Japanese Journal of Physiology, 34, 781-792, 1984

MINIREVIEW

The Modifiable Neuronal Network of the

M asao ITO

Department of Physiology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113 Japan

An outstanding feature of the cerebellum known since the classic histological work of Ramon y Cajal is the relative simplicity and highly ordered geometry of its neuronal network. The cerebellar neuronal network consists of five major types of cortical neurons (Purkinje, basket, stellate, Golgi, and granule cells), two major types of afferents (mossy and climbing fibers), and the subcortical cells in the vestibular and cerebellar nuclei. When the neuronal network structure of the cerebellum was comprehensively dissected and described in great detail in the 1960s, and summarized by ECCLES,ITO, and SZ.ENTAGOTHAI[8], it was taken as a challenge to understand more completely the complex functions of the using these fundamental studies of the brain as groundwork for future elucidation. As the gap between our understanding of the brain and our knowledge of neuronal networks is in general so large, hope has arisen that cere- bellar physiology may successfully fill the gap rather soon. Rigorous efforts using numerous newly-introduced techniques have been devoted during the past two decades, yielding remarkable progress that meets expectations at least to some extent. A number of problems remain to be solved, however, before we fully understand the cerebellum. It seems important at this point to review the major achievements of the past two decades in order to gain a clearer perspective of cerebellar physiology for the coming decade. I have recently written a monograph entitled "The Cerebellum and Neural Control" [23] in which I have taken this point of view. This article has a similar aim, but its theme is specifically centered around the plasticity of the cerebellar neuronal network and its function in cerebellar control mechanisms.

A. STRUCTURESOF THE CEREBELLARNEURONAL NETWORK Dissection of structures in the cerebellar neuronal network has advanced greatly in the 1970s with the aid of numerous new experimental techniques and materials, such as immunohistochemistry, marker techniques utilizing axonal flow, high voltage electronmicroscopy, intracellular dye injection, in vitro prep- arations, mutant animals, tissue cultures, etc. The success in identifying the

Received for publication August 18, 1984 伊藤正男

781 782 M. ITO synaptic action of cerebellar neurons in the 1960s was followed by efforts to specify neurotransmitters for these synaptic actions. It has now been established, or at least strongly suggested, that GABA mediates the inhibitory actions of Purkinje, basket, and Golgi cells, while taurine may mediate inhibition [42, 50]. Motilin, a 22-amino acid peptide, has been claimed to act as a neurotransmitter for a group of Purkinje cells [4], but the meaning of this chemical heterogeneity of Purkinje cells is not well understood. Since it is confirmed that motilin exerts inhibitory action on Deiters neurons which Purkinje cells innervate [3], there is not necessarily a conflict between the chemical heterogeneity and the functional exclusiveness of Purkinje cells as inhibitory neurons. Evidence has also ac- cumulated that gluatmate mediates the excitatory action of parallel fibers, i.e., axons of granule cells; while aspartate mediates the excitatory action of climbing fibers [49]. The neurotransmitters for minor groups of mossy fibers may include acetylcholine, substance P, or somatostatin. Since the 1970s, new elements thought to be incorporated in the cerebellar network include noradrenergic afferents arising from the locus ceruleus and serotonergic afferents arising from the raphe nuclei. Noradrenalin and serotonin may act to modulate other neurotransmitters rather than to mediate neurontransmission by themselves. Angiotensin-II-con- taining afferent fibers have also been found to impinge on Purkinje cells directly, and to modulate the action of GABA on them [46]. Despite this recent accumulation of new data, there are still details of the cerebellar neuronal network that remain obscure. 1) Lugarao cells in the granular layer of the cerebellar cortex have a distinct morphology and can be labeled with a specific monoclonal antibody [36]. Yet, neither their synaptic action nor neurotransmitter has been identified. 2) The neurotransmitters for the vast majority of mossy fibers remain un- known. 3) The functional implications of a variety of biochemical activities in cere- bellar neurons, involving cyclic GMP, cyclic AMP, calcium-binding proteins, prostaglandian D2 [48], and other enzymes and specific proteins, have not been clarified sufficiently. 4) The developmental evolution of the highly orderly cerebellar neuronal network remains largely obscure.

