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On the cerebellum and motor learning
On the cerebellum and motor learning Rodolfo Llin5s and John P Welsh New York University
Medical
Center, New York, USA
A critical review of the role of the cerebellum Specifically, olive
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in Neurobiology
Introduction Although much has been written about the possible role of the cerebellum in motor learning, many experimental findings disagree with this hypothesis. We wish to address the issue of motor learning, how it came to be believed that motor memories may be localized within the cerebellum, and why we disagree with this view. We present an alternative hypothesis, which emphasizes the role of the cerebellum and one of its major afferents, the inferior olive, in the coordination of movement.
viewed today?
Motor learning is a change in the accuracy and/or efficiency of movement, through practice, in order to produce a desirable or reinforcing outcome. When the desired outcome can be reliably obtained in successive attempts to perform the movement, it is agreed that a motor skill has been acquired and a memory for the motor skill has been established within the brain. This present day view is similar to that provided in 1890 by William James 111who believed motor skills to be instances of a larger class of behaviors, termed ‘habits’, which simplified movement, increased accuracy, and diminished fatigue. In James’ view, habits “economize(d) the expense of nervous and muscular energy” required to perform a movement 111.Whereas a child’s early attempts to walk, fasten a button, or tie a shoelace are slow and laborious, and require a sharp focus of attention, these acts are performed automatically and without concern in adulthood. The transformation of a motor act from a difficult and awk-
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evidence, at this time,
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It is concluded that there is no convincing
to support the view that a long-term
How is motor
in motor learning is presented. fibers that issue from the inferior
and
role for the
Future work in this
these two hypotheses.
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ward movement, requiring all of one’s attention, to a smooth and graceful movement, performed without effort, is the essence of motor learning.
Why is it believed
that motor
learning
is restricted
It has long been recognized that motor learning involves a neural process that is different from that involved in the learning of factual knowledge. For instance, motor skills are most easily acquired during childhood and may persist throughout a lifetime. Motor skills may not be performed over decades of years and yet be retained. Riding a bicycle, throwing and typing are familiar examples. In contrast, nonmotor memories, such as those of the Krebs’ cycle or Homer’s Odyssey, may be forgotten unless occasionally reviewed. The ability to learn and remember motor skills bears little relation to general intelligence in normal people. The belief that there is a neural process distinctly responsible for motor learning can be traced to the finding that non-motor learning is severely impaired by resection of the temporal lobe L&31.This finding suggested that memory was as discretely localized within the telencephalon as were sensory and speech functions. When it was found that a patient having undergone bilateral mesial temporal lobectomy had lost the ability to acquire new facts but not motor skills [41,the hypothesis of a separate substrate for motor learning was validated. More importantly, however, the finding of motor skill acquisition following temporal resection allowed for the hypothesis that a single locus of motor learning might be found if the proper lesion were
Abbreviations AMPA-a-3-hydroxy-5-methyl isoxazole_Q-propionic acid; CR-conditioned response; CS-conditioned stimulus; GABAqaminobutyric acid; HVOR-horizontal vestibule-ocular reflex; LT[)_long-term depression; UCR-unconditioned response; UCS-unconditioned stimulus.
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Biology
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specific brain site?
Ltd ISSN
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On the cerebellum and motor learning LlinL
discovered 141.Thus, the hypothesis of a ‘motor learning center’ developed as an analogy of a highly localizable process responsible for the acquisition of factual knowledge. Thirty-five years of research, however, has questioned the validity of the single memory store for factual knowledge, as it is now generally agreed that non-motor memories are distributed throughout the cerebrum [5-71. It is ironic that the concept of a center for motor learning has survived even though the model upon which it was predicated, that of a localized store for all factual knowledge, has been rejected. It is not difficult, however, to appreciate why the center hypothesis for motor learning endures, for, in the absence of data demonstrating distributed storage, the center hypothesis provides a simple, compartmentalized view of brain function that can be easily comprehended.
The conjecture: the cerebellar cortex as the locus of motor learning In 1969, Marr 181proposed that the function of the cerebellum was to learn motor skills. This initial hypothesis was then modified by Albus 191.These highly speculative proposals were inspired by the recently defined anatomy and physiology of the cerebellar cortex and Hebb’s postulate of modifiable-weight synapses. The fundamental assumption of both authors was that the two major inputs to the Purkinje cells in the cerebellar cortex (the parallel and climbing fibers) were organized such that the climbing fibers existed solely to modify the weight of the parallel fiber-Purkinje cell synapse. Together, the models not only localized motor learning to the cerebellum, they indicated a specific cell type in which to pursue the ‘engrams’ underlying motor memory. Both authors recognized that their theories depended entirely upon the conjecture of modifiable-weight synapses under the control of the climbing fibers. It is not commonly remembered that Marr later disavowed his hypothesis as a means of understanding the motor system 1101. The speculative models of motor learning were quickly embraced by a number of cerebellar physiologists because the models could conveniently explain a seemingly intractable enigma of the cerebellum: the function of the climbing fibers. It had been well known that the climbing fibers synapsed in a one-to-one manner with Purkinje cells in order to trigger the powerfully excitatory but infrequently occurring ‘complex spike’ 111,121. Prior to the Marr-Albus proposals 18,91, physiologists did not have a framework in which to understand the functional meaning of complex spikes [11,121. Whereas parallel fibers trigger simple spikes within Purkinje cells at about 6OHz, climbing fibers trigger complex spikes at an average rate of l-2Hz. Thus, it was questioned whether a single climbing fiber could meaningfully contribute to the output of a Purkinje cell, given that the Purkinje cell was already induced to fire at high rates by the thousands of parallel fibers synapsing within its dendritic tree 112,131.
and Welsh
When it was proposed that the climbing fiber could have an enduring influence on Purkinje cell output, one that distinguished it from the parallel fiber input and could account for the retention of motor skills (perhaps over decades of years), the long-lasting effects of the climbing fibers became the focus of attention for many investigating the function of the cerebellum.
The proposed basis for the cerebellum as a motor learning site The theoretical hypotheses of cerebellar learning were embraced by Ito 1141 who proposed, in experimental terms, a mechanism for cerebellar function based precisely on Albus’ formulation. It was proposed that, through learning, a modification of Purkinje cell responsiveness to parallel fiber input within the flocculus was responsible for the changes in the horizontal vestibulo-ocular reflex (I-NOR) that occurred through the lifetime of an animal. The I-NOR stabilizes retinal images by producing smooth and compensatory eye movements opposite in direction to the direction of head movement, in order to ensure visual acuity during head movement. A plasticity of this reflex was produced in a well-defined paradigm that combined rotation of the head with rotation of the visual field 1151. To modify the I-NOR, rabbits were sinusoidally rotated in the horizontal plane, while their visual world was rotated either in phase or out of phase with the head rotation. The magnitude of the eye movements elicited by head rotation was reduced by m-phase rotation of the visual field, whereas out-of-phase rotation of the visual field increased the magnitude of the eye movements. These changes were prevented by destruction of the flocculus 1151and the inferior olive 1161,which is consistent with a ‘teaching’ role for the climbing fibers and memory store within the cerebellar cortex. Based on the above findings, it was proposed that modification of the HVOR is induced by a change in the parallel fiber-Purkinje cell synapses under the control of the climbing fibers. During head rotation, the climbing fibers projecting to the flocculus were presumed to be driven by the slip of the visual image across the retina when the elicited eye movements would not permit visual acuity. By altering the weight of the parallel fiber-Purkinje cell synapses, the climb ing fibers were thought to modify cerebellar output on subsequent rotations of the head, and thereby change the magnitude of the eye movements. Another set of experiments has employed Pavlovian conditioning of the rabbit’s nictitating membrane response 117-201. In these experiments, rabbits are given contiguous presentations of an auditory or visual stimulus with a tactual stimulation of the cornea. Before conditioning, the auditory or visual stimulus does not elicit an overt nictitating membrane response, but cornea1 stimulation by a puff of air unconditionally elicits an nictitating membrane response (UCR). When the
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unconditioned stimulus WCS) of cornea1 air puff is reliably and repeatedly preceded by the visual or auditory conditioned stimulus (CS), an association between the two stimuli is formed, and the CS elicits the conditioned nictitating membrane response (CR). In the middle 1980s it was found that destruction of the anterior interpositus nucleus 1171 or simple lobule of the cerebellar cortex 1181 severely impaired or abolished the ability of rabbits to perform CRs. The deficit appeared to be selective for the CR and did not affect UCRs. It was immediately presumed that a modification in the weight of the parallel fiber-Purkinje cell synapses within the cerebellar cortex 1181 and/or the synapses of mossy fiber collaterals and interpositus neurons 1171was responsible for the learning and that, again, this process was under the control of the climbing fibers. This was an extremely seductive presumption, as the initial formulations of Marr and Albus l&91 regarding cerebellar learning were couched precisely in the vocabulary of Pavlovian conditioning. Climb ing fibers were presumed to ‘teach’ Purkinje cells to respond in a certain way to parallel fiber input, with the former serving as a UCS and the latter as a CS, just as the cornea1 air-puff UCS ‘teaches’ the rabbit to respond to the tone or light CS.
