCentralGoogle Scholar
  97. Deuschl G, Elble R (2009) Essential tremor--neurodegenerative or nondegenerative disease towards a working definition of ET. Mov Disord 24:2033–2041. Scholar
  98. Deuschl G, Toro C, Valls-Solé J, Zeffiro T, Zee DS, Hallett M (1994) Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain 117:775–788PubMedCrossRefPubMedCentralGoogle Scholar
  99. Deuschl G, Wenzelburger R, Löffler K, Raethjen J, Stolze H (2000) Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain 123:1568–1580PubMedCrossRefPubMedCentralGoogle Scholar
  100. Devor A, Yarom Y (2002a) Electrotonic coupling in the inferior olivary nucleus revealed by simultaneous double patch recordings. J Neurophysiol 87:3048–3058PubMedCrossRefPubMedCentralGoogle Scholar
  101. Devor A, Yarom Y (2002b) Generation and propagation of subthreshold waves in a network of inferior olivary neurons. J Neurophysiol 87:3059–3069PubMedCrossRefPubMedCentralGoogle Scholar
  102. Di Meglio T, Nguyen-Ba-Charvet KT, Tessier-Lavigne M, Sotelo C, Chédotal A (2008) Molecular mechanisms controlling midline crossing by precerebellar neurons. J Neurosci 28:6285–6294. 28/25/6285 [pii]. Scholar
  103. Dikranian K, Qin YQ, Labruyere J, Nemmers B, Olney JW (2005) Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures. Brain Res Dev Brain Res 155:1–13. S0165-3806(04)00367-0 [pii]. Scholar
  104. Duester G (2007) Retinoic acid regulation of the somitogenesis clock. Birth Defects Res C Embryo Today 81:84–92. Scholar
  105. Duggan AW, Lodge D, Headley PM, Biscoe TJ (1973) Effects of excitants on neurones and cerebellar-evoked field potentials in the inferior olivary complex of the rat. Brain Res 64:397–401PubMedCrossRefPubMedCentralGoogle Scholar
  106. Eccles J, Llinás R, Sasaki K (1964) Excitation of cerebellar Purkinje cells by the climbing fibres. Nature 203:245–246PubMedCrossRefPubMedCentralGoogle Scholar
  107. Egea J, Klein R (2007) Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol 17:230–238. S0962-8924(07)00072-4 [pii]. Scholar
  108. Eilers J, Plant TD, Marandi N, Konnerth A (2001) GABA-mediated Ca2+ signalling in developing rat cerebellar Purkinje neurones. J Physiol 536:429–437PubMedPubMedCentralCrossRefGoogle Scholar
  109. Ekerot CF, Jörntell H (2001) Parallel fibre receptive fields of Purkinje cells and interneurons are climbing fibre-specific. Eur J Neurosci 13:1303–1310. Scholar
  110. Ellenberger C Jr, Hanaway J, Netsky MG (1969) Embryogenesis of the inferior olivary nucleus in the rat: a radioautographic study and a re-evaluation of the rhombic lip. J Comp Neurol 137:71–79. Scholar
  111. Essick CR (1912) The development of the nuclei pontis and the nucleus arcuatus in man. Am J Anat 13:25–54CrossRefGoogle Scholar
  112. Farkas Z, Szirmai I, Kamondi A (2006) Impaired rhythm generation in essential tremor. Mov Disord 21:1196–1199. Scholar
  113. Foster RE, Peterson BE (1986) The inferior olivary complex of Guinea pig: cytoarchitecture and cellular morphology. Brain Res Bull 17:785–800PubMedCrossRefPubMedCentralGoogle Scholar
  114. Fraser S, Keynes R, Lumsden A (1990) Segmentation in the chick embryo hindbrain is defined by cell lineage restrictions. Nature 344:431–435. Scholar
  115. Frens MA, Mathoera AL, van der Steen J (2001) Floccular complex spike response to transparent retinal slip. Neuron 30:795–801PubMedCrossRefPubMedCentralGoogle Scholar
  116. Frohman MA, Martin GR, Cordes SP, Halamek LP, Barsh GS (1993) Altered rhombomere-specific gene expression and hyoid bone differentiation in the mouse segmentation mutant, kreisler (kr). Development 117:925–936PubMedPubMedCentralGoogle Scholar
  117. Fujita M (1982) Adaptive filter model of the cerebellum. Biol Cybern 45:195–206PubMedCrossRefPubMedCentralGoogle Scholar
  118. Gao Z, Van Beugen BJ, De Zeeuw CI (2012) Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci 13:619–635. Scholar
  119. Garcia-Dominguez M, Gilardi-Hebenstreit P, Charnay P (2006) PIASxb acts as an activator of Hoxb1 and is antagonized by Krox20 during hindbrain segmentation. EMBO J 25:2432–2442. 7601122 [pii]. Scholar
  120. Garden DLF, Rinaldi A, Nolan MF (2017) Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials. J Physiol 595:1239–1251. Scholar
  121. Gibson AR, Horn KM, Pong M (2004) Activation of climbing fibers. Cerebellum 3:212–221PubMedCrossRefPubMedCentralGoogle Scholar
  122. Giovannucci A et al (2017) Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning. Nat Neurosci 20:727–734. Scholar
  123. Glickstein M, Oberdick J, Voogd J (2007) Evolution of the cerebellum. In: Kaas JH (ed) Evolution of nervous systems, 1st edn. Academic, pp 413–442. Scholar
  124. Granit R, Phillips CG (1956) Excitatory and inhibitory processes acting upon individual Purkinje cells of the cerebellum in cats. J Physiol 133:520–547PubMedPubMedCentralCrossRefGoogle Scholar
  125. Guo C et al (2007) Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Development 134:317–325. Scholar
  126. Gutierrez-Castellanos N et al (2017) Motor learning requires Purkinje cell synaptic potentiation through activation of AMPA-receptor subunit GluA3. Neuron 93:409–424. Scholar
  127. Gwyn DG, Nicholson GP, Flumerfelt BA (1977) The inferior olivary nucleus of the rat: a light and electron microscopic study. J Comp Neurol 174:489–520. Scholar
  128. Halverson HE, Khilkevich A, Mauk MD (2015) Relating cerebellar Purkinje cell activity to the timing and amplitude of conditioned eyelid responses. J Neurosci 35:7813–7832. Scholar
  129. Hámori J, Szentágothai J (1966) Identification under the electron microscope of climbing fibers and their synaptic contacts. Exp Brain Res 1:65–81PubMedCrossRefPubMedCentralGoogle Scholar
  130. Hámori J, Szentágothai J (1980) Lack of evidence of synaptic contacts by climbing fibre collaterals to basket and stellate cells in developing rat cerebellar cortex. Brain Res 186:454–457. Scholar
  131. Handforth A et al (2010) T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor. Neuropharmacology 59:380–387. S0028-3908(10)00137-1 [pii]. Scholar
  132. Hansel C (2009) Reading the clock: how Purkinje cells decode the phase of olivary oscillations. Neuron 62:308–309. S0896-6273(09)00324-9 [pii]. Scholar
  133. Harkmark W (1954) Cell migrations from the rhombic lip to the inferior olive, the nucleus raphe and the pons; a morphological and experimental investigation on chick embryos. J Comp Neurol 100:115–209PubMedCrossRefPubMedCentralGoogle Scholar
  134. Harper RM, Woo MA, Alger JR (2000) Visualization of sleep influences on cerebellar and brainstem cardiac and respiratory control mechanisms. Brain Res Bull 53:125–131. Scholar
  135. Harvey JA, Romano AG (1993) Harmaline-induced impairment of Pavlovian conditioning in the rabbit. J Neurosci 13:1616–1623PubMedCrossRefPubMedCentralGoogle Scholar
  136. Hashimoto K, Ichikawa R, Kitamura K, Watanabe M, Kano M (2009a) Translocation of a “winner” climbing fiber to the Purkinje cell dendrite and subsequent elimination of “losers” from the soma in developing cerebellum. Neuron 63:106–118. S0896-6273(09)00461-9 [pii]. Scholar
  137. Hashimoto K et al (2001) Roles of glutamate receptor d2 subunit (GluRd2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development. J Neurosci 21:9701–9712PubMedCrossRefPubMedCentralGoogle Scholar
  138. Hashimoto K, Kano M (2003) Functional differentiation of multiple climbing fiber inputs during synapse elimination in the developing cerebellum. Neuron 38:785–796PubMedCrossRefPubMedCentralGoogle Scholar
  139. Hashimoto K, Kano M (2005) Postnatal development and synapse elimination of climbing fiber to Purkinje cell projection in the cerebellum. Neurosci Res 53:221–228PubMedCrossRefPubMedCentralGoogle Scholar
