Advertisement

The Cerebellum

, Volume 13, Issue 4, pp 452–461 | Cite as

Cerebellar Inhibitory Output Shapes the Temporal Dynamics of Its Somatosensory Inferior Olivary Input

  • Roni Hogri
  • Eyal Segalis
  • Matti Mintz
Original Paper

Abstract

The cerebellum is necessary and sufficient for the acquisition and execution of adaptively timed conditioned motor responses following repeated paired presentations of a conditioned stimulus and an unconditioned stimulus. The underlying plasticity depends on the convergence of conditioned and unconditioned stimuli signals relayed to the cerebellum by the pontine nucleus and the inferior olive (IO), respectively. Adaptive timing of conditioned responses relies on the correctly predicted onset of the unconditioned stimulus, usually a noxious somatosensory stimulus. We addressed two questions: First, does the IO relay information regarding the duration of somatosensory stimuli to the cerebellum? Multiple-unit recordings from the IO of anesthetized rats that received periorbital airpuffs of various durations revealed that sustained somatosensory stimuli are invariably transformed into phasic IO outputs. The phasic response was followed by a post-peak depression in IO activity as compared to baseline, providing the cerebellum with a highly synchronous signal, time-locked to the stimulus’ onset. Second, we sought to examine the involvement of olivocerebellar interactions in this signal transformation. Cerebello-olivary inhibition was interrupted using temporary pharmacological inactivation of cerebellar output nuclei, resulting in more sustained (i.e., less synchronous) IO responses to sustained somatosensory stimuli, in which the post-peak depression was substituted with elevated activity as compared to baseline. We discuss the possible roles of olivocerebellar negative-feedback loops and baseline cerebello-olivary inhibition levels in shaping the temporal dynamics of the IO’s response to somatosensory stimuli and the consequences of this shaping for cerebellar plasticity and its ability to adapt to varying contexts.

Keywords

Inferior olive Cerebellar nuclei Negative feedback Electrotonic coupling Classical conditioning 

Notes

Acknowledgments

We would like to thank Aryeh Taub, Ari Magal, and Dor Konforty for valuable discussions during the preparation of this manuscript. The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7) under grant agreement #216809, the Converging Technologies (ISF) research grant #1709/07, and ISF grant #390/12 to M.M.; R.H. was also funded by the Dan David Prize Scholarship and the Michael Myslobodsky Foundation.

Conflict of Interest

The authors declare that there is no conflict of interest, financial or otherwise, that might bias this work.