Has motor memory been localized to the cerebellum? After twenty years of research on ‘cerebellar learning’, the following questions can be posed. What evidence supports the hypothetical role for the climbing fibers in modifying Purkinje cell responsiveness to parallel fiber input and what is the relevance of this data? Has the study of HVOR modification and nictitating membrane response conditioning brought us any closer to understanding the operational principles of the cerebellum? The following points address these questions.
It remains to be demonstrated that a long-term influence of climbing fibers on Purkinje cells is a mechanism of cerebellar function
There are interesting pieces of data demonstrating that, under highly controlled conditions, a long-term depression (LTD) of Purkinje cell responsiveness to parallel fiber input may be induced by conjunctive climbing and parallel fiber stimulation. These experiments have been performed primarily with slices or cultures of cerebellar cortex. The mechanism for this depression is under investigation and involves a desensitization of the AMPA-selective glutamate receptor. LTD requires the induction of at least two intracellular processes (by a large influx of calcium through voltagegated calcium channels 1211), the first involving the activation of protein kinase C 122,231 and the second involving diffusion of nitric oxide into Purkinje cells,
synthesis of cGMP, and activation of protein kinase G 124-261. There are three problems in relating these findings to cerebellar function. Foremost, it has yet to be demonstrated in a well-defined behavioral paradigm that LTD operates within the cerebellum while a motor skill is acquired. In fact, a recent experiment of motor learning in a highly controlled behavioral paradigm could not find any evidence for climbing fiber modification of Purkinje cell activity associated with primates’ learning to perform a motor task with their arm 127”l. Second, LTD of Purkinje cell activity in vitro has only been demonstrated under harsh conditions that do not exist in the intact brain, requiring, for the most part, blockade of inhibitory transmission with GABA receptor antagonists or involving chronic exposure of glutamate receptor agonists. Third, demonstrations of LTD in vivo have only employed sustained and repetitive stimulations of cerebellar afferents that are not likely to exist under natural conditions. Maximal LTD is obtained by electrically stimulating the inferior olive at 4Hz for 25 to 120 seconds in close temporal conjunction with stimulation of mossy or parallel fibers 128-311. In contrast, inferior olivary neurons have an average firing rate of between l-2Hz, punctuated occasionally by 300-500 ms bouts of 6-10 Hz firing. More to the point, however, even if LTD should be proven to exist within the in vim cerebellum during normal function, the proof of its existence will not address the larger question of whether the cerebellum is the seat of motor learning.
it is unclear that the time-course of cerebellar LTD parallels the time-courses of motor skill acquisition and retention In order for cerebellar LTD to be considered the mechanism for motor learning, the temporal parameters of LTD and motor skill acquisition and retention must be similar. The rate of motor skill acquisition is highly variable and depends upon many factors. The acquisition of a motor skill can require hundreds or thousands of trials. Once acquired, motor skills can be retained with high fidelity over many years. In contrast, LTD is induced very rapidly, sometimes after only one or two bouts of conjunctive climbing and parallel fiber stimulation 128,311 and has been demonstrated under certain conditions to last on the order of hours 1291, although the time course has not been actively investigated. On the basis of the available evidence, LTD does not appear to have temporal properties that are consistent with a primary role in the physiology of motor learning.
It is unclear that modification of the HVOR involves a memory stored in the flocculus The evidence
that is cited in support of cerebellar learning during I-NOR modification is the finding that flocculectomy prevents modification of the HVOR 1151. Additional support comes from electrophysiological studies of Purkinje cell responsivity to head rotation
On the cerebellum and motor learning Llinds and Welsh
before and after modification of the HVOR. Reports have demonstrated changes in the phase or depth of modulation of Purkinje cell activity during head rotation in a direction consistent with the view that memory is stored in the flocculus [32-341. However, Purkinje cell simple spike firing in the flocculus is also driven by feedback from the oculomotor system, and so the interpretation of such changes is not always simple. It has been argued that changes in firing profiles after HVOR modification are not causally related to the modilication but are secondary to changes in eye velocity (1351; R Baker, AM Pastor, RR de la Cruz, JI Simpson, Sot Neu-
rosci Abstr 1992, 18:407X There is evidence that the brain stem contains sites of plasticity responsible for HVOR modification. The response properties of single neurons within the vestibular nuclei are altered during modification of the HVOR [36]. In addition, comparison of the firing latencies of floccular Purkinje cells with the latency of eye movements indicates that these cells become active at latenties that cannot account for the earliest components of the modified HVOR 1351. It has been suggested that the flocculus contains an essential pathway to the vestibular nucleus, through which retinal slip signals are transmitted via the mossy fiber afferent system 1351.That the memory which underlies the modification of the HVOR lies within the brain stem is supported by the observation that components of the modified HVOR are not affected by removal of the vestibulo-cerebellum [37**1.
There is substantial evidence demonstrating that the cerebellum is not required for Pavlovian conditioning
It has recently been demonstrated that Pavlovian conditioning of the nictitating membrane response is not affected by anesthesia of the interpositus nucleus 1191. This finding casts doubt upon the hypothesis that the memory for nictitating membrane response conditioning is localized to the interpositus nucleus. The loss of CRs induced by destructive lesions of the interpositus nucleus [17], therefore, results from a deficit in motor function and not from a deficit in learning. This conclusion is supported by direct evidence that interpositus or red nucleus lesions impair the motor system that expresses the CR ([38,391; V Bracha, ML Webster, JR Bloedel, Sot Neurosci Abstr 1992, l&1560; V Bracha, SL Stewart, JR Bloedel, Sot Neurosci Abstr 1989, 15507). Kinematic analyses indicate an impairment in long-latency components of the cornea1 reflex following interpositus lesions [4(r*l. The removal of the cerebellar cortex, including the paravernal and posterior lobe hemispheral cortex, neither prevents acquisition [411 nor abolishes the retention [42*1 of CRs, as does neither complete removal of the cerebellum in the decerebrate rabbit 1201. A recent experiment has indicated that learning can be impaired by the combined inactivation of the cerebellar cortex and deep nuclei 1431. Such a demonstration does not, however, indicate where memories are stored and does not clarify the operating principles of the cerebellum. Conversely, electrophysiological investigation of interposi-
tus neurons has cast doubt on the view that synaptic modification within this nucleus is responsible for nictitating membrane response conditioning, as virtually no representation of the sensory modalities that induce conditioning were found in this nucleus [44**1. Instead, interpositus neurons manifest an activity that is timelocked to the movement, again supporting a role for this structure in motor function. These conclusions are consistent with findings from Russia over the last 65 years that consistently demonstrated that the cerebellum is not required for the conditioning of a wide variety of reflexes in a wide variety of species (reviewed in [45*1).