  140. Hashimoto K, Yoshida T, Sakimura K, Mishina M, Watanabe M, Kano M (2009b) Influence of parallel fiber-Purkinje cell synapse formation on postnatal development of climbing fiber-Purkinje cell synapses in the cerebellum. Neuroscience 162:601–611. S0306-4522(08)01854-X [pii]. Scholar
  141. Häusser M, Clark BA (1997) Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19:665–678PubMedCrossRefPubMedCentralGoogle Scholar
  142. Hernandez-Miranda LR, Müller T, Birchmeier C (2017) The dorsal spinal cord and hindbrain: from developmental mechanisms to functional circuits. Dev Biol 432:34–42. Scholar
  143. Hernandez RE, Rikhof HA, Bachmann R, Moens CB (2004) vhnf1 integrates global RA patterning and local FGF signals to direct posterior hindbrain development in zebrafish. Development 131:4511–4520. [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  144. Hidalgo-Sánchez M, Millet S, Bloch-Gallego E, Alvarado-Mallart RM (2005) Specification of the meso-isthmo-cerebellar region: the Otx2/Gbx2 boundary. Brain Res Brain Res Rev 49:134–149. S0165-0173(05)00023-8 [pii]. Scholar
  145. Hidalgo-Sánchez M, Millet S, Simeone A, Alvarado-Mallart RM (1999) Comparative analysis of Otx2, Gbx2, Pax2, Fgf8 and Wnt1 gene expressions during the formation of the chick midbrain/hindbrain domain. Mech Dev 81:175–178PubMedCrossRefPubMedCentralGoogle Scholar
  146. Hilson JB, Merchant SN, Adams JC, Joseph JT (2009) Wolfram syndrome: a clinicopathologic correlation. Acta Neuropathol 118:415–428. Scholar
  147. Hirai H et al (2005) Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8:1534–1541. nn1576 [pii]. Scholar
  148. His W (1891) Die Entwicklung des menschlichen Rautenhirns vom Ende des ersten bis zum Beginn des dritten Monats. Abhandlungen der mathematisch-physischen Classe der Königlichen Sachsischen Gesellschaft der Wissenschaften 17:1–74Google Scholar
  149. Hisatsune C et al (2013) IP3R1 deficiency in the cerebellum/brainstem causes basal ganglia-independent dystonia by triggering tonic Purkinje cell firings in mice. Front Neural Circuits 7:156. Scholar
  150. Hoebeek FE, Witter L, Ruigrok TJH, De Zeeuw CI (2010) Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei. Proc Natl Acad Sci U S A 107:8410–8415. 0907118107 [pii]. Scholar
  151. Hoge GJ, Davidson KGV, Yasumura T, Castillo PE, Rash JE, Pereda AE (2011) The extent and strength of electrical coupling between inferior olivary neurons is heterogeneous. J Neurophysiol 105:1089–1101. Scholar
  152. Holmberg M et al (1998) Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 7:913–918. Scholar
  153. Hoogland TM, De Gruijl JR, Witter L, Canto CB, De Zeeuw CI (2015) Role of synchronous activation of cerebellar Purkinje cell ensembles in multi-joint movement control. Curr Biol 25:1157–1165. Scholar
  154. Horn KM, Deep A, Gibson AR (2013) Progressive limb ataxia following inferior olive lesions. J Physiol 591:5475–5489. Scholar
  155. Horn KM, Pong M, Gibson AR (2010) Functional relations of cerebellar modules of the cat. J Neurosci 30:9411–9423. Scholar
  156. Ichikawa R et al (2002) Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor d2. J Neurosci 22:8487–8503PubMedCrossRefPubMedCentralGoogle Scholar
  157. Iskusnykh IY, Steshina EY, Chizhikov VV (2016) Loss of Ptf1a leads to a widespread cell-fate misspecification in the brainstem, affecting the development of somatosensory and viscerosensory nuclei. J Neurosci 36:2691–2710. Scholar
  158. Ito M (1984) The cerebellum and neural control. Raven Press, New YorkGoogle Scholar
  159. Ito M, Kano M (1982) Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci Lett 33:253–258PubMedCrossRefPubMedCentralGoogle Scholar
  160. Ito M, Sakurai M, Tongroach P (1982) Climbing fibre induced depression of both mossy fibre responsiveness and glutamate sensitivity of cerebellar Purkinje cells. J Physiol 324:113–134PubMedPubMedCentralCrossRefGoogle Scholar
  161. Izhikevic EM (2007) Dynamical systems in neuroscience: the geometry of excitability and bursting. MIT Press, CambridgeGoogle Scholar
  162. Jacobson GA, Rokni D, Yarom Y (2008a) A model of the olivo-cerebellar system as a temporal pattern generator. Trends Neurosci 31:617–625. Scholar
  163. Jacobson SW et al (2008b) Impaired eyeblink conditioning in children with fetal alcohol syndrome. Alcohol Clin Exp Res 32:365–372. ACER585 [pii]. Scholar
  164. Jahnsen H (1986) Electrophysiological characteristics of neurones in the Guinea-pig deep cerebellar nuclei in vitro. J Physiol Lond 372:129–147PubMedPubMedCentralCrossRefGoogle Scholar
  165. Jirenhed DA, Bengtsson F, Hesslow G (2007) Acquisition, extinction, and reacquisition of a cerebellar cortical memory trace. J Neurosci 27:2493–2502. 27/10/2493 [pii]. Scholar
  166. Joyner AL, Liu A, Millet S (2000) Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Curr Opin Cell Biol 12:736–741. Scholar
  167. Kakizawa S, Miyazaki T, Yanagihara D, Iino M, Watanabe M, Kano M (2005) Maintenance of presynaptic function by AMPA receptor-mediated excitatory postsynaptic activity in adult brain. Proc Natl Acad Sci U S A 102:19180–19185. 0504359103 [pii]. Scholar
  168. Kamei I et al (1981) Comparative anatomy of the distribution of catecholamines within the inferior olivary complex from teleosts to primates. J Comp Neurol 202:125–133. Scholar
  169. Kania A, Klein R (2016) Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nature Reviews Molecular and Cellular Biology 17:240–256. Scholar
  170. Kano M, Hashimoto K (2009) Synapse elimination in the central nervous system. Curr Opin Neurobiol 19:154–161. S0959-4388(09)00042-7 [pii]. Scholar
  171. Katz LC, Shatz CJ (1996) Synaptic activity and the construction of cortical circuits. Science 274:1133–1138CrossRefGoogle Scholar
  172. Kawamura Y, Nakayama H, Hashimoto K, Sakimura K, Kitamura K, Kano M (2013) Spike timing-dependent selective strengthening of single climbing fibre inputs to Purkinje cells during cerebellar development. Nat Commun 4:2732. Scholar
  173. Kazantsev VB, Nekorkin VI, Makarenko VI, Llinas R (2003) Olivo-cerebellar cluster-based universal control system. Proc Natl Acad Sci U S A 100:13064–13068. Scholar
  174. Kemp HA, Cooke JE, Moens CB (2009) EphA4 and EfnB2a maintain rhombomere coherence by independently regulating intercalation of progenitor cells in the zebrafish neural keel. Dev Biol 327:313–326. S0012-1606(08)01428-0 [pii]. Scholar
  175. Kesner RP, Jackson-Smith P, Henry C, Amann K (1995) Effects of ibogaine on sensory-motor function, activity, and spatial learning in rats. Pharmacol Biochem Behav 51:103–109PubMedCrossRefPubMedCentralGoogle Scholar
  176. Khosrovani S, Van Der Giessen RS, De Zeeuw CI, De Jeu MTG (2007) In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns. Proc Natl Acad Sci U S A 104:15911–15916PubMedPubMedCentralCrossRefGoogle Scholar
  177. Kikuta H, Kanai M, Ito Y, Yamasu K (2003) gbx2 Homeobox gene is required for the maintenance of the isthmic region in the zebrafish embryonic brain. Dev Dyn 228:433–450. Scholar
  178. Kim FA, Sing IA, Kaneko T, Bieman M, Stallwood N, Sadl VS, Cordes SP (2005) The vHNF1 homeodomain protein establishes early rhombomere identity by direct regulation of Kreisler expression. Mech Dev 122:1300–1309. S0925-4773(05)00136-X [pii]. Scholar
  179. Kistler WM 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 978:391–404PubMedCrossRefPubMedCentralGoogle Scholar
  180. Kistler WM, De Zeeuw CI (2002) Dynamical working memory and timed responses: the role of reverberating loops in the olivo-cerebellar system. Neural Comput 14:2597–2626. Scholar
  181. Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398. Scholar
  182. Koeppen AH, Barron KD, Dentinger MP (1980) Olivary hypertrophy: histochemical demonstration of hydrolytic enzymes. Neurology 30:471–480PubMedCrossRefPubMedCentralGoogle Scholar