References

  1. 1.
    Thompson RF, Steinmetz JE. The role of the cerebellum in classical conditioning of discrete behavioral responses. Neuroscience. 2009;162(3):732–55.PubMedCrossRefGoogle Scholar
  2. 2.
    Freeman JH, Steinmetz AB. Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning. Learn Mem. 2011;18(10):666–77.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Gao Z, van Beugen BJ, De Zeeuw CI. Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci. 2012;13(9):619–35.PubMedCrossRefGoogle Scholar
  4. 4.
    Smith MC, Coleman SR, Gormezano I. Classical conditioning of the rabbit’s nictitating membrane response at backward, simultaneous, and forward CS-US intervals. J Comp Physiol Psychol. 1969;69(2):226–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Mauk MD, Ruiz BP. Learning-dependent timing of Pavlovian eyelid responses: differential conditioning using multiple interstimulus intervals. Behav Neurosci. 1992;106(4):666–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Rogers RF, Britton GB, Steinmetz JE. Learning-related interpositus activity is conserved across species as studied during eyeblink conditioning in the rat. Brain Res. 2001;905(1–2):171–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Van Der Giessen RS, Koekkoek SK, van Dorp S, De Gruijl JR, Cupido A, Khosrovani S, et al. Role of olivary electrical coupling in cerebellar motor learning. Neuron. 2008;58(4):599–612.CrossRefGoogle Scholar
  8. 8.
    Mauk MD, Steinmetz JE, Thompson RF. Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus. Proc Natl Acad Sci U S A. 1986;83(14):5349–53.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Steinmetz JE, Lavond DG, Thompson RF. Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus. Synapse. 1989;3(3):225–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Medina JF, Nores WL, Mauk MD. Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses. Nature. 2002;416(6878):330–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Rasmussen A, Jirenhed D, Zucca R, Johansson F, Svensson P, Hesslow G. Number of spikes in climbing fibers determines the direction of cerebellar learning. J Neurosci. 2013;33(33):13436–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Thompson RF, Thompson JK, Kim JJ, Krupa DJ, Shinkman PG. The nature of reinforcement in cerebellar learning. Neurobiol Learn Mem. 1998;70(1–2):150–76.PubMedCrossRefGoogle Scholar
  13. 13.
    Apps R, Garwicz M. Anatomical and physiological foundations of cerebellar information processing. Nat Rev Neurosci. 2005;6(4):297–311.PubMedCrossRefGoogle Scholar
  14. 14.
    Badura A, Schonewille M, Voges K, Galliano E, Renier N, Gao Z, et al. Climbing fiber input shapes reciprocity of Purkinje cell firing. Neuron. 2013;78(4):700–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Chapman PF, Steinmetz JE, Sears LL, Thompson RF. Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses. Brain Res. 1990;537(1):149–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Lavond DG, Kim JJ, Thompson RF. Mammalian brain substrates of aversive classical conditioning. Annu Rev Psychol. 1993;44(1):317–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Hesslow G. Correspondence between climbing fibre input and motor output in eyeblink-related areas in cat cerebellar cortex. J Physiol. 1994;476(2):229–44.PubMedCentralPubMedGoogle Scholar
  18. 18.
    De Zeeuw C, Holstege J, Calkoen F, Ruigrok T, Voogd J. 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. 1988;447(2):369–75.PubMedCrossRefGoogle Scholar
  19. 19.
    Ruigrok TJH, Voogd J. Cerebellar nucleo-olivary projections in the rat: an anterograde tracing study with Phaseolus vulgaris-leucoagglutinin (PHA-L). J Comp Neurol. 1990;298(3):315–33.PubMedCrossRefGoogle Scholar
  20. 20.
    Fredette BJ, Adams JC, Mugnaini E. GABAergic neurons in the mammalian inferior olive and ventral medulla detected by glutamate decarboxylase immunocytochemistry. J Comp Neurol. 1992;321(4):501–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Sears LL, Steinmetz JE. Dorsal accessory inferior olive activity diminishes during acquisition of the rabbit classically conditioned eyelid response. Brain Res. 1991;545(1–2):114–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim JJ, Krupa DJ, Thompson RF. Inhibitory cerebello-olivary projections and blocking effect in classical conditioning. Science. 1998;279(5350):570–3.PubMedCrossRefGoogle Scholar