An alternative hypothesis: climbing fibers, timing, and movement coordination An alternative view is that the climbing fiber system has an important role in the coordination of movement. This view is based upon a wealth of carefully analyzed data from a number of preparations that have allowed the study of the biophysical and structural characteristics of inferior olivary neurons, as well as their anatomical and physiological relations to the cerebellum. The climbing fiber system may be viewed as having a function clearly related to the coordination of movement, and not to the modification of the cerebellar cortex in order to store information. Neurons of the inferior olive possess a set of ionic conductances that produce oscillatory firing at approximately 10 Hz 146,471. The repetitive firing of individual olivary neurons is usually not sustained for longer than 500 ms. The critical conductance that is responsible for the oscillation is the T-type calcium channel, which generates the ‘low-threshold’ calcium spike. Olivary neurons are electrically coupled via dendrito-dendritic gap junctions 148,491,‘through which subthreshold oscillations in membrane potential or spike activity may be distributed [501. Electronic coupling among groups of olivary neurons permits multicellular oscillatory events to occur in the absence of all-or-none electroresponsiveness. Thus, neurons of the inferior olive possess intrinsic mechanisms that allow them to fire coherently as a synchronized and oscillatory neuronal ensemble. Coupling between olivaxy neurons ensures that sustained output iS not restricted by the limited cycle time over which individual neurons can oscillate. Electrophysiological analysis of the olivocerebellar system has demonstrated that oscillatory activity within the inferior olive may be recorded both at the level of the Purkinje cell and at the level of the cerebellar nuclei. In vivo research with many electrodes simultaneously implanted within the cerebellum also indicates that the olivocerebellar system tends to fire at a welldefined frequency that is close to 10Hz. This 10 Hz activity is limited to periods of 2W500ms that are separated by much longer intervals of 1 Hz activity. In vim measurements of the rhythmic activity within
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the olivocerebellar system has revealed highly synchronous firing, with intervals between the climbing fiber activation of parasagittally oriented Purkinje cells as short as a fraction of a millisecond 1511. In addition, experiments with many electrodes placed both on the cortical surface and in the depths of the cerebellar folia indicate that there is a close to constant conduction time between the inferior olive and the Purkinje cell, regardless of axonal length 152”l. Furthermore, it has been demonstrated, at the level of the cerebellar nuclei, that highly rhythmic inhibitory potentials may be obtained following synchronous activation of the inferior olive 1531. Thus, climbing fibers that activate Purkinje cells 1111, in turn, produce a well-orchestrated inhibition of the deep cerebellar nuclei. The final result is a well-defined influence on the rest of the nervous system via the cerebellar nuclei, which constitute the final output of the cerebellum.
Fig. 1. The functional organization of the olivocerebellar system. The olivocerebellar system consists of three elements: Purkinje cells (PCs); cerebellar nuclei neurons (CNs) (excitatory and inhibitory); and inferior olivary neurons (10s) (excitatory). 10s are electro-tonitally coupled (junctional contacts depicted by areas of overlap between short dendrites). Their axons project to the PCs as climbing fibers (clear arrows) and to the CNs via axon collaterals. For simplicity, only one of these collaterals is shown. The PCs project to the CNs (black arrows). Climbing-fiber activify fires PCs synchronously, generating powerful coherent inhibitory-postsynaptic potentials in the CNs. They follow the early excitation produced by the IO-axon-collateral systems. The inhibitory feedback implemented by CN inhibition to IO fgrey arrow in the lower left) projects to the IO glomeruli, the site of IO electro-tonic interaction. In these diagrams, 10s being electro-tonically coupled and intrinsically oscillating are viewed as pacemakers, which forward their rhythmic activity to the cerebellum via climbing fibers and axon collaterals. Activation of the CN inhibitory feedback to IO is viewed as a superimposed pattern generator that regulates, dynamically, the degree of coupling between IO neurons and, in this manner, the number of pacemaker groupings that may be active at any particular time in the IO. CNs not projecting to the inferior olive are excitatory and serve as pacemakers projecting to the forebrain, brain stem, and spinal cord. PCs are viewed as controlling the dynamic properties of the CN pattern generator. In this scheme, mossy- and climbing-fiber afferents ineract mainly at the CNs where maximum convergence of PC activity with afferent collateral activity takes place.
It is difficult to refute the fact that the climbing fiber has functions within the nervous system other than the alleged modification of the parallel fiber-Purkinje cell synapse. It is now well accepted, both at the anatomical and functional levels, that a significant fraction of the output of the cerebellum returns to the inferior olive, where it provides an inhibitory input, mostly at the sites of electrical coupling 154,551 (see Fig. 1). It is hypothesized that this inhibitory feedback produces a synaptic modulation of the electrical coupling between olivary neurons by shunting current away from gap junctions, in effect, fragmenting an entirely coupled nucleus into discrete clusters of coupled neurons. This has been supported by the observation that lesions of the deep nuclei dramatically increase the spatial breadth of synchronous climbing fiber activation of Purkinje cells, indicating an increased coupling among large groups of olivary neurons (EJ Lang, I Sug-
On the cerebellum and motor learning Llink and Welsh
ihara, R Llimis, Sac Newosci Abstr 1990, 16:894X The Inferior olivaty nucleus can thus be considered to be a pacemaker, which distributes highly rhythmic activity to the cerebellar cortex. The deep nuclei, in turn, distribute this rhythm to the rest of the nervous system. Through their inhibitory projections to the inferior olive, the deep nuclei dynamically uncouple the olivary nucleus into groups of coupled neurons, thereby determining the pattern of activity that is to be returned to the cerebellum. The relation between rhythmic activity within the inferior olive and a coordinated movement has become evident in recent experiments. In these experiments, the climbing fiber activity of about 35 Purkinje cells has simultaneously been recorded while rats protrude their tongue (IP Welsh, EJ Lang, I Sugihara, R Llinas, Sot Nettrasc~ Abstr 1992, 18:407; JP Welsh, R Llinb, Congr Intemat Union Physiol Sci Abstr 1933, 168.15). A highly significant temporal relation between rhythmic olivocerebellar activity and rhythmic movement has been revealed with this approach. We propose that this activity reflects olivary control of movement and this has been supported by correlating complex spike activity with individual muscle groups. The experiments further indicate that olivocerebellar coordination of movement is a distributed process that is not easily observed by recording the activity of individual Purkinje cells one at a time. The activity of the single neuron may not appear to be significantly related to particular instances of movement but the activity of groups of olivary neurons, producing distributed but synchronous activity within sets of Purkinje cells, is unambiguously related to movement. We hypothesize that distributed, synchronous, and rhythmic olivary activity becomes focused onto deep nuclear neurons in order to produce a highly significant and rhythmic modulation of the motor systems as movement proceeds. Future experiments will determine the validity of this hypothesis. At this time, however, the sum of the data outlined above indicates that the olivocerebellar system has a function in its own right - a function that is independent of the parallel fiber system and that is related to coordinated movement.
it is difficult to comprehend how an interdependence of the two systems could be the main operating principle for cerebellar function. From a different perspective, if the climbing fibers actually reduce the strength of the parallel fiber-Purkinje cell synapse, the responsivity of Purkinje cells to parallel-fiber input would be continuously changing during the execution of movement. That is, from the evidence that the climbing-fiber system is rhythmically active during movement, ‘motor memories’ would be altered by the act of moving itself, regardless of the suitability of the movement at hand. Moreover, during times of quiescence, previously stored motor memories would be distorted (or lost) by spontaneous climbing fiber input. From all of the above, it seems quite evident that the function of the cerebellum, and, in particular, the role of the olivocerebellar system will continue to generate interesting discussions. This is, in many ways, quite surprising given the enormous amount of detailed information presently available for this system from the evolutionary, developmental, morphological, biophysical, physiological, and pathological points of view.