  183. Kooy FH (1917) The inferior olive in vertebrates. Folia Neurobiol 10:205–369Google Scholar
  184. Köster B, Deuschl G, Lauk M, Timmer J, Guschlbauer B, Lücking CH (2002) Essential tremor and cerebellar dysfunction: abnormal ballistic movements. J Neurol Neurosurg Psychiatry 73:400–405PubMedPubMedCentralCrossRefGoogle Scholar
  185. Kronenbuerger M, Gerwig M, Brol B, Block F, Timmann D (2007) Eyeblink conditioning is impaired in subjects with essential tremor. Brain 130:1538–1551. awm081 [pii]. Scholar
  186. Kros L et al (2017) Synchronicity and rhythmicity of Purkinje cell firing during generalized spike-and-wave discharges in a natural mouse model of absence epilepsy. Front Cell Neurosci 11:346. Scholar
  187. Lampl I, Yarom Y (1993) Subthreshold oscillations of the membrane potential: a functional synchronizing and timing device. J Neurophysiol 70:2181–2186PubMedCrossRefPubMedCentralGoogle Scholar
  188. Lampl I, Yarom Y (1997) Subthreshold oscillations and resonant behavior: two manifestations of the same mechanism. Neuroscience 78:325–341PubMedCrossRefPubMedCentralGoogle Scholar
  189. Landsberg RL, Awatramani RB, Hunter NL, Farago AF, DiPietrantonio HJ, Rodriguez CI, Dymecki SM (2005) Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by Pax6. Neuron 48:933–947. S0896-6273(05)01043-3 [pii]. Scholar
  190. Lang EJ (2001) Organization of olivocerebellar activity in the absence of excitatory glutamatergic input. J Neurosci 21:1663–1675. Scholar
  191. Lang EJ (2002) GABAergic and glutamatergic modulation of spontaneous and motor-cortex-evoked complex spike activity. J Neurophysiol 87:1993–2008. Scholar
  192. Lang EJ, Sugihara I, Llinás R (1996) GABAergic modulation of complex spike activity by the cerebellar nucleoolivary pathway in rat. J Neurophysiol 76:255–275PubMedCrossRefPubMedCentralGoogle Scholar
  193. Lang EJ, Sugihara I, Llinás R (2006) Olivocerebellar modulation of motor cortex ability to generate vibrissal movements in rat. J Physiol 571:101–120PubMedCrossRefPubMedCentralGoogle Scholar
  194. Lang EJ, Sugihara I, Welsh JP, Llinás R (1999) Patterns of spontaneous Purkinje cell complex spike activity in the awake rat. J Neurosci 19:2728–2739PubMedCrossRefPubMedCentralGoogle Scholar
  195. Larsell O (1947) The development of the cerebellum in man in relation to its comparative anatomy. J Comp Neurol 87:85–129PubMedCrossRefPubMedCentralGoogle Scholar
  196. Latorre R, Aguirre C, Rabinovich MI, Varona P (2013) Transient dynamics and rhythm coordination of inferior olive spatio-temporal patterns. Front Neural Circuits 7:138. Scholar
  197. Lecaudey V, Anselme I, Rosa F, Schneider-Maunoury S (2004) The zebrafish Iroquois gene iro7 positions the r4/r5 boundary and controls neurogenesis in the rostral hindbrain. Development 131:3121–3131. dev.01190 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  198. LeDoux MS (2011) Animal models of dystonia: lessons from a mutant rat. Neurobiol Dis 42:152–161. Scholar
  199. Lee SMK, Danielian PS, Fritzsch B, McMahon AP (1997) Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Development 124:959–969PubMedPubMedCentralGoogle Scholar
  200. Lefler Y, Torben-Nielsen B, Yarom Y (2013) Oscillatory activity, phase differences, and phase resetting in the inferior olivary nucleus. Front Syst Neurosci 7:22. Scholar
  201. Lefler Y, Yarom Y, Uusisaari MY (2014) Cerebellar inhibitory input to the inferior olive decreases electrical coupling and blocks subthreshold oscillations. Neuron 81:1389–1400. Scholar
  202. Leto K et al (2016) Consensus paper: cerebellar development. Cerebellum 15:789–828. Scholar
  203. Leznik E, Llinás R (2005) Role of gap junctions in synchronized neuronal oscillations in the inferior olive. J Neurophysiol 94:2447–2456. Scholar
  204. Leznik E, Makarenko V, Llinás R (2002) Electrotonically mediated oscillatory patterns in neuronal ensembles: an in vitro voltage-dependent dye-imaging study in the inferior olive. J Neurosci 22:2804–2815. Scholar
  205. Liao K, Hong S, Zee DS, Optican LM, Leigh RJ (2008) Impulsive head rotation resets oculopalatal tremor: examination of a model. Prog Brain Res 171:227–234. S0079-6123(08)00632-8 [pii]. Scholar
  206. Lim CCT, Lim SA (2009) Pendular nystagmus and palatomyoclonus from hypertrophic olivary degeneration. New Engl J Med 360:e12PubMedCrossRefPubMedCentralGoogle Scholar
  207. Liu Z et al (2008) Control of precerebellar neuron development by Olig3 bHLH transcription factor. J Neurosci 28:10124–10133. 28/40/10124 [pii]. Scholar
  208. Llano I, DiPolo R, Marty A (1994) Calcium-induced calcium release in cerebellar Purkinje cells. Neuron 12:663–673PubMedCrossRefPubMedCentralGoogle Scholar
  209. Llinás R, Baker R, Sotelo C (1974) Electrotonic coupling between neurons in cat inferior olive. J Neurophysiol 37:560–571PubMedCrossRefPubMedCentralGoogle Scholar
  210. Llinás R, Mühlethaler M (1988) Electrophysiology of Guinea-pig cerebellar nuclear cells in the in vitro brain stem-cerebellar preparation. J Physiol 404:241–258PubMedPubMedCentralCrossRefGoogle Scholar
  211. Llinás R, Sasaki K (1989) The functional organization of the olivo-cerebellar system as examined by multiple Purkinje cell recordings. Eur J Neurosci 1:587–602. ejn_01060587 [pii]PubMedCrossRefPubMedCentralGoogle Scholar
  212. Llinás R, Sugimori M (1980) Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J Physiol 305:171–195PubMedPubMedCentralCrossRefGoogle Scholar
  213. Llinás R, Sugimori M, Lin JW, Cherksey B (1989) Blocking and isolation of a calcium channel from neurons in mammals and cephalopods utilizing a toxin fraction (FTX) from funnel-web spider poison. Proc Natl Acad Sci U S A 86:1689–1693PubMedPubMedCentralCrossRefGoogle Scholar
  214. Llinás R, Volkind RA (1973) The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res 18:69–87PubMedCrossRefPubMedCentralGoogle Scholar
  215. Llinás R, Walton K, Hillman DE, Sotelo C (1975) Inferior olive: its role in motor learning. Science 190:1230–1231PubMedCrossRefPubMedCentralGoogle Scholar
  216. Llinás R, Yarom Y (1981a) Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances. J Physiol 315:549–567PubMedPubMedCentralCrossRefGoogle Scholar
  217. Llinás R, Yarom Y (1981b) Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol 315:569–584PubMedPubMedCentralCrossRefGoogle Scholar
  218. Llinás R, Yarom Y (1986) Oscillatory properties of Guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study. J Physiol 376:163–182PubMedPubMedCentralCrossRefGoogle Scholar
  219. Llinás RR (2009) Inferior olive oscillation as the temporal basis for motricity and oscillatory reset as the basis for motor error correction. Neuroscience 162:797–804. S0306-4522(09)00652-6 [pii]. Scholar
  220. Long MA, Deans MR, Paul DL, Connors BW (2002) Rhythmicity without synchrony in the electrically uncoupled inferior olive. J Neurosci 22:10898–10905. Scholar
  221. Louis ED, Ferreira JJ (2010) How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 25:534–541PubMedCrossRefPubMedCentralGoogle Scholar
  222. Louis ED, Zheng W, Jurewicz EC, Watner D, Chen J, Factor-Litvak P, Parides M (2002) Elevation of blood b-carboline alkaloids in essential tremor. Neurology 59:1940–1944PubMedPubMedCentralCrossRefGoogle Scholar
  223. Luebke AE, Robinson DA (1994) Gain changes of the cat’s vestibulo-ocular reflex after flocculus deactivation. Experimental brain research Experimentelle Hirnforschung 98:379–390PubMedCrossRefPubMedCentralGoogle Scholar
  224. Lumsden A, Krumlauf R (1996) Patterning the vertebrate neuraxis. Science 274:1109–1115PubMedCrossRefPubMedCentralGoogle Scholar
  225. Mahmood R, Mason IJ, Morriss-Kay GM (1996) Expression of Fgf-3 in relation to hindbrain segmentation, otic pit position and pharyngeal arch morphology in normal and retinoic acid-exposed mouse embryos. Anat Embryol (Berl) 194:13–22CrossRefGoogle Scholar
