Abstract
The vestibulo-ocular reflex (VOR) can be viewed as an adaptive control system that maintains compensatory eye movements during head motion. As the cerebellar flocculus is intimately involved in this adaptive motor control of the VOR, the VOR has been a popular model system for investigating cerebellar motor learning. Long-term depression (LTD) and long-term potentiation (LTP) at the parallel fiber–Purkinje cell synapses are considered to play major roles in cerebellar motor learning. A recent study using mutant mice demonstrated cerebellar motor learning with hampered LTD; the study concluded that the parallel fiber–Purkinje cell LTD is not essential. More recently, multiple forms of plasticity have been found in the cerebellum, and they are believed to contribute to cerebellar motor learning. However, it is still unclear how synaptic plasticity modifies the signal processing that underlies motor learning in the flocculus. A computational simulation suggested that the plasticity present in mossy fiber–granule cell synapses improves VOR-related sensory-motor information transferred into granule cells, whereas the plasticity in the molecular layer stores this information as a memory under guidance from climbing fiber teaching signals. Thus, motor learning and memory are thought to be induced mainly by LTD and LTP at parallel fiber–Purkinje cell synapses and by rebound potentiation at molecular interneuron–Purkinje cell synapses among the multiple forms of plasticity in the cerebellum. In this study, we focused on the LTD and LTP at parallel fiber–Purkinje cell synapses. Based on our simulation, we propose that acute VOR motor learning accomplishes by simultaneous enhancement of eye movement signals via LTP and suppression of vestibular signals via LTD to increase VOR gain (gain-up learning). To decrease VOR gain (gain-down learning), these two signals are modified in the opposite directions; namely, LTD suppresses eye movement signals, whereas LTP enhances vestibular signals.
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References
Ito M, Jastreboff PJ, Miyashita Y. Specific effects of unilateral lesions in the flocculus upon eye movements in albino rabbits. Exp Brain Res. 1982;45:233–42.
Nagao S, Kitazawa H. Effects of reversible shutdown of the monkey flocculus on the retention of adaptation of the horizontal vestibulo-ocular reflex. Neuroscience. 2003;118:563–70.
Rambold H, Churchland A, Selig Y, Jasmin L, Lisberger SG. Partial ablations of the flocculus and ventral paraflocculus in monkeys causes linked deficits in smooth pursuit eye movements and adaptive modification of the VOR. J Neurophysiol. 2002;87:912–24.
Robinson DA. Adaptive gain control of vestibuloocular reflex by the cerebellum. J Neurophysiol. 1976;39:954–69.
Dean P, Porrill J, Ekerot CF, Jörntell H. The cerebellar microcircuit as an adaptive filter: experimental and computational evidence. Nat Rev Neurosci. 2010;11:30–43.
Kobayashi Y, Kawano K, Takemura A, Inoue Y, Kitama T, Gomi H, Kawato M. Temporal firing patterns of Purkinje cells in the cerebellar ventral paraflocculus during ocular following responses in monkeys II. Complex spikes J Neurophysiol. 1998;80:832–48.
Blazquez PM, Hirata Y, Heiney SA, Green AM, Highstein SM. Cerebellar signatures of vestibulo-ocular reflex motor learning. J Neurosci. 2003;23:9742–51.
Hirata Y, Highstein SM. Acute adaptation of the vestibuloocular reflex: signal processing by floccular and ventral parafloccular Purkinje cells. J Neurophysiol. 2001;85:2267–88.
Kuki Y, Hirata Y, Blazquez PM, Heiney SA, Highstein SM. Memory retention of vestibuloocular reflex motor learning in squirrel monkeys. Neuroreport. 2004;15:1007–11.
Boyden ES, Katoh A, Raymond JL. Cerebellum-dependent learning: the role of multiple plasticity mechanisms. Annu Rev Neurosci. 2004;27:581–609.
Marr D. A theory of cerebellar cortex. J Physiol. 1969;202:437–70.
Albus JS. A theory of cerebellar function. Math Biosci. 1971;10:25–61.
Ito M. The cerebellum and neural control. Raven Press; 1984.
Ito M. Long-term depression. Annu Rev Neurosci. 1989;12:85–102.
Ito M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev. 2001;81:1143–95.
Ito M. The cerebellum: brain for an implicit self. Financial Press; 2012.
Coesmans M, Weber JT, De Zeeuw CI, Hansel C. Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron. 2004;44:691–700.
Hirano T. Depression and potentiation of the synaptic transmission between a granule cell and a Purkinje cell in rat cerebellar culture. Neurosci Lett. 1990;119:141–4.
Sakurai M. Synaptic modification of parallel fibre - Purkinje cell transmission in in virto guinea-pig cerebellar slices. J Physiol. 1987;394:463–80.
Sakurai M. Calcium is an intracellular mediator of the climbing fiber in induction of cerebellar long-term depression. Proc Natl Acad Sci U S A. 1990;87:3383–5.