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Thus, the two affercnt systems appear to function independently during this task. The authors conclude that the cerebellum is im-
portant for the refinement of movement but not for the storage of memories that undcdie motor skii. 28.
EKEROTC-F, KANO M: StimuIatIon Paramctcrs Inllucncing CIimbing Fibre Induced LongTerm Dcprcssion of ParaIIcI Fibtc Synapses. Neurosci Res 1989, 6:264-268.
29.
EKER~TC-F, KANOM: LowTerm Dcprcssion of Pa&cl Fibrc Synapses FoRowIng StimuIation of climbing FIhcrs. Emfn Res 1985, 342:357-360.
Basis for Learning of Simple Motor 1988, 242:728-735.
Modified Pathways for Motor Learning In the Primate VcstibuI&uIar Rcfla. Science 1988, 242:771-773.
PASTORAM, DE LA CRUZ RR, BAKER R: CcrcbclIar Role in Adaptation of the Goldfish VcstibuIoOcuIar Rcfla. J Neumpbysid 1994, in press. Thii study demonstrates that the neural plasticity underlying mod& cation of the HVOR in the goldfish lies in the brain stem, including withii the three-neuron arc of thii reflex, and not in the cerebellum. Acute cerebckctomy after HVOR modification impaired the long-latency components of the modiied HVOR without affecting the shortest latency-modified component related to head acceleration. In addition, the latency of Purkmje cell discharge elicited by vestibular or visual velocity steps was found to bc later than could be accounted for by a possible Involvement of the cerebellum in modifying the earliest components of the HVOR. In chronic cerebellcctomized and naive goldfish, the later components of the HVOR could be significantly increased or decreased by vestibular-visual stimulation. It was concluded that the vestibulo-cercbeUum is not likely to be the site where memories for the modified HVOR arc stored. Purkinje cell activity during HVOR modification sugggests that an Integration of visual, vestibular, and eye velocity signals may be important for the execution and full expression of the rcflex.
37. ..
38.
WELSHJP, HARVEY JA: CerchcIIar Lesions and the Nictitating Membrane Rcflcx: Rrformancc Dcliciw of the Conditioned and Unconditioned Rcsponsc. J Newasci 1989, 9~299-311.
39.
WELSHJP, HAR~ZYJA: ModuIatIon of Conditioned and Unconditioned Rcflaes. In l%e Olivccere&lkar @stem in Motor Control. Experimental Bmfn Resm-cb Se&s, vol 17. Edited by P Strata. Berlin-Heidelberg: Springer-Verlag; 1989:374379.
27. ..
OJAKANCA~ CL, EBNER T: Puddnjc Ccl1 Compla Spike Changes During a Voluntary Arm Movement Learning Task In the Monkey. J Neuropbvsiol 1992, 68:2222-2236. . . . . . . . . This study tested the hypothesis that a moduIation ot simple spike activity of Purkinjc cells during motor learning is induced by cIiibiig fiber activation. A well defined paradigm of motor learning required monkeys to perform amr movements under visual guidance. By altering the visuaI feedback, the experimenters introduced errors Into monkeys’ arm movements, in turn, causing the subjects to rescaIe thcii movement. It was found that a subset of Purkinje cells altered their rate of firing simple or complex spikes during the rescahng of arm movements, but that the changes In simple spike firing were not t&ted to the change in complex spike fir@, as wouId be predicted by the Man-AIbus formulations [8,91 of cercbcku function.
Skills. Sctice
WELCHJP: Changes in the Motor Pattern of Lcamcd and Unlearned Rcsponscs Following CercbcIIar Lesions: a KinematIc AnaIysii of the Nictitating Membrane Response Neuroscience 1992, 47:1-19. This study employed kinematic analyses of nictitating membrane rcsponses to invest&ate the nature of the motor dcftcits that are induced by ccr&eUar damage. It was demonstrated that CRs of normal amplitude before ccr&eUar lesions accelerated In two stages. Cercbe&r lesions that impaired CR amplitude reduced the magnitude of the second acceleration component but did not affect the earIy acceleration component. Analysis of UCRs a&r interpositus lesions revealed a sign&ant reduction in their acceleration that was man& festcd only after the UCR attained a threshold amplitude. This deficit was observed across a wide range of comcal air-puff intensitiis consistent with a role for the cerebellum In n@atii the polysynaptic component of the comeal reflex. It was concluded that the involvement of the cerebellum In this widely studied reflex is not ditTerent than that recognized for many other behaviors, namely, one of mod40. ..
On the cerebellum and motor learning Llinds and Welsh Inferior Ollvary Neuroncs In V&m. / Pb@ol (Zond) 1981, 315:56!%584.
ulating the degree to which long-latency neural systems contribute to the real-time performance of both learned and unlearned movement. 41.
L.AVOND DC, S?EINMFIZ JE: Acquisition of Classical Conditioning Without CcrebelIar Cortex. Bebau Brain Res 1989, 33:113-164.
48.
LUNAS R, BAKERR, S~TELO C: Elcctrotonic Coupling Bo tween Neurons in Cat Inferior Olive. J Nettropbysfol 1974, 37560-571.
42.
HARVEY JA, WELSHJP, YEO CH, ROMANOAG: Recoverable and Nonrecoverable Deficits in Conditioned Responses after Cerebellar Cortical Lesions. / Narroscf 1993, 13:1624-1635.
49.
SO?ELOC, Ltt~lis R, BAKERR: Structural Study of Inferior ORvary Nucleus of the Cat: Morphological Correlates of Electrotonic Coupling. J Nerrropbytol 1974, 37541-559.
43.
KRUPADJ, THOMPSON JK, THOMPWN RF: Localization of a Memory Trace in the Mammalian Brain. Science 1993, 260989-991.
50.
LLIN~ R, YAROM Y: Oscllkuory Properties of Guinea-pip In ferior Ollvaty Neurones and Their Pharmacological Mod& tion: an In V&m Study. J Pbysiol Gmc@ 1986, 376:163182.
GRUARTA, DELGADO-GARCIA JM: Discharge of Identified Deep Cerebellar Nuclei Neurons Related to Eyeblinks in the Alert Cat. Netrmscknce 1994, in press. A comprehensive study of the firing characteristics of neurons of the cerebellar deep nuclei during reflexive eyebllnks evoked by stimuli commonly employed during classical conditioning of this behavior. It was found that the firing of deep nuclear neurons, including the lnterpositus nucleus, during reflexive eye blinks followed the details of eyelid excursion. This finding suggests an important role for the deep nuclei ln the motor function associated with this reflex. Electroanatomical identification of the projection of these neurons indicated that the performance-related acitvity within the deep nuclei is dlstrlbuted throughout the brain stem and may be involved ln controlling the interplay of reciprocal motoneuronal activities that determines the displacement of the eyelid on a moment-to-moment basis.
51.
SASAKIK, BOWERJM, LLIN~ R: Multiple Purklnjc Cell Record ing ln Rodent CerebelIar Cortex. Enr J Netrmci 1989, 1:572-586.
44. ..