  226. Manor Y, Rinzel J, Segev I, Yarom Y (1997) Low-amplitude oscillations in the inferior olive: a model based on electrical coupling of neurons with heterogeneous channel densities. J Neurophysiol 77:2736–2752PubMedCrossRefPubMedCentralGoogle Scholar
  227. Manzanares M, Cordes S, Ariza-McNaughton L, Sadl V, Maruthainar K, Barsh G, Krumlauf R (1999) Conserved and distinct roles of kreisler in regulation of the paralogous Hoxa3 and Hoxb3 genes. Development 126:759–769PubMedPubMedCentralGoogle Scholar
  228. Manzanares M, Cordes S, Kwan CT, Sham MH, Barsh GS, Krumlauf R (1997) Segmental regulation of Hoxb-3 by kreisler. Nature 387:191–195. Scholar
  229. Maqbool A, Batten TFC, Berry PA, McWilliam PN (1993) Distribution of dopamine-containing neurons and fibres in the feline medulla oblongata: a comparative study using catecholamine-synthesizing enzyme and dopamine immunohistochemistry. Neuroscience 53:717–733PubMedCrossRefPubMedCentralGoogle Scholar
  230. Marcos S, Backer S, Causeret F, Tessier-Lavigne M, Bloch-Gallego E (2009) Differential roles of Netrin-1 and its receptor DCC in inferior olivary neuron migration. Mol Cell Neurosci 41:429–439. S1044-7431(09)00087-6 [pii]. Scholar
  231. Mariani J, Changeux JP (1981) Ontogenesis of olivocerebellar relationships I. Studies by intracellular recordings of the multiple innervation of Purkinje cells by climbing fibers in the developing rat cerebellum. J Neurosci 1:696–702PubMedCrossRefPubMedCentralGoogle Scholar
  232. Marillat V, Sabatier C, Failli V, Matsunaga E, Sotelo C, Tessier-Lavigne M, Chédotal A (2004) The slit receptor Rig-1/Robo3 controls midline crossing by hindbrain precerebellar neurons and axons. Neuron 43:69–79. S0896627304003939 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  233. Marin F, Charnay P (2000) Hindbrain patterning: FGFs regulate Krox20 and mafB/kr expression in the otic/preotic region. Development 127:4925–4935PubMedPubMedCentralGoogle Scholar
  234. Mark M et al (1993) Two rhombomeres are altered in Hoxa-1 mutant mice. Development 119:319–338PubMedPubMedCentralGoogle Scholar
  235. Marr D (1969) A theory of cerebellar cortex. J Physiol 202:437–470PubMedPubMedCentralCrossRefGoogle Scholar
  236. Marshall SP, van der Giessen RS, de Zeeuw CI, Lang EJ (2007) Altered olivocerebellar activity patterns in the connexin36 knockout mouse. Cerebellum (London, England):1–13. 772833012 [pii]. Scholar
  237. Martin FC, Thu Le A, Handforth A (2005) Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications. Mov Disord 20:298–305. Scholar
  238. Martin GF, Dom R, King JS, RoBards M, Watson CRR (1975) The inferior olivary nucleus of the opossum (Didelphis marsupialis virginiana), its organization and connections. J Comp Neurol 160:507–533. Scholar
  239. Martinez S, Andreu A, Mecklenburg N, Echevarria D (2013) Cellular and molecular basis of cerebellar development. Front Neuroanat 7:18. Scholar
  240. Maruta J, Hensbroek RA, Simpson JI (2007) Intraburst and interburst signaling by climbing fibers. J Neurosci 27:11263–11270PubMedCrossRefPubMedCentralGoogle Scholar
  241. Mason CA, Christakos S, Catalano SM (1990) Early climbing fiber interactions with Purkinje cells in the postnatal mouse cerebellum. J Comp Neurol 297:77–90PubMedCrossRefPubMedCentralGoogle Scholar
  242. Mastick GS, Fan CM, Tessier-Lavigne M, Serbedzija GN, McMahon AP, Easter SS Jr (1996) Early deletion of neuromeres in Wnt-1−/− mutant mice: evaluation by morphological and molecular markers. J Comp Neurol 374:246–258. [pii].<246::AID-CNE7>3.0.CO;2-2CrossRefPubMedPubMedCentralGoogle Scholar
  243. Mathews PJ, Lee KH, Peng Z, Houser CR, Otis TS (2012) Effects of climbing fiber driven inhibition on Purkinje neuron spiking. J Neurosci 32:17988–17997. Scholar
  244. Mathy A, Clark BA, Häusser M (2014) Synaptically induced long-term modulation of electrical coupling in the inferior olive. Neuron 81:1290–1296. Scholar
  245. Mathy A, Ho SSN, Davie JT, Duguid IC, Clark BA, Häusser M (2009) Encoding of oscillations by axonal bursts in inferior olive neurons. Neuron 62:388–399. S0896-6273(09)00248-7 [pii]. Scholar
  246. Matschke J, Laas R (2007) Sudden death due to central alveolar hypoventilation syndrome (Ondine’s curse) in a 39-year-old woman with heterotopia of the inferior olive. Am J Forensic Med Pathol 28:141–144. 00000433-200706000-00011 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  247. Matsumoto-Makidono Y et al (2016) Ionic basis for membrane potential resonance in neurons of the inferior olive. Cell Rep 16:994–1004. Scholar
  248. Maves L, Jackman W, Kimmel CB (2002) FGF3 and FGF8 mediate a rhombomere 4 signaling activity in the zebrafish hindbrain. Development 129:3825–3837PubMedPubMedCentralGoogle Scholar
  249. McCormick DA, Steinmetz JE, Thompson RF (1985) Lesions of the inferior olivary complex cause extinction of the classically conditioned eyeblink response. Brain Res 359:120–130PubMedCrossRefPubMedCentralGoogle Scholar
  250. McKay BE, Turner RW (2005) Physiological and morphological development of the rat cerebellar Purkinje cell. J Physiol 567:829–850PubMedPubMedCentralCrossRefGoogle Scholar
  251. Mcmahon AP, Bradley A (1990) The Wnt-1 (Int-1) Protooncogene is required for development of a large region of the mouse-brain. Cell 62:1073–1085PubMedCrossRefPubMedCentralGoogle Scholar
  252. Medina JF, Garcia KS, Nores WL, Taylor NM, Mauk MD (2000) Timing mechanisms in the cerebellum: testing predictions of a large-scale computer simulation. J Neurosci 20:5516–5525PubMedCrossRefPubMedCentralGoogle Scholar
  253. Medina JF, Nores WL, Mauk MD (2002) Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses. Nature 416:330–333PubMedCrossRefPubMedCentralGoogle Scholar
  254. Mikuni T, Uesaka N, Okuno H, Hirai H, Deisseroth K, Bito H, Kano M (2013) Arc/Arg3.1 is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum. Neuron 78:1024–1035. Scholar
  255. Millet S, Bloch-Gallego E, Simeone A, Alvarado-Mallart RM (1996) The caudal limit of Otx2 gene expression as a marker of the midbrain/hindbrain boundary: a study using in situ hybridisation and chick/quail homotopic grafts. Development 122:3785–3797PubMedPubMedCentralGoogle Scholar
  256. Millet S, Campbell K, Epstein DJ, Losos K, Harris E, Joyner AL (1999) A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature 401:161–164. Scholar
  257. Miyashita Y, Nagao S (1984) Contribution of cerebellar intracortical inhibition to Purkinje cell response during vestibulo-ocular reflex of alert rabbits. J Physiol 351:251–262PubMedPubMedCentralCrossRefGoogle Scholar
  258. Miyazaki T, Hashimoto K, Shin HS, Kano M, Watanabe M (2004) P/Q-type Ca2+ channel α1A regulates synaptic competition on developing cerebellar Purkinje cells. J Neurosci 24:1734–1743. Scholar
  259. Miyazaki T, Yamasaki M, Takeuchi T, Sakimura K, Mishina M, Watanabe M (2010) Ablation of glutamate receptor GluRd2 in adult Purkinje cells causes multiple innervation of climbing fibers by inducing aberrant invasion to parallel fiber innervation territory. J Neurosci 30:15196–15209. 30/45/15196 [pii]. Scholar
  260. Montagna P, Gambetti P, Cortelli P, Lugaresi E (2003) Familial and sporadic fatal insomnia. Lancet Neurol 2:167–176. Scholar
  261. Morara S, van der Want JJL, de Weerd H, Provini L, Rosina A (2001) Ultrastructural analysis of climbing fiber-Purkinje cell synaptogenesis in the rat cerebellum. Neuroscience 108:655–671PubMedCrossRefPubMedCentralGoogle Scholar
  262. Mukamel EA, Nimmerjahn A, Schnitzer MJ (2009) Automated analysis of cellular signals from large-scale calcium imaging data. Neuron 63:747–760. S0896-6273(09)00619-9 [pii]. Scholar