Nagao S, Ito M. Subdural application of hemoglobin to the cerebellum blocks vestibuloocular reflex adaptation. Neuroreport. 1991;2:193–6.
Li J, Smith SS, McElligott JG. Cerebellar nitric oxide is necessary for vestibulo-ocular reflex adaptation, a sensorimotor model of learning. J Neourophysiol. 1995;74:489–94.
De Zeeuw CI, Hansel C, Bian F, Koekkoek SK, van Alphen AM, Linden DJ, Oberdick J. Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron. 1998;20:495–508.
Schonewille M, Gao Z, Boele HJ, Veloz MF, Amerika WE, Simek AA, De Jeu MT, Steinberg JP, Takamiya K, Hoebeek FE, Linden DJ, Huganir RL, De Zeeuw CI. Reevaluating the role of LTD in cerebellar motor learning. Neuron. 2011;70:43–50.
D'Angelo E, Mapelli L, Casellato C, Garrido JA, Luque N, Monaco J, Prestori F, Pedrocchi A, Ros E. Distributed circuit plasticity: new clues for the cerebellar mechanisms of learning. Cerebellum. 2015;15:1–13.
D’Angelo E, Rossi P, Armano S, Taglietti V. Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber-granule cell transmission in rat cerebellum. J Neurophysiol. 1999;81:277–87.
D’Angelo E, Rossi P, Gall D, Prestori F, Nieus T, Maffei A, Sola E. Long-term potentiation of synaptic transmission at the mossy fiber-granule cell relay of cerebellum. Prog Brain Res. 2005;148:69–80.
D’Errico A, Prestori F, D’Angelo E. Differential induction of bidirectional long-term changes in neurotransmitter release by frequency-coded patterns at the cerebellar input. J Physiol. 2009;587:5843–57.
Robberechts Q, Wijnants M, Giugliano M, De Schutter E. Long-term depression at parallel fiber to Golgi cell synapses. J Neurophysiol. 2010;104:3413–23.
Bender VA, Pugh JR, Jahr CE. Presynaptically expressed long-term potentiation increases multivesicular release at parallel fiber synapses. J Neurosci. 2009;29:10974–8.
Soler-Llavina GJ, Sabatini BL. Synapse-specific plasticity and compartmentalized signaling in cerebellar stellate cells. Nat Neurosci. 2006;9:798–806.
Kano M, Rexhausen U, Dreessen J, Konnerth A. Synaptic excitation produces a long-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells. Nature. 1992;356:601–4.
Hirano T, Yamazaki Y, Nakamura Y. LTD, RP, and motor learning. Cerebellum. 2015;15:51–3.
Galiana HL, Outerbridge JS. A bilateral model for central neural pathways in vestibuloocular reflex. J Neurophysiol. 1984;51:210–41.
Galiana HL, Smith HLH, Katsarkas A. Modelling non-linearities in the vestibuloocular reflex (VOR) after unilateral or bilateral loss of peripheral vestibular function. Exp Brain Res. 2001;137:369–86.
Lisberger SG, Sejnowski T. Motor learning in a recurrent neural network model based on the vestibulo-ocular reflex. Nature. 1992;360:159–61.
Tabata H, Yamamoto K, Kawato M. Computational study on monkey VOR adaptation and smooth pursuit based on the parallel control-pathway theory. J Neurophysiol. 2002;87:2176–89.
Hirata Y, Takeuchi I, Highstein SM. A dynamical model for the vertical vestibuloocular reflex and optokinetic response in primate. Neurocomputing. 2003;52-54:531–40.
Yamazaki T, Nagao S, Lennon W, Tanaka S. Modeling memory consolidation during posttraining periods in cerebellovestibular learning. Proc Natl Acad Sci U S A. 2015;112:3541–456.
Inagaki K, Hirata Y. The model of vestibuloocular reflex explicitly describing cerebellar neuronal network model, Institute of Electronics. Information and Communication Engineers. 2007;J90:1293–304. In Japanese
Inagaki K, Kobayashi S, Hiata Y. Analysis of frequency selective vestibuloocular reflex motor learning using cerebellar spiking neuron network model. Institute of Electronics, Information and Communication Engineers. 2011;J91:919–28. In Japanese
Eccles JC, Ito M, Szentagothai, J. The cerebellum as a neuronal machine. Springer-Verlag; 1967.
D'Angelo E, De Filippi G, Rossi P, Taglietti V. Synaptic excitation of individual rat cerebellar granule cells in situ: evidence for the role of NMDA receptors. J Physiol. 1995;484:397–413.
Galliano E, Mazzarello P, D'Angelo E. Discovery and rediscoveries of Golgi cells. J Physiol. 2010;588:3639–55.
Brickley SG, Cull-Candy SG, Farrant M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J Physiol. 1996;497:753–9.