WELCH JP, H~~RVEY JA: The Role of the Cerebellum ln Voluntary and ReIIcdve Movements: History and Current Status. In I%? Cerebellum Revisited. Edited by Llimis R, Sotelo C. New York: Springer Vedag; 1992301334. A review of the history of research of cerebellar involvement in Pavlovian conditioned reflexes conducted ln Russia. This paper presents original figures of research beglnnlng with one of Pavlov’s students, NF Popov, on cerebellar regulation of the conditioned flexlon reflex, and the results of a number of Russian and Armenlan investigators that studied cerebellar regulation of conditioned flexlon, salivation, and cardiopulmonary reflexes ln a variety of species. It is noted that over this history of cerebellar research, investigators consistently emphasized the importance of the cerebellum ln motor functions permitting optimal expression of conditioned responses, but not ln leamlng. Thll research is placed in the context of hlstorlcal research performed ln the West by Rolando, Flourens, Lucianl and Holmes and current work on the conditioned eyebllnk.
45. .
46.
I&IN& R, YAROMY: Electrophysiology of Mammalian Inferior OIlvary Neurones in Vum Diierent Types of VoltageDependent Ionic Conductances. / Pbysfol @or& 1981, 315:549-567.
47.
h.IN,iS R, YAROM Y: Properties and Distribution of Ionic Con
ductances Generating Electroresponslveness
of Mammalian
SUGlHAR.4I,LANG EJ, LLlNi.5 R: Uniform OlIvocerebellar Con duction Time Underlies Purkinje Cell Complex Spike Sytt chronlcity ln the Rat Cerebellum. J Pbysfol &mdl 1993, 470~243271. This study employed multiple-electrode recording, latency, and anatomical measurements of climbing fibers to demonstrate that differential conduction velocity ln the cllmbll fiber system underlies the highly synchronous acivity that ls extant in the olivocerebellar system. Experiments revealed up to a 47% difference ln the length of climbing fibers projecting to different cerebellar lobules but a nearly identical conduction time. Long branches of climbing fiber axons were demonstrated to be thicker than short branches, accounting for the differential conduction velocity. The conclusion is that although the cerebellar cortex is spatially folded, it functions as an unfolded surface ln the time domain because the conduction time for the climbing fiber system is highly tuned.
52. ..
53.
LLIN.&SR, MUHLETHALER M: Elcctrophysiology of Guinea-P@ Cerebellar Nuclear Cells ln the in VurO BralnstemCerebeIlar Preparation. J Pbystol &wad) 1988, 404:241-258.
54.
DEZEEUWCl, HOSIEGE JC, RUICROK ‘IJH, VOO~D J: Ultrastructural Study of the GABAerglc, Cerebellar, and Mcso dlencephlc Innervation of the Medial Accessory Olive in the Cat: Antcrograde Tracing Combined with Immunocyto chemistry. J Comp Newvl 1989, 284:12-35.
55.
-LO C, Gorow T, WASSEF M: Localization of GlutamicAcid-Decarboxylase-Immunorea~ Axon Terminals ln the Inferior Olive of the Rat, with Special Emphasis on Anatomlcal Relations Between GABAergic Synapses and Dendroden drltlc Gap Junctions. J Comp Newvll986, 252:32-50.
R Lll&, JP Welsh, Department of Physiology and Biophysics, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA.
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A critical review of the role of the cerebellum Specifically, olive
the hypothesis
serve
evaluated.
to modify
that the climbing
the
responsiveness
either the basis of motor
learning
function.
An alternative
view,
ensemble
properties
olivocerebellar interesting
of olivary
modification
will
of movements.
in Neurobiology
Introduction Although much has been written about the possible role of the cerebellum in motor learning, many experimental findings disagree with this hypothesis. We wish to address the issue of motor learning, how it came to be believed that motor memories may be localized within the cerebellum, and why we disagree with this view. We present an alternative hypothesis, which emphasizes the role of the cerebellum and one of its major afferents, the inferior olive, in the coordination of movement.
viewed today?
Motor learning is a change in the accuracy and/or efficiency of movement, through practice, in order to produce a desirable or reinforcing outcome. When the desired outcome can be reliably obtained in successive attempts to perform the movement, it is agreed that a motor skill has been acquired and a memory for the motor skill has been established within the brain. This present day view is similar to that provided in 1890 by William James 111who believed motor skills to be instances of a larger class of behaviors, termed ‘habits’, which simplified movement, increased accuracy, and diminished fatigue. In James’ view, habits “economize(d) the expense of nervous and muscular energy” required to perform a movement 111.Whereas a child’s early attempts to walk, fasten a button, or tie a shoelace are slow and laborious, and require a sharp focus of attention, these acts are performed automatically and without concern in adulthood. The transformation of a motor act from a difficult and awk-
is is
of cerebellar
anatomical
suggests an important distinguish
cells
cell activity
mechanism
based on the biophysical, neurons,
system in the coordination
Opinion
Purkinje
evidence, at this time,
of Purkinje
or an authentic
area of neuroscience
Current
learning
of cerebellar
It is concluded that there is no convincing
to support the view that a long-term
How is motor
in motor learning is presented. fibers that issue from the inferior
and
role for the
Future work in this
these two hypotheses.
1993,
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ward movement, requiring all of one’s attention, to a smooth and graceful movement, performed without effort, is the essence of motor learning.
Why is it believed
that motor
learning
is restricted
It has long been recognized that motor learning involves a neural process that is different from that involved in the learning of factual knowledge. For instance, motor skills are most easily acquired during childhood and may persist throughout a lifetime. Motor skills may not be performed over decades of years and yet be retained. Riding a bicycle, throwing and typing are familiar examples. In contrast, nonmotor memories, such as those of the Krebs’ cycle or Homer’s Odyssey, may be forgotten unless occasionally reviewed. The ability to learn and remember motor skills bears little relation to general intelligence in normal people. The belief that there is a neural process distinctly responsible for motor learning can be traced to the finding that non-motor learning is severely impaired by resection of the temporal lobe L&31.This finding suggested that memory was as discretely localized within the telencephalon as were sensory and speech functions. When it was found that a patient having undergone bilateral mesial temporal lobectomy had lost the ability to acquire new facts but not motor skills [41,the hypothesis of a separate substrate for motor learning was validated. More importantly, however, the finding of motor skill acquisition following temporal resection allowed for the hypothesis that a single locus of motor learning might be found if the proper lesion were
Abbreviations AMPA-a-3-hydroxy-5-methyl isoxazole_Q-propionic acid; CR-conditioned response; CS-conditioned stimulus; GABAqaminobutyric acid; HVOR-horizontal vestibule-ocular reflex; LT[)_long-term depression; UCR-unconditioned response; UCS-unconditioned stimulus.
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Q Current
Biology
to a
specific brain site?
Ltd ISSN
0959-4388
On the cerebellum and motor learning LlinL
discovered 141.Thus, the hypothesis of a ‘motor learning center’ developed as an analogy of a highly localizable process responsible for the acquisition of factual knowledge. Thirty-five years of research, however, has questioned the validity of the single memory store for factual knowledge, as it is now generally agreed that non-motor memories are distributed throughout the cerebrum [5-71. It is ironic that the concept of a center for motor learning has survived even though the model upon which it was predicated, that of a localized store for all factual knowledge, has been rejected. It is not difficult, however, to appreciate why the center hypothesis for motor learning endures, for, in the absence of data demonstrating distributed storage, the center hypothesis provides a simple, compartmentalized view of brain function that can be easily comprehended.