  23. 23.
    Hofstotter C, Mintz M, Verschure PFMJ. The cerebellum in action: a simulation and robotics study. Eur J Neurosci. 2002;16:1361–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Bengtsson F, Jirenhed DA, Svensson P, Hesslow G. Extinction of conditioned blink responses by cerebello-olivary pathway stimulation. Neuroreport. 2007;18(14):1479–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Rasmussen A, Jirenhed D, Hesslow G. Simple and complex spike firing patterns in Purkinje cells during classical conditioning. Cerebellum. 2008;7(4):563–6.PubMedCrossRefGoogle Scholar
  26. 26.
    de Zeeuw CI, Ruigrok TJ, Schalekamp MP, Boesten AJ, Voogd J. Ultrastructural study of the cat hypertrophic inferior olive following anterograde tracing, immunocytochemistry, and intracellular labeling. Eur J Morphol. 1990;28(2–4):240–55.PubMedGoogle Scholar
  27. 27.
    Ruigrok TTH, De Zeeuw CI, Voogd J. Hypertrophy of inferior olivary neurons: a degenerative, regenerative or plasticity phenomenon. Eur J Morphol. 1990;28(2–4):224–39.PubMedGoogle Scholar
  28. 28.
    Lang EJ. GABAergic and glutamatergic modulation of spontaneous and motor-cortex-evoked complex spike activity. J Neurophysiol. 2002;87(4):1993–2008.PubMedGoogle Scholar
  29. 29.
    Leznik E, Makarenko V, Llinas R. Electrotonically mediated oscillatory patterns in neuronal ensembles: an in vitro voltage-dependent dye-imaging study in the inferior olive. J Neurosci. 2002;22(7):2804–15.PubMedGoogle Scholar
  30. 30.
    Leznik E, Llinas R. Role of gap junctions in synchronized neuronal oscillations in the inferior olive. J Neurophysiol. 2005;94(4):2447–56.PubMedCrossRefGoogle Scholar
  31. 31.
    Placantonakis DG, Bukovsky AA, Aicher SA, Kiem H, Welsh JP. Continuous electrical oscillations emerge from a coupled network: a study of the inferior olive using lentiviral knockdown of connexin36. J Neurosci. 2006;26(19):5008–16.PubMedCrossRefGoogle Scholar
  32. 32.
    Khosrovani S, Van Der Giessen RS, De Zeeuw CI, De Jeu MTG. In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns. Proc Natl Acad Sci U S A. 2007;104(40):15911–6.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Best AR, Regehr WG. Inhibitory regulation of electrically coupled neurons in the inferior olive is mediated by asynchronous release of GABA. Neuron. 2009;62(4):555–65.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Kawato M, Kuroda S, Schweighofer N. Cerebellar supervised learning revisited: biophysical modeling and degrees-of-freedom control. Curr Opin Neurobiol. 2011;21(5):791–800.PubMedCrossRefGoogle Scholar
  35. 35.
    Onizuka M, Hoang H, Kawato M, Tokuda IT, Schweighofer N, Katori Y, et al. Solution to the inverse problem of estimating gap-junctional and inhibitory conductance in inferior olive neurons from the spike trains by network model simulation. Neural Netw. 2013;47:51–63.PubMedCrossRefGoogle Scholar
  36. 36.
    Kitai S, McCrea R, Preston R, Bishop G. Electrophysiological and horseradish peroxidase studies of precerebellar afferents to the nucleus interpositus anterior. I. Climbing fiber system. Brain Res. 1977;122(2):197–214.PubMedCrossRefGoogle Scholar
  37. 37.
    De Zeeuw CI, Van Alpehn AM, Hawkins RK, Ruigrok TJH. Climbing fibre collaterals contact neurons in the cerebellar nuclei that provide a GABAergic feedback to the inferior olive. Neuroscience. 1997;80(4):981–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Witter L, Canto CB, Hoogland TM, De Gruijl JR, De Zeeuw CI. Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation. Front Neural Circ. 2013;7:133.Google Scholar
  39. 39.
    Nicholson DA, Freeman Jr JH. Developmental changes in eye-blink conditioning and neuronal activity in the inferior olive. J Neurosci. 2000;20(21):8218–26.PubMedGoogle Scholar
  40. 40.
    Ruigrok TJH, Voogd J. Organization of projections from the inferior olive to the cerebellar nuclei in the rat. J Comp Neurol. 2000;426(2):209–28.PubMedCrossRefGoogle Scholar
  41. 41.
    Mojtahedian S, Kogan DR, Kanzawa SA, Thompson RF, Lavond DG. Dissociation of conditioned eye and limb responses in the cerebellar interpositus. Physiol Behav. 2007;91:9–14.PubMedCrossRefGoogle Scholar
  42. 42.
    Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 4th ed. New York: Academic Press; 1998.Google Scholar
  43. 43.
    Armstrong DM, Eccles JC, Harvey RJ, Matthews PBC. Responses in the dorsal accessory olive of the cat to stimulation of hind limb afferents. J Physiol. 1968;194(1):125–45.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Nicholson DA, Freeman Jr JH. Developmental changes in evoked Purkinje cell complex spike responses. J Neurophysiol. 2003;90(4):2349–57.PubMedCrossRefGoogle Scholar
  45. 45.
    Wise AK, Cerminara NL, Marple-Horvat DE, Apps R. Mechanisms of synchronous activity in cerebellar Purkinje cells. J Physiol. 2010;588(13):2373–90.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Svensson P, Bengtsson F, Hesslow G. Cerebellar inhibition of inferior olivary transmission in the decerebrate ferret. Exp Brain Res. 2006;168(1):241–53.PubMedCrossRefGoogle Scholar
  47. 47.
    Hesslow G, Ivarsson M. Inhibition of the inferior olive during conditioned responses in the decerebrate ferret. Exp Brain Res. 1996;110(1):36–46.PubMedCrossRefGoogle Scholar
  48. 48.
    Bengtsson F, Ekerot C, Jorntell H. In vivo analysis of inhibitory synaptic inputs and rebounds in deep cerebellar nuclear neurons. PLoS ONE. 2011;6(4):e18822.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Welsh JP, Schwartz C. Multielectrode recording from the cerebellum. In: Nicolelis MAL, editor. Methods for neural ensemble recordings. Boca Raton: CRC; 1999. p. 79–100.Google Scholar
  50. 50.
    Gauck V, Jaeger D. The control of rate and timing of spikes in the deep cerebellar nuclei by inhibition. J Neurosci. 2000;20(8):3006–16.PubMedGoogle Scholar
  51. 51.
    Bengtsson F, Svensson P, Hesslow G. Feedback control of Purkinje cell activity by the cerebello-olivary pathway. Eur J Neurosci. 2004;20(11):2999–3005.PubMedCrossRefGoogle Scholar
  52. 52.
    Mathy A, Ho SSN, Davie JT, Duguid IC, Clark BA, Hausser M. Encoding of oscillations by axonal bursts in inferior olive neurons. Neuron. 2009;62(3):388–99.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Perciavalle V, Apps R, Bracha V, Delgado-García JM, Gibson AR, Leggio M, et al. Consensus paper: current views on the role of cerebellar interpositus nucleus in movement control and emotion. Cerebellum. 2013;12(5):738–57.PubMedCrossRefGoogle Scholar
  54. 54.
    Blenkinsop TA, Lang EJ. Synaptic action of the olivocerebellar system on cerebellar nuclear spike activity. J Neurosci. 2011;31(41):14708–20.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Simons DJ. Response properties of vibrissa units in rat SI somatosensory neocortex. J Neurophysiol. 1978;41(3):798–820.PubMedGoogle Scholar
  56. 56.
    Lichtenstein S, Carvell G, Simons D. Responses of rat trigeminal ganglion neurons to movements of vibrissae in different directions. Somatosens Mot Res. 1990;7(1):47–65.PubMedCrossRefGoogle Scholar
  57. 57.
    Meng ID, Hu JW, Benetti AP, Bereiter DA. Encoding of corneal input in two distinct regions of the spinal trigeminal nucleus in the rat: cutaneous receptive field properties, responses to thermal and chemical stimulation, modulation by diffuse noxious inhibitory controls, and projections to the parabrachial area. J Neurophysiol. 1997;77(1):43–56.PubMedGoogle Scholar
  58. 58.
    Cairns BE, McErlane SA, Fragoso MC, Soja PJ. Tooth pulp—and facial hair mechanoreceptor—evoked responses of trigeminal sensory neurons are attenuated during ketamine anesthesia. Anesthesiology. 1999;91(4):1025–35.PubMedCrossRefGoogle Scholar
  59. 59.
    Weiss C, Houk JC, Gibson AR. Inhibition of sensory responses of cat inferior olive neurons produced by stimulation of red nucleus. J Neurophysiol. 1990;64(4):1170–85.PubMedGoogle Scholar
  60. 60.
    Teune TM, der Burg J, Ruigrok TJH. Cerebellar projections to the red nucleus and inferior olive originate from separate populations of neurons in the rat: a non-fluorescent double labeling study. Brain Res. 1995;673(2):313–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Horn KM, Hamm TM, Gibson AR. Red nucleus stimulation inhibits within the inferior olive. J Neurophysiol. 1998;80(6):3127–36.PubMedGoogle Scholar
  62. 62.
    Bull MS, Berkley KJ. Cerebellar projections to the somatic pretectum in the cat. Somatosens Mot Res. 1991;8(2):117–26.PubMedCrossRefGoogle Scholar
  63. 63.