Lisberger SG, Fuchs AF. Role of primate flocculus during rapid behavioral modification of vestibuloocular reflex. II. Mossy fiber firing patterns during horizontal head rotation and eye movement. J. Neurophysiology. 1978;41:764–77.
Dieudonne S. Submillisecond kinetics and low efficacy of parallel fibre-Golgi cell synaptic currents in the rat cerebellum. J Physiol. 1998;510:845–66.
Llano I, Gerschenfeld HM. Inhibitory synaptic currents in stellate cells of rat cerebellar slices. J Physiol. 1993;468:177–200.
Kaneda M, Farrant M, Cull-Candy SG. Whole-cell and single-channel currents activated by GABA and glycine in granule cells of the rat cerebellum. J Physiol. 1995;485:419–35.
Simpson JI, Wylie DR, De Zeeuw CI. On climbing fiber signals and their consequence(s). Behav and Brain Science. 1996;19:368–83.
Vincent P, Marty A. Fluctuations of inhibitory postsynaptic currents in Purkinje cells from rat cerebellar slices. J Physiol. 1996;494:183–99.
Medina JF, Garcia KS, Nores WL, Taylor NM, Mauk MD. Timing mechanisms in the cerebellum: testing predictions of a large-scale computer simulation. J Neurosci. 2000;20:5516–25.
Hirata Y, Blazquez PM, Inagaki K, Furuta K, Highstein SM. Flocculus Purkinje cell complex spikes during acute motor learning of the horizontal vestibuloocular reflex in squirrel monkeys. Soc for Neurosci. 2007:805–6.
Matsumoto M, Nishimura T. Mersenne twister: a 623-dimensionally equidistributed uniform pseudo-random number generator. ACM Transactions on Modeling and Computer Simulation. 1998;8:3–30.
Ogasawara H, Doi T, Kawato M. System biology perspectives on cerebellar long-term depression. Neurosignals. 2008;16:300–17.
Suvrathan A, Payne HL, Raymond JL. Timing rules for synaptic plasticity matched to behavioral function. Neuron. 2016;92:959–67.
Chen C, Thompson RF. Temporal specificity of long-term depression in parallel fiber-Purkinje synapses in rat cerebellar slice. Learn Mem. 1995;2:185–98.
Raymond JL, Lisberger SG. Neural learning rules for the vestibulo-ocular reflex. J Neurosci. 1998;21:9112–29.
Pastor A, De La Cruz RR, Baker R. Characterization and adaptive modification of the goldfish vestibuloocular reflex by sinusoidal and velocity step vestibular stimulation. J Neurophysiol. 1992;68:2003–15.
Watanabe E. Neuronal events correlated with long-term adaptation of the horizontal vestibulo-ocular reflex in the primate flocculus. Brain Res. 1984;297:169–74.
Broussard DM, Kassardjian CD. Learning in a simple motor system. Learn Mem. 2004;11:127–36.
Broussard DM, Titley HK, Antflick J, Hampson DR. Motor learning in the VOR: the cerebellar component. Exp Brain Res. 2011;210:451–63.
Wada N, Funabiki K, Nakanishi S. Role of granule-cell transmission in memory trace of cerebellum-dependent optokinetic motor learning. Proc Natl Acad Sci U S A. 2014;8:5373–8.
Dean P, Porrill J. Adaptive-filter models of the cerebellum: computational analysis. Cerebellum. 2008;7:567–71.
Dean P, Porrill J. Evaluating the adaptive-filter model of the cerebellum. J Physiol. 2011;589:3459–70.
D'Angelo E, De Zeeuw CI. Timing and plasticity in the cerebellum: focus on the granular layer. Trends Neurosci. 2009;32:30–40.
Hirata Y, Lockard JM, Highstein SM. Capacity of vertical VOR adaptation in squirrel monkey. J Neurophysiol. 2002;88:3194–207.
Titley HK, Hansel C. Asymmetries in cerebellar plasticity and motor learning. Cerebellum. 2015:1–6.
Fujita M. Adaptive filter model of the cerebellum. Biol Cybern. 1982;45:195–206.
Fujita M. Simulation of adaptive modification of the vestibulo-ocular reflex with an adaptive filter model of the cerebellum. Biol Cybern. 1982;45:207–14.
Acknowledgements
The authors would like to thank the late Prof. Stephen Highstein for his valuable comments. The authors also thank Dr. Josh Bassett for proofreading the manuscript. This study was supported in part by a JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (24300115, YH) and a Grant-in-Aid for Young Scientists (B) (15K16086 and 17K12781, KI).
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Inagaki, K., Hirata, Y. Computational Theory Underlying Acute Vestibulo-ocular Reflex Motor Learning with Cerebellar Long-Term Depression and Long-Term Potentiation. Cerebellum 16, 827–839 (2017). https://doi.org/10.1007/s12311-017-0857-6
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DOI: https://doi.org/10.1007/s12311-017-0857-6