  263. Najafi F, Giovannucci A, Wang SSH, Medina JF (2014) Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice. elife 3:e03663. Scholar
  264. Najafi F, Medina JF (2013) Beyond “all-or-nothing” climbing fibers: graded representation of teaching signals in Purkinje cells. Front Neural Circuits 7:115. Scholar
  265. Nelson BJ, Mugnaini E (1988) The rat inferior olive as seen with immunostaining for glutamate decarboxylase. Anat Embryol (Berl) 179:109–127CrossRefGoogle Scholar
  266. Nemecek S, Wolff J (1969) Light and electron microscopic evidence of complex synapses (glomeruli) in Oliva inferior (cat). Experientia 25:634–635PubMedCrossRefPubMedCentralGoogle Scholar
  267. Nishida K, Hoshino M, Kawaguchi Y, Murakami F (2010) Ptf1a directly controls expression of immunoglobulin superfamily molecules Nephrin and Neph3 in the developing central nervous system. J Biol Chem 285:373–380. M109.060657 [pii]. Scholar
  268. Nonchev S et al (1996) Segmental expression of Hoxa-2 in the hindbrain is directly regulated by Krox-20. Development 122:543–554PubMedPubMedCentralGoogle Scholar
  269. O’Leary JL, Inukai J, Smith JM (1971) Histogenesis of the cerebellar climbing fiber in the rat. J Comp Neurol 142:377–391PubMedCrossRefPubMedCentralGoogle Scholar
  270. Ohmae S, Medina JF (2015) Climbing fibers encode a temporal-difference prediction error during cerebellar learning in mice. Nat Neurosci 18:1798–1803. Scholar
  271. Ohtsuki G, Hirano T (2008) Bidirectional plasticity at developing climbing fiber-Purkinje neuron synapses. Eur J Neurosci 28:2393–2400. EJN6539 [pii]. Scholar
  272. Ohtsuki G, Kawaguchi SY, Mishina M, Hirano T (2004) Enhanced inhibitory synaptic transmission in the cerebellar molecular layer of the GluRd2 knock-out mouse. J Neurosci 24:10900–10907. 24/48/10900 [pii]. Scholar
  273. Onodera S, Hicks TP (1995) Patterns of transmitter labelling and connectivity of the cat’s nucleus of Darkschewitsch: a wheat germ agglutinin-horseradish peroxidase and immunocytochemical study at light and electron microscopical levels. J Comp Neurol 361:553–573PubMedCrossRefPubMedCentralGoogle Scholar
  274. Osumi-Yamashita N, Ninomiya Y, Doi H, Eto K (1996) Rhombomere formation and hind-brain crest cell migration from prorhombomeric origins in mouse embryos. Develop Growth Differ 38:107–118CrossRefGoogle Scholar
  275. Oxtoby E, Jowett T (1993) Cloning of the zebrafish krox-20 gene (krx-20) and its expression during hindbrain development. Nucleic Acids Res 21:1087–1095PubMedPubMedCentralCrossRefGoogle Scholar
  276. Ozden I, Dombeck DA, Hoogland TM, Tank DW, Wang SS (2012) Widespread state-dependent shifts in cerebellar activity in locomoting mice. PLoS One 7:e42650. Scholar
  277. Ozden I, Sullivan MR, Lee HM, Wang SSH (2009) Reliable coding emerges from coactivation of climbing fibers in microbands of cerebellar Purkinje neurons. J Neurosci 29:10463–10473PubMedPubMedCentralCrossRefGoogle Scholar
  278. Packer AI, Crotty DA, Elwell VA, Wolgemuth DJ (1998) Expression of the murine Hoxa4 gene requires both autoregulation and a conserved retinoic acid response element. Development 125:1991–1998PubMedPubMedCentralGoogle Scholar
  279. Paré M, Descarries L, Wiklund L (1987) Innervation and reinnervation of rat inferior olive by neurons containing serotonin and substance P: an immunohistochemical study after 5,6-dihydroxytryptamine lesioning. J Neurocytol 16:155–167PubMedCrossRefPubMedCentralGoogle Scholar
  280. Park YG et al (2010) Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc Natl Acad Sci U S A 107:10731–10736PubMedPubMedCentralCrossRefGoogle Scholar
  281. Placantonakis D, Welsh J (2001) Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive. J Physiol 534:123–140PubMedPubMedCentralCrossRefGoogle Scholar
  282. Placantonakis DG, Schwarz C, Welsh JP (2000) Serotonin suppresses subthreshold and suprathreshold oscillatory activity of rat inferior olivary neurones in vitro. J Physiol 524(Pt 3):833–851PubMedPubMedCentralCrossRefGoogle Scholar
  283. Porrill J, Dean P, Stone JV (2004) Recurrent cerebellar architecture solves the motor-error problem. Proc Biol Sci 271:789–796. Scholar
  284. Powers RE, O’Connor DT, Price DL (1990) Noradrenergic innervation of human inferior olivary complex. Brain Res 523:151–155PubMedCrossRefPubMedCentralGoogle Scholar
  285. Prandota J (2010) Neuropathological changes and clinical features of autism spectrum disorder participants are similar to that reported in congenital and chronic cerebral toxoplasmosis in humans and mice. Res Autism Spectrum Disord 4:103–118CrossRefGoogle Scholar
  286. Purves D, Lichtman JW (1980) Elimination of synapses in the developing nervous system. Science 210:153–157PubMedCrossRefPubMedCentralGoogle Scholar
  287. Rahmati N et al (2014) Cerebellar potentiation and learning a whisker-based object localization task with a time response window. J Neurosci 34:1949–1962. Scholar
  288. Raike RS, Jinnah HA, Hess EJ (2005) Animal models of generalized dystonia. NeuroRx 2:504–512PubMedPubMedCentralCrossRefGoogle Scholar
  289. Raman IM, Bean BP (1999) Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J Neurosci 19:1663–1674PubMedCrossRefPubMedCentralGoogle Scholar
  290. Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés, vol 2. Maloine, ParisGoogle Scholar
  291. Ray RS, Dymecki SM (2009) Rautenlippe redux – toward a unified view of the precerebellar rhombic lip. Curr Opin Cell Biol 21:741–747. S0955-0674(09)00186-0 [pii]. Scholar
  292. Renier N et al (2010) Genetic dissection of the function of hindbrain axonal commissures. PLoS Biol 8:e1000325. Scholar
  293. Robain O, Bideau I, Farkas E (1981) Developmental changes of synapses in the cerebellar cortex of the rat. A quantitative analysis. Brain Res 206:1–8. Scholar
  294. Romano V, De Propris L, Bosman LWJ, Warnaar P, ten Brinke MM, Lindeman S, Ju C, Velauthapillai A, Spanke JK, Guerra EM, Hoogland TM, Negrello M, D’Angelo E, De Zeeuw CI (2018) Potentiation of cerebellar Purkinje cells facilitates whisker reflex adaptation through increased simple spike activity. eLife 2018;7:e38852
  295. Rondi-Reig L, Delhaye-Bouchaud N, Mariani J, Caston J (1997) Role of the inferior olivary complex in motor skills and motor learning in the adult rat. Neuroscience 77:955–963PubMedCrossRefPubMedCentralGoogle Scholar
  296. Rossel M, Capecchi MR (1999) Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126:5027–5040PubMedPubMedCentralGoogle Scholar
  297. Rubenstein JLR, Martinez S, Shimamura K, Puelles L (1994) The embryonic vertebrate forebrain: the prosomeric model. Science 266:578–580PubMedCrossRefPubMedCentralGoogle Scholar
  298. Ruigrok TJ, Voogd J (2000) Organization of projections from the inferior olive to the cerebellar nuclei in the rat. J Comp Neurol 426:209–228.<209::AID-CNE4>3.0.CO;2-0. [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  299. Ruigrok TJH (1997) Cerebellar nuclei: the olivary connection. Prog Brain Res 114:167–192PubMedCrossRefPubMedCentralGoogle Scholar
  300. Ruigrok TJH, de Zeeuw CI, van der Burg J, Voogd J (1990) Intracellular labeling of neurons in the medial accessory olive of the cat: I. Physiology and light microscopy. J Comp Neurol 300:462–477. Scholar
  301. Sakurai Y, Kurokawa D, Kiyonari H, Kajikawa E, Suda Y, Aizawa S (2010) Otx2 and Otx1 protect diencephalon and mesencephalon from caudalization into metencephalon during early brain regionalization. Dev Biol 347:392–403. S0012-1606(10)01039-0 [pii]. Scholar
  302. Sasaki K, Bower JM, Llinás R (1989) Multiple Purkinje cell recording in rodent cerebellar cortex. Eur J Neurosci 1:572–586. Scholar
  303. Sato Y, Miura A, Fushiki H, Kawasaki T, Watanabe Y (1993) Complex spike responses of cerebellar Purkinje cells to constant velocity optokinetic stimuli in the cat flocculus. Acta Otolaryngol Suppl 504:13–16PubMedCrossRefPubMedCentralGoogle Scholar