    Zagon A, Terenzi M, Roberts M. Direct projections from the anterior pretectal nucleus to the ventral medulla oblongata in rats. Neuroscience. 1995;65(1):253–72.PubMedCrossRefGoogle Scholar
  64. 64.
    Nakamura H, Wu R, Watanabe K, Onozuka M, Itoh K. Projections of glutamate decarboxylase positive and negative cerebellar neurons to the pretectum in the cat. Neurosci Lett. 2006;403(1):30–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Batini C, Buisseret-Delmas C, Compoint C, Daniel H. The GABAergic neurones of the cerebellar nuclei in the rat: projections to the cerebellar cortex. Neurosci Lett. 1989;99(3):251–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Batini C, Compoint C, Buisseret-Delmas C, Daniel H, Guegan M. Cerebellar nuclei and the nucleocortical projections in the rat: retrograde tracing coupled to GABA and glutamate immunohistochemistry. J Comp Neurol. 1992;315(1):74–84.PubMedCrossRefGoogle Scholar
  67. 67.
    Uusisaari M, Knöpfel T. Functional classification of neurons in the mouse lateral cerebellar nuclei. Cerebellum. 2011;10(4):637–46.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Armstrong DM, Rawson JA. Activity patterns of cerebellar cortical neurones and climbing fibre afferents in the awake cat. J Physiol. 1979;289(1):425–48.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Gellman R, Houk JC, Gibson AR. Somatosensory properties of the inferior olive of the cat. J Comp Neurol. 1983;215(2):228–43.PubMedCrossRefGoogle Scholar
  70. 70.
    Lang EJ, Sugihara I, Welsh JP, Llinás R. Patterns of spontaneous Purkinje cell complex spike activity in the awake rat. J Neurosci. 1999;19(7):2728–39.PubMedGoogle Scholar
  71. 71.
    Bosman LW, Koekkoek SK, Shapiro J, Rijken BF, Zandstra F, Van Der Ende B, et al. Encoding of whisker input by cerebellar Purkinje cells. J Physiol. 2010;588(19):3757–83.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Bengtsson F, Jörntell H. Ketamine and xylazine depress sensory-evoked parallel fiber and climbing fiber responses. J Neurophysiol. 2007;98(3):1697–705.PubMedCrossRefGoogle Scholar
  73. 73.
    Loewenstein Y, Mahon S, Chadderton P, Kitamura K, Sompolinsky H, Yarom Y, et al. Bistability of cerebellar Purkinje cells modulated by sensory stimulation. Nat Neurosci. 2005;8(2):202–11.PubMedCrossRefGoogle Scholar
  74. 74.
    Schonewille M, Khosrovani S, Winkelman BH, Hoebeek FE, De Jeu MT, Larsen IM, et al. Purkinje cells in awake behaving animals operate at the upstate membrane potential. Nat Neurosci. 2006;9(4):459–61.PubMedCrossRefGoogle Scholar
  75. 75.
    De Zeeuw CI, Simpson JI, Hoogenraad CC, Galjart N, Koekkoek SKE, Ruigrok TJH. Microcircuitry and function of the inferior olive. Trends Neurosci. 1998;21(9):391–400.PubMedCrossRefGoogle Scholar
  76. 76.
    Medina JF, Lisberger SG. Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys. Nat Neurosci. 2008;11(10):1185–92.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Jacobson GA, Rokni D, Yarom Y. A model of the olivo-cerebellar system as a temporal pattern generator. Trends Neurosci. 2008;31(12):617–25.PubMedCrossRefGoogle Scholar
  78. 78.
    Marshall SP, Lang EJ. Local changes in the excitability of the cerebellar cortex produce spatially restricted changes in complex spike synchrony. J Neurosci. 2009;29(45):14352–62.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Braitenberg V, Heck D, Sultan F. The detection and generation of sequences as a key to cerebellar function: experiments and theory. Behav Brain Sci. 1997;20:229–77.PubMedCrossRefGoogle Scholar
  80. 80.
    Penhune VB, Doyon J. Cerebellum and M1 interaction during early learning of timed motor sequences. NeuroImage. 2005;26(3):801–12.PubMedCrossRefGoogle Scholar
  81. 81.
    Stefanescu M, Thürling M, Maderwald S, Wiestler T, Ladd M, Diedrichsen J, et al. A 7 T fMRI study of cerebellar activation in sequential finger movement tasks. Exp Brain Res. 2013;228:1–12.CrossRefGoogle Scholar
  82. 82.
    Andersson G. Mutual inhibition between olivary cell groups projecting to different cerebellar microzones in the cat. Exp Brain Res. 1984;54(2):293–303.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Psychobiology Research Unit, School of Psychological Sciences and Sagol School of NeuroscienceTel Aviv UniversityTel AvivIsrael

Personalised recommendations