Cerebellar implementation of movement sequences through feedback

Most movements are not unitary, but are comprised of sequences. Although patients with cerebellar pathology display severe deficits in the execution and learning of sequences (Doyon et al., 1997; Shin and Ivry, 2003), most of our understanding of cerebellar mechanisms has come from analyses of single component movements. Eyelid conditioning is a cerebellar-mediated behavior that provides the ability to control and restrict inputs to the cerebellum through stimulation of mossy fibers. We utilized this advantage to test directly how the cerebellum can learn a sequence of inter-connected movement components in rabbits. We show that the feedback signals from one component are sufficient to serve as a cue for the next component in the sequence. In vivo recordings from Purkinje cells demonstrated that all components of the sequence were encoded similarly by cerebellar cortex. These results provide a simple yet general framework for how the cerebellum can use simple associate learning processes to chain together a sequence of appropriately timed responses.

[1]  G. Fleming,et al.  Somatic Motor and Sensory Representation in the Cerebral Cortex of Man as Studied by Electrical Stimulation. (Brain, vol. lx, p. 389, Dec., 1937.) Penfield, W., and Boldrey, E. , 1938 .

[2]  J. Summers,et al.  Current status of the motor program: revisited. , 2009, Human movement science.

[3]  M. Glickstein,et al.  Corticopontine projection in the macaque: The distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei , 1985, The Journal of comparative neurology.

[4]  P. Strick,et al.  Response-mode shifts during sequence learning of macaque monkeys , 2013, Psychological research.

[5]  John T. Green,et al.  Spontaneous recovery but not reinstatement of the extinguished conditioned eyeblink response in the rat. , 2011, Behavioral neuroscience.

[6]  E. Kehoe,et al.  Recovery of the rabbit’s conditioned nictitating membrane response without direct reinforcement after extinction , 2004, Learning & behavior.

[7]  L. Henderson,et al.  Serial reaction time learning and Parkinson's disease: Evidence for a procedural learning deficit , 1995, Neuropsychologia.

[8]  W. T. Thach,et al.  Motor mechanisms of the CNS: cerebrocerebellar interrelations. , 1969, Annual review of physiology.

[9]  G. Hesslow,et al.  Learned response sequences in cerebellar Purkinje cells , 2017, Proceedings of the National Academy of Sciences.

[10]  D Goodman,et al.  On the nature of human interlimb coordination. , 1979, Science.

[11]  H. Diener,et al.  Pathophysiology of cerebellar ataxia , 1992, Movement disorders : official journal of the Movement Disorder Society.

[12]  M. Mauk,et al.  A Decrementing Form of Plasticity Apparent in Cerebellar Learning , 2010, The Journal of Neuroscience.

[13]  C. I. Connolly,et al.  Building neural representations of habits. , 1999, Science.

[14]  J. Doyon,et al.  Distinct basal ganglia territories are engaged in early and advanced motor sequence learning. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. J. Siegel,et al.  Persistent Activity in Prefrontal Cortex during Trace Eyelid Conditioning: Dissociating Responses That Reflect Cerebellar Output from Those That Do Not , 2013, The Journal of Neuroscience.

[16]  Zhanmin Lin,et al.  Excitatory Cerebellar Nucleocortical Circuit Provides Internal Amplification during Associative Conditioning , 2016, Neuron.

[17]  R. F. Thompson,et al.  Neuronal responses of the rabbit cerebellum during acquisition and performance of a classically conditioned nictitating membrane-eyelid response , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  Michael D Mauk,et al.  Cerebellar cortex contributions to the expression and timing of conditioned eyelid responses. , 2010, Journal of neurophysiology.

[19]  Michael D Mauk,et al.  A Subtraction Mechanism of Temporal Coding in Cerebellar Cortex , 2011, The Journal of Neuroscience.

[20]  S. Lisberger Neural basis for motor learning in the vestibuloocular reflex of primates. III. Computational and behavioral analysis of the sites of learning. , 1994, Journal of neurophysiology.

[21]  J. J. Siegel,et al.  Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning. , 2012, Journal of neurophysiology.

[22]  M. Mauk,et al.  Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses , 1998, Neuropharmacology.

[23]  Ben Deverett,et al.  Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning , 2017, Nature Neuroscience.

[24]  J. Krakauer,et al.  Error correction, sensory prediction, and adaptation in motor control. , 2010, Annual review of neuroscience.

[25]  Richard B. Ivry,et al.  Multidimensional sequence learning in patients with focal basal ganglia lesions , 2005, Brain and Cognition.

[26]  Michael D Mauk,et al.  Temporal patterns of inputs to cerebellum necessary and sufficient for trace eyelid conditioning. , 2010, Journal of neurophysiology.

[27]  V. Bracha,et al.  A long-range, wide field-of-view infrared eyeblink detector , 2006, Journal of Neuroscience Methods.

[28]  A. Person,et al.  Cerebellar premotor output neurons collateralize to innervate the cerebellar cortex , 2015, The Journal of comparative neurology.