  304. Scelfo B, Strata P (2005) Correlation between multiple climbing fibre regression and parallel fibre response development in the postnatal mouse cerebellum. Eur J Neurosci 21:971–978PubMedCrossRefPubMedCentralGoogle Scholar
  305. Scelfo B, Strata P, Knöpfel T (2003) Sodium imaging of climbing fiber innervation fields in developing mouse Purkinje cells. J Neurophysiol 89:2555–2563PubMedCrossRefPubMedCentralGoogle Scholar
  306. Scheibel ME, Scheibel AB (1954) Observations on the intracortical relations of the climbing fibers of the cerebellum; a Golgi study. J Comp Neurol 101:733–763PubMedCrossRefPubMedCentralGoogle Scholar
  307. Scheibel ME, Scheibel AB (1955) The inferior olive; a Golgi study. J Comp Neurol 102:77–131PubMedCrossRefPubMedCentralGoogle Scholar
  308. Schonewille M et al (2010) Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron 67:618–628PubMedPubMedCentralCrossRefGoogle Scholar
  309. Schulman JA, Bloom FE (1981) Golgi cells of the cerebellum are inhibited by inferior olive activity. Brain Res 210:350–355. Scholar
  310. Schultz SR, Kitamura K, Post-Uiterweer A, Krupic J, Häusser M (2009) Spatial pattern coding of sensory information by climbing fiber-evoked calcium signals in networks of neighboring cerebellar Purkinje cells. J Neurosci 29:8005–8015. Scholar
  311. Schweighofer N, Doya K, Fukai H, Chiron JV, Furukawa T, Kawato M (2004) Chaos may enhance information transmission in the inferior olive. Proc Natl Acad Sci U S A 101:4655–4660. Scholar
  312. Schweighofer N, Doya K, Kawato M (1999) Electrophysiological properties of inferior olive neurons: a compartmental model. J Neurophysiol 82:804–817PubMedCrossRefPubMedCentralGoogle Scholar
  313. Schweighofer N, Spoelstra J, Arbib MA, Kawato M (1998) Role of the cerebellum in reaching movements in humans. II. A neural model of the intermediate cerebellum. Eur J Neurosci 10:95–105PubMedCrossRefPubMedCentralGoogle Scholar
  314. Sham MH et al (1993) The zinc finger gene Krox20 regulates HoxB2 (Hox2.8) during hindbrain segmentation. Cell 72:183–196. Scholar
  315. Shimozono S, Iimura T, Kitaguchi T, Higashijima S, Miyawaki A (2013) Visualization of an endogenous retinoic acid gradient across embryonic development. Nature 496:363–366. Scholar
  316. Silver RA, Momiyama A, Cull-Candy SG (1998) Locus of frequency-dependent depression identified with multiple-probability fluctuation analysis at rat climbing fibre-Purkinje cell synapses. J Physiol 510:881–902PubMedPubMedCentralCrossRefGoogle Scholar
  317. Simeone A (2000) Positioning the isthmic organizer where Otx2 and Gbx2 meet. Trends Genet 16:237–240. Scholar
  318. Simeone A, Acampora D, Gulisano M, Stornaiuolo A, Boncinelli E (1992) Nested expression domains of four homeobox genes in developing rostral brain. Nature 358:687–690. Scholar
  319. Simonyan K, Ludlow CL, Vortmeyer AO (2010) Brainstem pathology in spasmodic dysphonia. Laryngoscope 120:121–124. Scholar
  320. Simpson JI, Wylie DR, De Zeeuw CI (1996) On climbing fiber signals and their consequence(s). BehBrain Sciences 19:380–394Google Scholar
  321. Sladek JR Jr, Bowman JP (1975) The distribution of catecholamines within the inferior olivary complex of the cat and rhesus monkey. J Comp Neurol 163:203–213. Scholar
  322. Sladek JR Jr, Hoffman GE (1980) Monoaminergic innervation of the mammalian inferior olivary complex. In: Courville J, de Montigny C, Lamarre Y (eds) The inferior olivary nucleus. Raven Press, New YorkGoogle Scholar
  323. Smirnow AE (1897) Ueber eine besondere Art von Nervenzellen der Molecularschicht des Kleinhirns bei erwachsenen Saugetieren und beim Menschen. Anat Anz 13:636–642Google Scholar
  324. Sotelo C, Chédotal A (2005) Development of the olivocerebellar system: migration and formation of cerebellar maps. Prog Brain Res 148:1–20CrossRefGoogle Scholar
  325. Sotelo C, Hillman DE, Zamora AJ, Llinás R (1975) Climbing fiber deafferentation: its action on Purkinje cell dendritic spines. Brain Res 98:574–581PubMedCrossRefPubMedCentralGoogle Scholar
  326. Sotelo C, Llinás R, Baker R (1974) Structural study of inferior olivary nucleus of the cat: morphological correlates of electrotonic coupling. J Neurophysiol 37:541–559PubMedCrossRefPubMedCentralGoogle Scholar
  327. Spoelstra J, Schweighofer N, Arbib MA (2000) Cerebellar learning of accurate predictive control for fast-reaching movements. Biol Cybern 82:321–333. Scholar
  328. Srinivas M et al (1999) Functional properties of channels formed by the neuronal gap junction protein connexin36. J Neurosci 19:9848–9855PubMedCrossRefPubMedCentralGoogle Scholar
  329. Stone LS, Lisberger SG (1986) Detection of tracking errors by visual climbing fiber inputs to monkey cerebellar flocculus during pursuit eye movements. Neurosci Lett 72:163–168PubMedCrossRefPubMedCentralGoogle Scholar
  330. Storm R et al (2009) The bHLH transcription factor Olig3 marks the dorsal neuroepithelium of the hindbrain and is essential for the development of brainstem nuclei. Development 136:295–305. dev.027193 [pii]. Scholar
  331. Strata P (ed) (1989) The olivocerebellar system in motor control, vol 17, 1st edn. Springer, BerlinGoogle Scholar
  332. Studer M, Gavalas A, Marshall H, Ariza-McNaughton L, Rijli FM, Chambon P, Krumlauf R (1998) Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development 125:1025–1036PubMedPubMedCentralGoogle Scholar
  333. Sugihara I (2005) Microzonal projection and climbing fiber remodeling in single olivocerebellar axons of newborn rats at postnatal days 4-7. J Comp Neurol 487:93–106PubMedCrossRefPubMedCentralGoogle Scholar
  334. Sugihara I (2006) Organization and remodeling of the olivocerebellar climbing fiber projection. Cerebellum 5:15–22PubMedCrossRefPubMedCentralGoogle Scholar
  335. Sugihara I, Lang EJ, Llinás R (1993) Uniform olivocerebellar conduction time underlies Purkinje cell complex spike synchronicity in the rat cerebellum. J Physiol 470:243–271PubMedPubMedCentralCrossRefGoogle Scholar
  336. Sugihara I, Marshall SP, Lang EJ (2007) Relationship of complex spike synchrony bands and climbing fiber projection determined by reference to aldolase. C compartments in crus IIa of the rat cerebellar cortex. J Comp Neurol 501:13–29. Scholar
  337. Sugihara I, Wu H, Shinoda Y (1999) Morphology of single olivocerebellar axons labeled with biotinylated dextran amine in the rat. J Comp Neurol 414:131–148PubMedCrossRefPubMedCentralGoogle Scholar
  338. Sugihara I, Wu HS, Shinoda Y (2001) The entire trajectories of single olivocerebellar axons in the cerebellar cortex and their contribution to cerebellar compartmentalization. J Neurosci 21:7715–7723PubMedCrossRefPubMedCentralGoogle Scholar
  339. Sun Z, Hopkins N (2001) vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. Genes Dev 15:3217–3229. Scholar
  340. Swayze VW, Johnson VP et al (1997) Magnetic resonance imaging of brain anomalies in fetal alcohol syndrome. Pediatrics 99:232–240PubMedCrossRefPubMedCentralGoogle Scholar
  341. Swenson C (1983) The afferent connections of the inferior olivary complex in rats. An anterograde study using autoradiographic and axonal degeneration techniques. Neuroscience 8:259–275PubMedCrossRefPubMedCentralGoogle Scholar
  342. Szapiro G, Barbour B (2007) Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover. Nat Neurosci 10:735–742PubMedCrossRefPubMedCentralGoogle Scholar
  343. Takebayashi H et al (2002) Non-overlapping expression of Olig3 and Olig2 in the embryonic neural tube. Mech Dev 113:169–174. Scholar
  344. Tang T, Blenkinsop TA, Lang EJ (2019) Complex spike synchrony dependent modulation of rat deep cerebellar nuclear activity. Elife. vol 9 no 8, pii: e40101.