The conjecture: the cerebellar cortex as the locus of motor learning In 1969, Marr 181proposed that the function of the cerebellum was to learn motor skills. This initial hypothesis was then modified by Albus 191.These highly speculative proposals were inspired by the recently defined anatomy and physiology of the cerebellar cortex and Hebb’s postulate of modifiable-weight synapses. The fundamental assumption of both authors was that the two major inputs to the Purkinje cells in the cerebellar cortex (the parallel and climbing fibers) were organized such that the climbing fibers existed solely to modify the weight of the parallel fiber-Purkinje cell synapse. Together, the models not only localized motor learning to the cerebellum, they indicated a specific cell type in which to pursue the ‘engrams’ underlying motor memory. Both authors recognized that their theories depended entirely upon the conjecture of modifiable-weight synapses under the control of the climbing fibers. It is not commonly remembered that Marr later disavowed his hypothesis as a means of understanding the motor system 1101. The speculative models of motor learning were quickly embraced by a number of cerebellar physiologists because the models could conveniently explain a seemingly intractable enigma of the cerebellum: the function of the climbing fibers. It had been well known that the climbing fibers synapsed in a one-to-one manner with Purkinje cells in order to trigger the powerfully excitatory but infrequently occurring ‘complex spike’ 111,121. Prior to the Marr-Albus proposals 18,91, physiologists did not have a framework in which to understand the functional meaning of complex spikes [11,121. Whereas parallel fibers trigger simple spikes within Purkinje cells at about 6OHz, climbing fibers trigger complex spikes at an average rate of l-2Hz. Thus, it was questioned whether a single climbing fiber could meaningfully contribute to the output of a Purkinje cell, given that the Purkinje cell was already induced to fire at high rates by the thousands of parallel fibers synapsing within its dendritic tree 112,131.
and Welsh
When it was proposed that the climbing fiber could have an enduring influence on Purkinje cell output, one that distinguished it from the parallel fiber input and could account for the retention of motor skills (perhaps over decades of years), the long-lasting effects of the climbing fibers became the focus of attention for many investigating the function of the cerebellum.
The proposed basis for the cerebellum as a motor learning site The theoretical hypotheses of cerebellar learning were embraced by Ito 1141 who proposed, in experimental terms, a mechanism for cerebellar function based precisely on Albus’ formulation. It was proposed that, through learning, a modification of Purkinje cell responsiveness to parallel fiber input within the flocculus was responsible for the changes in the horizontal vestibulo-ocular reflex (I-NOR) that occurred through the lifetime of an animal. The I-NOR stabilizes retinal images by producing smooth and compensatory eye movements opposite in direction to the direction of head movement, in order to ensure visual acuity during head movement. A plasticity of this reflex was produced in a well-defined paradigm that combined rotation of the head with rotation of the visual field 1151. To modify the I-NOR, rabbits were sinusoidally rotated in the horizontal plane, while their visual world was rotated either in phase or out of phase with the head rotation. The magnitude of the eye movements elicited by head rotation was reduced by m-phase rotation of the visual field, whereas out-of-phase rotation of the visual field increased the magnitude of the eye movements. These changes were prevented by destruction of the flocculus 1151and the inferior olive 1161,which is consistent with a ‘teaching’ role for the climbing fibers and memory store within the cerebellar cortex. Based on the above findings, it was proposed that modification of the HVOR is induced by a change in the parallel fiber-Purkinje cell synapses under the control of the climbing fibers. During head rotation, the climbing fibers projecting to the flocculus were presumed to be driven by the slip of the visual image across the retina when the elicited eye movements would not permit visual acuity. By altering the weight of the parallel fiber-Purkinje cell synapses, the climb ing fibers were thought to modify cerebellar output on subsequent rotations of the head, and thereby change the magnitude of the eye movements. Another set of experiments has employed Pavlovian conditioning of the rabbit’s nictitating membrane response 117-201. In these experiments, rabbits are given contiguous presentations of an auditory or visual stimulus with a tactual stimulation of the cornea. Before conditioning, the auditory or visual stimulus does not elicit an overt nictitating membrane response, but cornea1 stimulation by a puff of air unconditionally elicits an nictitating membrane response (UCR). When the
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unconditioned stimulus WCS) of cornea1 air puff is reliably and repeatedly preceded by the visual or auditory conditioned stimulus (CS), an association between the two stimuli is formed, and the CS elicits the conditioned nictitating membrane response (CR). In the middle 1980s it was found that destruction of the anterior interpositus nucleus 1171 or simple lobule of the cerebellar cortex 1181 severely impaired or abolished the ability of rabbits to perform CRs. The deficit appeared to be selective for the CR and did not affect UCRs. It was immediately presumed that a modification in the weight of the parallel fiber-Purkinje cell synapses within the cerebellar cortex 1181 and/or the synapses of mossy fiber collaterals and interpositus neurons 1171was responsible for the learning and that, again, this process was under the control of the climbing fibers. This was an extremely seductive presumption, as the initial formulations of Marr and Albus l&91 regarding cerebellar learning were couched precisely in the vocabulary of Pavlovian conditioning. Climb ing fibers were presumed to ‘teach’ Purkinje cells to respond in a certain way to parallel fiber input, with the former serving as a UCS and the latter as a CS, just as the cornea1 air-puff UCS ‘teaches’ the rabbit to respond to the tone or light CS.
Has motor memory been localized to the cerebellum? After twenty years of research on ‘cerebellar learning’, the following questions can be posed. What evidence supports the hypothetical role for the climbing fibers in modifying Purkinje cell responsiveness to parallel fiber input and what is the relevance of this data? Has the study of HVOR modification and nictitating membrane response conditioning brought us any closer to understanding the operational principles of the cerebellum? The following points address these questions.
It remains to be demonstrated that a long-term influence of climbing fibers on Purkinje cells is a mechanism of cerebellar function
There are interesting pieces of data demonstrating that, under highly controlled conditions, a long-term depression (LTD) of Purkinje cell responsiveness to parallel fiber input may be induced by conjunctive climbing and parallel fiber stimulation. These experiments have been performed primarily with slices or cultures of cerebellar cortex. The mechanism for this depression is under investigation and involves a desensitization of the AMPA-selective glutamate receptor. LTD requires the induction of at least two intracellular processes (by a large influx of calcium through voltagegated calcium channels 1211), the first involving the activation of protein kinase C 122,231 and the second involving diffusion of nitric oxide into Purkinje cells,
synthesis of cGMP, and activation of protein kinase G 124-261. There are three problems in relating these findings to cerebellar function. Foremost, it has yet to be demonstrated in a well-defined behavioral paradigm that LTD operates within the cerebellum while a motor skill is acquired. In fact, a recent experiment of motor learning in a highly controlled behavioral paradigm could not find any evidence for climbing fiber modification of Purkinje cell activity associated with primates’ learning to perform a motor task with their arm 127”l. Second, LTD of Purkinje cell activity in vitro has only been demonstrated under harsh conditions that do not exist in the intact brain, requiring, for the most part, blockade of inhibitory transmission with GABA receptor antagonists or involving chronic exposure of glutamate receptor agonists. Third, demonstrations of LTD in vivo have only employed sustained and repetitive stimulations of cerebellar afferents that are not likely to exist under natural conditions. Maximal LTD is obtained by electrically stimulating the inferior olive at 4Hz for 25 to 120 seconds in close temporal conjunction with stimulation of mossy or parallel fibers 128-311. In contrast, inferior olivary neurons have an average firing rate of between l-2Hz, punctuated occasionally by 300-500 ms bouts of 6-10 Hz firing. More to the point, however, even if LTD should be proven to exist within the in vim cerebellum during normal function, the proof of its existence will not address the larger question of whether the cerebellum is the seat of motor learning.
it is unclear that the time-course of cerebellar LTD parallels the time-courses of motor skill acquisition and retention In order for cerebellar LTD to be considered the mechanism for motor learning, the temporal parameters of LTD and motor skill acquisition and retention must be similar. The rate of motor skill acquisition is highly variable and depends upon many factors. The acquisition of a motor skill can require hundreds or thousands of trials. Once acquired, motor skills can be retained with high fidelity over many years. In contrast, LTD is induced very rapidly, sometimes after only one or two bouts of conjunctive climbing and parallel fiber stimulation 128,311 and has been demonstrated under certain conditions to last on the order of hours 1291, although the time course has not been actively investigated. On the basis of the available evidence, LTD does not appear to have temporal properties that are consistent with a primary role in the physiology of motor learning.