[29]  J. Mink THE BASAL GANGLIA: FOCUSED SELECTION AND INHIBITION OF COMPETING MOTOR PROGRAMS , 1996, Progress in Neurobiology.

[30]  N. M. Gerrits,et al.  Laterality in the vestibulo-cerebellar mossy fiber projection to flocculus and caudal vermis in the rabbit: A retrograde fluorescent double-labeling study , 1992, Neuroscience.

[31]  D. Lavond,et al.  The effects of reversible inactivation of the red nucleus on learning-related and auditory-evoked unit activity in the pontine nuclei of classically conditioned rabbits. , 1997, Learning & memory.

[32]  Timothy H. Murphy,et al.  Distinct Cortical Circuit Mechanisms for Complex Forelimb Movement and Motor Map Topography , 2012, Neuron.

[33]  Michel Desmurget,et al.  Motor Sequences and the Basal Ganglia: Kinematics, Not Habits , 2010, The Journal of Neuroscience.

[34]  Inah Lee,et al.  Associative Plasticity in the Medial Auditory Thalamus and Cerebellar Interpositus Nucleus during Eyeblink Conditioning , 2010, The Journal of Neuroscience.

[35]  Peer Wulff,et al.  Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice , 2015, Cell reports.

[36]  Leslie G. Ungerleider,et al.  Experience-dependent changes in cerebellar contributions to motor sequence learning , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Richard B. Ivry,et al.  Spatial and Temporal Sequence Learning in Patients with Parkinson's Disease or Cerebellar Lesions , 2003, Journal of Cognitive Neuroscience.

[38]  Richard B. Ivry,et al.  Sequence Learning is Preserved in Individuals with Cerebellar Degeneration when the Movements are Directly Cued , 2009, Journal of Cognitive Neuroscience.

[39]  Yosef Yarom,et al.  A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity , 2015, eLife.

[40]  J. Ashe,et al.  Neural correlates of encoding and expression in implicit sequence learning , 2005, Experimental Brain Research.

[41]  Joseph E. Steinmetz,et al.  Classical conditioning of the rabbit eyelid response with mossy fiber stimulation as the conditioned stimulus , 1985 .

[42]  A. Bastian Learning to predict the future: the cerebellum adapts feedforward movement control , 2006, Current Opinion in Neurobiology.

[43]  June-Seek Choi,et al.  Cerebellar neuronal activity expresses the complex topography of conditioned eyeblink responses. , 2003, Behavioral neuroscience.

[44]  Andrei Khilkevich,et al.  Relating Cerebellar Purkinje Cell Activity to the Timing and Amplitude of Conditioned Eyelid Responses , 2015, The Journal of Neuroscience.

[45]  D. Marr A theory of cerebellar cortex , 1969, The Journal of physiology.

[46]  W. Penfield,et al.  SOMATIC MOTOR AND SENSORY REPRESENTATION IN THE CEREBRAL CORTEX OF MAN AS STUDIED BY ELECTRICAL STIMULATION , 1937 .

[47]  Claudius F. Kratochwil,et al.  The Long Journey of Pontine Nuclei Neurons: From Rhombic Lip to Cortico-Ponto-Cerebellar Circuitry , 2017, Front. Neural Circuits.

[48]  J. J. Siegel,et al.  bridging the temporal gap in trace eyelid conditioning Persistent activity in a cortical-to-subcortical circuit : , 2011 .

[49]  J. W. Moore,et al.  Conditioned response timing and integration in the cerebellum. , 1997, Learning & memory.

[50]  D. Nicholson,et al.  Ontogeny of eyeblink conditioned response timing in rats. , 2003, Behavioral neuroscience.

[51]  Amy J Bastian,et al.  Cerebellar damage impairs internal predictions for sensory and motor function , 2015, Current Opinion in Neurobiology.

[52]  J. Doyon,et al.  Role of the Striatum, Cerebellum, and Frontal Lobes in the Learning of a Visuomotor Sequence , 1997, Brain and Cognition.

[53]  R. Parenti,et al.  Laterality of the pontocerebellar projections in the rat , 2002, The European journal of neuroscience.

[54]  M. Mauk,et al.  Cerebellar Cortex Lesions Prevent Acquisition of Conditioned Eyelid Responses , 1999, The Journal of Neuroscience.

[55]  Richard F. Thompson,et al.  Localization of a memory trace in the mammalian brain. , 1993, Science.

[56]  Umberto Castiello,et al.  The bilateral reach to grasp movement , 1993, Behavioural Brain Research.

[57]  George J Augustine,et al.  Precise Control of Movement Kinematics by Optogenetic Inhibition of Purkinje Cell Activity , 2014, The Journal of Neuroscience.

[58]  P. Strick,et al.  Cerebellar Loops with Motor Cortex and Prefrontal Cortex of a Nonhuman Primate , 2003, The Journal of Neuroscience.

[59]  M. Graziano,et al.  Complex Movements Evoked by Microstimulation of Precentral Cortex , 2002, Neuron.