  345. Ten Brinke MM, Boele HJ, De Zeeuw CI (2019) Conditioned climbing fiber responses in cerebellar cortex and nuclei. Neurosci Lett 688:26–36PubMedCrossRefPubMedCentralGoogle Scholar
  346. Ten Brinke MM et al (2015) Evolving models of Pavlovian conditioning: cerebellar cortical dynamics in awake behaving mice. Cell Rep 13:1977–1988. Scholar
  347. Ten Brinke MM et al (2017) Dynamic modulation of activity in cerebellar nuclei neurons during Pavlovian eyeblink conditioning in mice. Elife 6.
  348. ten Donkelaar HJ, Lammens M (2009) Development of the human cerebellum and its disorders. Clin Perinatol 36:513–530. S0095-5108(09)00026-8 [pii]. Scholar
  349. Toonen M et al (1998) Light microscopic and ultrastructural investigation of the dopaminergic innervation of the ventrolateral outgrowth of the rat inferior olive. Brain Res 802:267–273PubMedCrossRefPubMedCentralGoogle Scholar
  350. Tümpel S, Wiedemann LM, Krumlauf R (2009) Hox genes and segmentation of the vertebrate hindbrain. Curr Top Dev Biol 88:103–137. S0070-2153(09)88004-6 [pii]. Scholar
  351. Turecek J, Han VZ, Cuzon Carlson VC, Grant KA, Welsh JP (2016) Electrical coupling and synchronized subthreshold oscillations in the inferior olive of the rhesus macaque. J Neurosci 36:6497–6502. Scholar
  352. Turecek J, Yuen GS, Han VZ, Zeng XH, Beyer KU, Welsh JP (2014) NMDA receptor activation strengthens weak electrical coupling in mammalian brain. Neuron 81:1375–1388. Scholar
  353. Turker KS, Miles TS (1984) Harmaline disrupts acquisition of conditioned nictitating membrane responses. Brain Res Bull 13:229–233PubMedCrossRefPubMedCentralGoogle Scholar
  354. Turker KS, Miles TS (1986) Climbing fiber lesions disrupt conditioning of the nictitating membrane response in the rabbit. Brain Res 363:376–378PubMedCrossRefPubMedCentralGoogle Scholar
  355. Uesaka N et al (2014) Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain. Science 344:1020–1023. Scholar
  356. Ulloa F, Martí E (2010) Wnt won the war: antagonistic role of Wnt over Shh controls dorso-ventral patterning of the vertebrate neural tube. Dev Dyn 239:69–76. Scholar
  357. Urbano FJ, Simpson JI, Llinas RR (2006) Somatomotor and oculomotor inferior olivary neurons have distinct electrophysiological phenotypes. Proc Natl Acad Sci U S A 103:16550–16555PubMedPubMedCentralCrossRefGoogle Scholar
  358. Vaage S (1969) The segmentation of the primitive neural tube in chick embryos (Gallus domesticus). A morphological, histochemical and autoradiographical investigation. Ergeb Anat Entwicklungsgesch 41:3–87PubMedPubMedCentralGoogle Scholar
  359. Van Der Giessen RS et al (2008) Role of olivary electrical coupling in cerebellar motor learning. Neuron 58:599–612. S0896-6273(08)00262-6 [pii]. Scholar
  360. Van der Want JJL, Wiklund L, Guegan M, Ruigrok T, Voogd J (1989) Anterograde tracing of the rat olivocerebellar system with Phaseolus vulgaris leucoagglutinin (PHA-L). Demonstration of climbing fiber collateral innervation of the cerebellar nuclei. J Comp Neurol 288:1–18PubMedCrossRefPubMedCentralGoogle Scholar
  361. van Essen TA et al (2010) Anti-malaria drug mefloquine induces motor learning deficits in humans. Front Neurosci 4:191PubMedPubMedCentralCrossRefGoogle Scholar
  362. Velarde MG, Nekorkin VI, Kazantsev VB, Makarenko VI, Llinas R (2002) Modeling inferior olive neuron dynamics. Neural Netw 15:5–10PubMedCrossRefPubMedCentralGoogle Scholar
  363. Verbeek DS (2009) Spinocerebellar ataxia type 23: a genetic update. Cerebellum 8:104–107. Scholar
  364. Voges K, Wu B, Post L, Schonewille M, De Zeeuw CI (2017) Mechanisms underlying vestibulo-cerebellar motor learning in mice depend on movement direction. J Physiol 595:5301–5326. Scholar
  365. Voneida TJ, Christie D, Bogdanski R, Chopko B (1990) Changes in instrumentally and classically conditioned limb-flexion responses following inferior olivary lesions and olivocerebellar tractotomy in the cat. J Neurosci 10:3583–3593PubMedCrossRefPubMedCentralGoogle Scholar
  366. Voogd J, Pardoe J, Ruigrok TJH, Apps R (2003) The distribution of climbing and mossy fiber collateral branches from the copula pyramidis and the paramedian lobule: congruence of climbing fiber cortical zones and the pattern of zebrin banding within the rat cerebellum. J Neurosci 23:4645–4656. Scholar
  367. Vrieler N, Loyola S, Yarden-Rabinowitz Y, Hoogendorp J, Medvedev N, Hoogland TM, De Zeeuw CI, Schutter ED, Yarom Y, Negrello M, Torben-Nielsen B, Uusisaari MY (2019) Variability and directionality of inferior olive neuron dendrites revealed by detailed 3D characterization of an extensive morphological library. Brain Structure and Function. In Press.Google Scholar
  368. Wada N, Kishimoto Y, Watanabe D, Kano M, Hirano T, Funabiki K, Nakanishi S (2007) Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission. Proc Natl Acad Sci U S A 104:16690–16695. 0708165104 [pii]. Scholar
  369. Walberg F, Ottersen OP (1989) Demonstration of GABA immunoreactive cells in the inferior olive of baboons (Papio papio and Papio anubis). Neurosci Lett 101:149–155. Scholar
  370. Walshe J, Maroon H, McGonnell IM, Dickson C, Mason I (2002) Establishment of hindbrain segmental identity requires signaling by FGF3 and FGF8. Curr Biol 12:1117–1123. Scholar
  371. Wang HL, Chou AH, Lin AC, Chen SY, Weng YH, Yeh TH (2010a) Polyglutamine-expanded ataxin-7 upregulates Bax expression by activating p53 in cerebellar and inferior olivary neurons. Exp Neurol 224:486–494. S0014-4886(10)00169-X [pii]. Scholar
  372. Wang VY, Rose MF, Zoghbi HY (2005) Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48:31–43. S0896-6273(05)00699-9 [pii]. Scholar
  373. Wang X et al (2010b) Spinocerebellar ataxia type 6: systematic patho-anatomical study reveals different phylogenetically defined regions of the cerebellum and neural pathways undergo different evolutions of the degenerative process. Neuropathology 30:501–514. NEU1094 [pii]. Scholar
  374. Wassarman KM, Lewandoski M, Campbell K, Joyner AL, Rubenstein JLR, Martinez S, Martin GR (1997) Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. Development 124:2923–2934PubMedPubMedCentralGoogle Scholar