It is unclear that modification of the HVOR involves a memory stored in the flocculus The evidence
that is cited in support of cerebellar learning during I-NOR modification is the finding that flocculectomy prevents modification of the HVOR 1151. Additional support comes from electrophysiological studies of Purkinje cell responsivity to head rotation
On the cerebellum and motor learning Llinds and Welsh
before and after modification of the HVOR. Reports have demonstrated changes in the phase or depth of modulation of Purkinje cell activity during head rotation in a direction consistent with the view that memory is stored in the flocculus [32-341. However, Purkinje cell simple spike firing in the flocculus is also driven by feedback from the oculomotor system, and so the interpretation of such changes is not always simple. It has been argued that changes in firing profiles after HVOR modification are not causally related to the modilication but are secondary to changes in eye velocity (1351; R Baker, AM Pastor, RR de la Cruz, JI Simpson, Sot Neu-
rosci Abstr 1992, 18:407X There is evidence that the brain stem contains sites of plasticity responsible for HVOR modification. The response properties of single neurons within the vestibular nuclei are altered during modification of the HVOR [36]. In addition, comparison of the firing latencies of floccular Purkinje cells with the latency of eye movements indicates that these cells become active at latenties that cannot account for the earliest components of the modified HVOR 1351. It has been suggested that the flocculus contains an essential pathway to the vestibular nucleus, through which retinal slip signals are transmitted via the mossy fiber afferent system 1351.That the memory which underlies the modification of the HVOR lies within the brain stem is supported by the observation that components of the modified HVOR are not affected by removal of the vestibulo-cerebellum [37**1.
There is substantial evidence demonstrating that the cerebellum is not required for Pavlovian conditioning
It has recently been demonstrated that Pavlovian conditioning of the nictitating membrane response is not affected by anesthesia of the interpositus nucleus 1191. This finding casts doubt upon the hypothesis that the memory for nictitating membrane response conditioning is localized to the interpositus nucleus. The loss of CRs induced by destructive lesions of the interpositus nucleus [17], therefore, results from a deficit in motor function and not from a deficit in learning. This conclusion is supported by direct evidence that interpositus or red nucleus lesions impair the motor system that expresses the CR ([38,391; V Bracha, ML Webster, JR Bloedel, Sot Neurosci Abstr 1992, l&1560; V Bracha, SL Stewart, JR Bloedel, Sot Neurosci Abstr 1989, 15507). Kinematic analyses indicate an impairment in long-latency components of the cornea1 reflex following interpositus lesions [4(r*l. The removal of the cerebellar cortex, including the paravernal and posterior lobe hemispheral cortex, neither prevents acquisition [411 nor abolishes the retention [42*1 of CRs, as does neither complete removal of the cerebellum in the decerebrate rabbit 1201. A recent experiment has indicated that learning can be impaired by the combined inactivation of the cerebellar cortex and deep nuclei 1431. Such a demonstration does not, however, indicate where memories are stored and does not clarify the operating principles of the cerebellum. Conversely, electrophysiological investigation of interposi-
tus neurons has cast doubt on the view that synaptic modification within this nucleus is responsible for nictitating membrane response conditioning, as virtually no representation of the sensory modalities that induce conditioning were found in this nucleus [44**1. Instead, interpositus neurons manifest an activity that is timelocked to the movement, again supporting a role for this structure in motor function. These conclusions are consistent with findings from Russia over the last 65 years that consistently demonstrated that the cerebellum is not required for the conditioning of a wide variety of reflexes in a wide variety of species (reviewed in [45*1).
An alternative hypothesis: climbing fibers, timing, and movement coordination An alternative view is that the climbing fiber system has an important role in the coordination of movement. This view is based upon a wealth of carefully analyzed data from a number of preparations that have allowed the study of the biophysical and structural characteristics of inferior olivary neurons, as well as their anatomical and physiological relations to the cerebellum. The climbing fiber system may be viewed as having a function clearly related to the coordination of movement, and not to the modification of the cerebellar cortex in order to store information. Neurons of the inferior olive possess a set of ionic conductances that produce oscillatory firing at approximately 10 Hz 146,471. The repetitive firing of individual olivary neurons is usually not sustained for longer than 500 ms. The critical conductance that is responsible for the oscillation is the T-type calcium channel, which generates the ‘low-threshold’ calcium spike. Olivary neurons are electrically coupled via dendrito-dendritic gap junctions 148,491,‘through which subthreshold oscillations in membrane potential or spike activity may be distributed [501. Electronic coupling among groups of olivary neurons permits multicellular oscillatory events to occur in the absence of all-or-none electroresponsiveness. Thus, neurons of the inferior olive possess intrinsic mechanisms that allow them to fire coherently as a synchronized and oscillatory neuronal ensemble. Coupling between olivaxy neurons ensures that sustained output iS not restricted by the limited cycle time over which individual neurons can oscillate. Electrophysiological analysis of the olivocerebellar system has demonstrated that oscillatory activity within the inferior olive may be recorded both at the level of the Purkinje cell and at the level of the cerebellar nuclei. In vivo research with many electrodes simultaneously implanted within the cerebellum also indicates that the olivocerebellar system tends to fire at a welldefined frequency that is close to 10Hz. This 10 Hz activity is limited to periods of 2W500ms that are separated by much longer intervals of 1 Hz activity. In vim measurements of the rhythmic activity within
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the olivocerebellar system has revealed highly synchronous firing, with intervals between the climbing fiber activation of parasagittally oriented Purkinje cells as short as a fraction of a millisecond 1511. In addition, experiments with many electrodes placed both on the cortical surface and in the depths of the cerebellar folia indicate that there is a close to constant conduction time between the inferior olive and the Purkinje cell, regardless of axonal length 152”l. Furthermore, it has been demonstrated, at the level of the cerebellar nuclei, that highly rhythmic inhibitory potentials may be obtained following synchronous activation of the inferior olive 1531. Thus, climbing fibers that activate Purkinje cells 1111, in turn, produce a well-orchestrated inhibition of the deep cerebellar nuclei. The final result is a well-defined influence on the rest of the nervous system via the cerebellar nuclei, which constitute the final output of the cerebellum.
Fig. 1. The functional organization of the olivocerebellar system. The olivocerebellar system consists of three elements: Purkinje cells (PCs); cerebellar nuclei neurons (CNs) (excitatory and inhibitory); and inferior olivary neurons (10s) (excitatory). 10s are electro-tonitally coupled (junctional contacts depicted by areas of overlap between short dendrites). Their axons project to the PCs as climbing fibers (clear arrows) and to the CNs via axon collaterals. For simplicity, only one of these collaterals is shown. The PCs project to the CNs (black arrows). Climbing-fiber activify fires PCs synchronously, generating powerful coherent inhibitory-postsynaptic potentials in the CNs. They follow the early excitation produced by the IO-axon-collateral systems. The inhibitory feedback implemented by CN inhibition to IO fgrey arrow in the lower left) projects to the IO glomeruli, the site of IO electro-tonic interaction. In these diagrams, 10s being electro-tonically coupled and intrinsically oscillating are viewed as pacemakers, which forward their rhythmic activity to the cerebellum via climbing fibers and axon collaterals. Activation of the CN inhibitory feedback to IO is viewed as a superimposed pattern generator that regulates, dynamically, the degree of coupling between IO neurons and, in this manner, the number of pacemaker groupings that may be active at any particular time in the IO. CNs not projecting to the inferior olive are excitatory and serve as pacemakers projecting to the forebrain, brain stem, and spinal cord. PCs are viewed as controlling the dynamic properties of the CN pattern generator. In this scheme, mossy- and climbing-fiber afferents ineract mainly at the CNs where maximum convergence of PC activity with afferent collateral activity takes place.
It is difficult to refute the fact that the climbing fiber has functions within the nervous system other than the alleged modification of the parallel fiber-Purkinje cell synapse. It is now well accepted, both at the anatomical and functional levels, that a significant fraction of the output of the cerebellum returns to the inferior olive, where it provides an inhibitory input, mostly at the sites of electrical coupling 154,551 (see Fig. 1). It is hypothesized that this inhibitory feedback produces a synaptic modulation of the electrical coupling between olivary neurons by shunting current away from gap junctions, in effect, fragmenting an entirely coupled nucleus into discrete clusters of coupled neurons. This has been supported by the observation that lesions of the deep nuclei dramatically increase the spatial breadth of synchronous climbing fiber activation of Purkinje cells, indicating an increased coupling among large groups of olivary neurons (EJ Lang, I Sug-
On the cerebellum and motor learning Llink and Welsh
ihara, R Llimis, Sac Newosci Abstr 1990, 16:894X The Inferior olivaty nucleus can thus be considered to be a pacemaker, which distributes highly rhythmic activity to the cerebellar cortex. The deep nuclei, in turn, distribute this rhythm to the rest of the nervous system. Through their inhibitory projections to the inferior olive, the deep nuclei dynamically uncouple the olivary nucleus into groups of coupled neurons, thereby determining the pattern of activity that is to be returned to the cerebellum. The relation between rhythmic activity within the inferior olive and a coordinated movement has become evident in recent experiments. In these experiments, the climbing fiber activity of about 35 Purkinje cells has simultaneously been recorded while rats protrude their tongue (IP Welsh, EJ Lang, I Sugihara, R Llinas, Sot Nettrasc~ Abstr 1992, 18:407; JP Welsh, R Llinb, Congr Intemat Union Physiol Sci Abstr 1933, 168.15). A highly significant temporal relation between rhythmic olivocerebellar activity and rhythmic movement has been revealed with this approach. We propose that this activity reflects olivary control of movement and this has been supported by correlating complex spike activity with individual muscle groups. The experiments further indicate that olivocerebellar coordination of movement is a distributed process that is not easily observed by recording the activity of individual Purkinje cells one at a time. The activity of the single neuron may not appear to be significantly related to particular instances of movement but the activity of groups of olivary neurons, producing distributed but synchronous activity within sets of Purkinje cells, is unambiguously related to movement. We hypothesize that distributed, synchronous, and rhythmic olivary activity becomes focused onto deep nuclear neurons in order to produce a highly significant and rhythmic modulation of the motor systems as movement proceeds. Future experiments will determine the validity of this hypothesis. At this time, however, the sum of the data outlined above indicates that the olivocerebellar system has a function in its own right - a function that is independent of the parallel fiber system and that is related to coordinated movement.
it is difficult to comprehend how an interdependence of the two systems could be the main operating principle for cerebellar function. From a different perspective, if the climbing fibers actually reduce the strength of the parallel fiber-Purkinje cell synapse, the responsivity of Purkinje cells to parallel-fiber input would be continuously changing during the execution of movement. That is, from the evidence that the climbing-fiber system is rhythmically active during movement, ‘motor memories’ would be altered by the act of moving itself, regardless of the suitability of the movement at hand. Moreover, during times of quiescence, previously stored motor memories would be distorted (or lost) by spontaneous climbing fiber input. From all of the above, it seems quite evident that the function of the cerebellum, and, in particular, the role of the olivocerebellar system will continue to generate interesting discussions. This is, in many ways, quite surprising given the enormous amount of detailed information presently available for this system from the evolutionary, developmental, morphological, biophysical, physiological, and pathological points of view.
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OJAKANCA~ CL, EBNER T: Puddnjc Ccl1 Compla Spike Changes During a Voluntary Arm Movement Learning Task In the Monkey. J Neuropbvsiol 1992, 68:2222-2236. . . . . . . . . This study tested the hypothesis that a moduIation ot simple spike activity of Purkinjc cells during motor learning is induced by cIiibiig fiber activation. A well defined paradigm of motor learning required monkeys to perform amr movements under visual guidance. By altering the visuaI feedback, the experimenters introduced errors Into monkeys’ arm movements, in turn, causing the subjects to rescaIe thcii movement. It was found that a subset of Purkinje cells altered their rate of firing simple or complex spikes during the rescahng of arm movements, but that the changes In simple spike firing were not t&ted to the change in complex spike fir@, as wouId be predicted by the Man-AIbus formulations [8,91 of cercbcku function.
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WELCHJP: Changes in the Motor Pattern of Lcamcd and Unlearned Rcsponscs Following CercbcIIar Lesions: a KinematIc AnaIysii of the Nictitating Membrane Response Neuroscience 1992, 47:1-19. This study employed kinematic analyses of nictitating membrane rcsponses to invest&ate the nature of the motor dcftcits that are induced by ccr&eUar damage. It was demonstrated that CRs of normal amplitude before ccr&eUar lesions accelerated In two stages. Cercbe&r lesions that impaired CR amplitude reduced the magnitude of the second acceleration component but did not affect the earIy acceleration component. Analysis of UCRs a&r interpositus lesions revealed a sign&ant reduction in their acceleration that was man& festcd only after the UCR attained a threshold amplitude. This deficit was observed across a wide range of comcal air-puff intensitiis consistent with a role for the cerebellum In n@atii the polysynaptic component of the comeal reflex. It was concluded that the involvement of the cerebellum In this widely studied reflex is not ditTerent than that recognized for many other behaviors, namely, one of mod40. ..
On the cerebellum and motor learning Llinds and Welsh Inferior Ollvary Neuroncs In V&m. / Pb@ol (Zond) 1981, 315:56!%584.
ulating the degree to which long-latency neural systems contribute to the real-time performance of both learned and unlearned movement. 41.
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51.
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45. .
46.
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SUGlHAR.4I,LANG EJ, LLlNi.5 R: Uniform OlIvocerebellar Con duction Time Underlies Purkinje Cell Complex Spike Sytt chronlcity ln the Rat Cerebellum. J Pbysfol &mdl 1993, 470~243271. This study employed multiple-electrode recording, latency, and anatomical measurements of climbing fibers to demonstrate that differential conduction velocity ln the cllmbll fiber system underlies the highly synchronous acivity that ls extant in the olivocerebellar system. Experiments revealed up to a 47% difference ln the length of climbing fibers projecting to different cerebellar lobules but a nearly identical conduction time. Long branches of climbing fiber axons were demonstrated to be thicker than short branches, accounting for the differential conduction velocity. The conclusion is that although the cerebellar cortex is spatially folded, it functions as an unfolded surface ln the time domain because the conduction time for the climbing fiber system is highly tuned.
52. ..
53.
LLIN.&SR, MUHLETHALER M: Elcctrophysiology of Guinea-P@ Cerebellar Nuclear Cells ln the in VurO BralnstemCerebeIlar Preparation. J Pbystol &wad) 1988, 404:241-258.
54.
DEZEEUWCl, HOSIEGE JC, RUICROK ‘IJH, VOO~D J: Ultrastructural Study of the GABAerglc, Cerebellar, and Mcso dlencephlc Innervation of the Medial Accessory Olive in the Cat: Antcrograde Tracing Combined with Immunocyto chemistry. J Comp Newvl 1989, 284:12-35.
55.
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R Lll&, JP Welsh, Department of Physiology and Biophysics, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA.
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