  375. Wassef M, Chédotal A, Cholley B, Thomasset M, Heizmann CW, Sotelo C (1992) Development of the olivocerebellar projection in the rat: I. Transient biochemical compartmentation of the inferior olive. J Comp Neurol 323:519–536PubMedCrossRefPubMedCentralGoogle Scholar
  376. Watanabe M (2008) Molecular mechanisms governing competitive synaptic wiring in cerebellar Purkinje cells. Tohoku J Exp Med 214:175–190. Scholar
  377. Weickert S, Ray A, Zoidl G, Dermietzel R (2005) Expression of neural connexins and pannexin1 in the hippocampus and inferior olive: a quantitative approach. Brain Res Mol Brain Res 133:102–109. Scholar
  378. Welsh JP (1998) Systemic harmaline blocks associative and motor learning by the actions of the inferior olive. Eur J Neurosci 10:3307–3320PubMedCrossRefPubMedCentralGoogle Scholar
  379. Welsh JP (2002) Functional significance of climbing-fiber synchrony: a population coding and behavioral analysis. Ann N Y Acad Sci 978:188–204PubMedCrossRefPubMedCentralGoogle Scholar
  380. Welsh JP, Ahn ES, Placantonakis DG (2005) Is autism due to brain desynchronization? Int J Dev Neurosci 23:253–263PubMedCrossRefPubMedCentralGoogle Scholar
  381. Welsh JP, Harvey JA (1998) Acute inactivation of the inferior olive blocks associative learning. Eur J Neurosci 10:3321–3332PubMedCrossRefPubMedCentralGoogle Scholar
  382. Welsh JP, Lang EJ, Suglhara I, Llinas R (1995) Dynamic organization of motor control within the olivocerebellar system. Nature 374:453–457. Scholar
  383. White JJ, Sillitoe RV (2017) Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat Commun 8:14912. Scholar
  384. White RJ, Schilling TF (2008) How degrading: Cyp26s in hindbrain development. Dev Dyn 237:2775–2790. Scholar
  385. Wiellette EL, Sive H (2003) vhnf1 and Fgf signals synergize to specify rhombomere identity in the zebrafish hindbrain. Development 130:3821–3829PubMedCrossRefPubMedCentralGoogle Scholar
  386. Wiklund L, Björklund A, Sjölund B (1977) The indolaminergic innervation of the inferior olive. 1. Convergence with the direct spinal afferents in the areas projecting to the cerebellar anterior lobe. Brain Res 131:1–21PubMedCrossRefPubMedCentralGoogle Scholar
  387. Wiklund L, Toggenburger G, Cuénod M (1984) Selective retrograde labelling of the rat olivocerebellar climbing fiber system with D-[3H]aspartate. Neuroscience 13:441–468PubMedCrossRefPubMedCentralGoogle Scholar
  388. Wilkinson DG, Bhatt S, Cook M, Boncinelli E, Krumlauf R (1989) Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain. Nature 341:405–409. Scholar
  389. Wise AK, Cerminara NL, Marple-Horvat DE, Apps R (2010) Mechanisms of synchronous activity in cerebellar Purkinje cells. J Physiol 588:2373–2390. jphysiol.2010.189704 [pii]. Scholar
  390. Witter L, Canto CB, Hoogland TM, de Gruijl JR, De Zeeuw CI (2013) Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation. Front Neural Circuits 7:133. Scholar
  391. Woodward DJ, Hoffer BJ, Siggins GR, Bloom FE (1971) The ontogenetic development of synaptic junctions, synaptic activation and responsiveness to neurotransmitter substances in rat cerebellar Purkinje cells. Brain Res 34:73–97PubMedCrossRefPubMedCentralGoogle Scholar
  392. Wulff P et al (2009) Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning. Nat Neurosci 12:1042–1049. nn.2348 [pii]. Scholar
  393. Wylie DR, De Zeeuw CI, Simpson JI (1995) Temporal relations of the complex spike activity of Purkinje cell pairs in the vestibulocerebellum of rabbits. J Neurosci 15:2875–2887PubMedCrossRefPubMedCentralGoogle Scholar
  394. Xu W, Edgley SA (2008) Climbing fibre-dependent changes in Golgi cell responses to peripheral stimulation. J Physiol 586:4951–4959. jphysiol.2008.160879 [pii]. Scholar
  395. Yamada M, Terao M, Terashima T, Fujiyama T, Kawaguchi Y, Nabeshima Y, Hoshino M (2007) Origin of climbing fiber neurons and their developmental dependence on Ptf1a. J Neurosci 27:10924–10934. 27/41/10924 [pii]. Scholar
  396. Yamamoto M, Fujinuma M, Hirano S, Hayakawa Y, Clagett-Dame M, Zhang J, McCaffery P (2005) Retinoic acid influences the development of the inferior olivary nucleus in the rodent. Dev Biol 280:421–433. S0012-1606(05)00098-9 [pii]. Scholar
  397. Ye WL et al (2001) Distinct regulators control the expression of the mid-hindbrain organizer signal FGF8. Nat Neurosci 4:1175–1181PubMedCrossRefPubMedCentralGoogle Scholar
  398. Yee KT, Simon HH, Tessier-Lavigne M, O’Leary DDM (1999) Extension of long leading processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1. Neuron 24:607–622. Scholar
  399. Yeo CH, Hardiman MJ, Glickstein M (1986) Classical conditioning of the nictitating membrane response of the rabbit. IV. Lesions of the inferior olive experimental brain research. Experimentelle Hirnforschung 63:81–92PubMedCrossRefPubMedCentralGoogle Scholar
  400. Ypsilanti AR, Zagar Y, Chedotal A (2010) Moving away from the midline: new developments for Slit and Robo. Development 137:1939–1952. 137/12/1939 [pii]. Scholar
  401. Zervas M, Millet S, Ahn S, Joyner AL (2004) Cell behaviors and genetic lineages of the mesencephalon and rhombomere 1. Neuron 43:345–357. S0896627304004283 [pii]CrossRefGoogle Scholar
  402. Zhang Y et al (2017) Inferior olivary TMEM16B mediates cerebellar motor learning. Neuron 95:1103–1111 e1104. Scholar
  403. Zhao Y, Sharma N, LeDoux MS (2011) The DYT1 carrier state increases energy demand in the olivocerebellar network. Neuroscience 177:183–194. Scholar
  404. Zhou H et al (2014) Cerebellar modules operate at different frequencies. elife 3:e02536. Scholar

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Authors and Affiliations

  • S. Loyola
    • 1
    • 2
  • L. W. J. Bosman
    • 2
    Email author
  • J. R. De Gruijl
    • 1
  • M. T. G. De Jeu
    • 2
  • M. Negrello
    • 2
  • T. M. Hoogland
    • 1
    • 2
    Email author
  • C. I. De Zeeuw
    • 1
    • 2
  1. 1.Netherlands Institute for NeuroscienceThe Royal Netherlands Academy of Arts and Sciences (KNAW)AmsterdamThe Netherlands
  2. 2.Department of NeuroscienceErasmus MCRotterdamThe Netherlands

Section editors and affiliations

  • Donna L. Gruol
    • 1
  1. 1.Molecular and Integrative Neuroscience Department (MIND), The Scripps Research InstituteLa JollaUSA

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