B. PLASTICITY OF CEREBELLAR SYNAPSES

The intriguing question whether the cerebellar neuronal network contains synaptic plasticity as a memory device has been raised. Opinions have split into two camps : one ignores or denies the existence of a memory device and assumes that the cerebellar neuronal network intrinsically contains elaborate, hard-wired logic in a structure of intricate connections; the other views the memory device as essential in the cerebellar neuronal network's capability for self-reorganization

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through learning. The latter argument originated from theoretical considerations of structures in the cerebellum, especially the characteristic dual innervation of cerebellar Purkinje cells with parallel fibers and climbing fibers. Parallel fibers are axons of granule cells in the cerebellar cortex, and of each receive numerous (about 80,000) excitatory synapses from parallel fibers. Climbing fibers are axons of inferior olive neurons, and dendrites of each Purkinje cell receive powerful excitatory synapses from one . Stimulation of parallel fibers elicits simple spikes and that of climbing fibers complex spikes in Purkinje cells. Elaborating on Brindley's initial suggestion, MARR [35] assumed that conjunctive activation of parallel fibers and climbing fibers leads to facilita- tion of parallel fiber-Purkinje cell synapses, while ALBUS[1] postulated the op- posite, i.e., depression of synaptic transmission. Based on these assumptions of plasticity, theories of the cerebellar neuronal network incorporating learning capabilities have been developed [1,11, 14, 35]. Assumptions of plasticity can be tested experimentally by stimulation of parallel fibers and climbing fibers, but tests performed early in the 1970s ap- parently failed to support the idea. Only indirect evidence was derived from the correlation of observed Purkinje cell behavior with adaptive modification of the rabbit's vestibulo-ocular reflex during visual-vestibular interactions [21] and also with adaptive adjustment of the monkey's hand movement to sudden load changes [14]. Direct evidence in support of the plasticity assumptions has been obtained very recently and has now been confirmed with a variety of testing methods, including: 1) Indirect stimulation of parallel fibers via afferents in con- junction with stimulation of climbing fibers, and recording from individual Purkinje cells with an extracellular microelectrode [27]. 2) Conjunctive stimulation of parallel fibers and climbing fibers, and record- ing of mass field potentials from the molecular layer of the cerebellar cortex [25]. 3) Conjunctive stimulation of parallel fibers and climbing fibers, and record- ing from individual Purkinje cells [12]. 4) Application of glutamate, i.e., the putative neurotransmitter for parallel fibers to Purkinje cells, in conjunction with climbing fiber stimulation [27]. These studies have consistently revealed that parallel fiber-Purkinje cell synapses undergo a long-term change in transmission efficacy subsequent to con- junctive stimulation of the parallel and climbing fibers. The change observed has been a depression, in conformity with ALBUS'assumption [1]. No evidence has been obtained for facilitation. The reasons that this important phenomenon, the long-term depression (LTD), has been overlooked in earlier studies can now be elucidated. 1) In earlier studies, climbing fibers were stimulated at a too-high frequency, so that a generally depressed status was produced in Purkinje cells, masking sub- sequent observation of parallel fiber-Purkinje cell transmission [27]. Low-

Vol. 34, No. 5, 1984 784 M. ITO frequency stimulation of climbing fibers at 1-4 Hz is adequate for producing the LTD. 2) Mass field potentials were observed in order to test parallel fiber-Purkinje cell transmission. These potentials are, however, a rather insensitive index for representing parallel fiber-Purkinje cell transmission, because many other cortical cells (basket, stellate, and Golgi cells) are also activated by parallel fiber stimula- tion [27]. 3) Parallel fibers were strongly stimulated, which might have activated stellate cells. It is now apparent that stellate cell inhibition on Purkinje cell dendrites prevents the LTD (see below). Attempts to reproduce the LTD in vitro, i.e., in slices of the cerebellum or artificially irrigated cerebella [32], have so far been unsuccessful. These negative observations, however, do not nullify the plasticity assumptions, because in vitro preparations may be devoid of subtle conditions prerequisite to the LTD. Con- sidering that studies of synaptic plasticity in the hippocampus and Aplysia have been greatly facilitated by in vitro experiments, it seems highly desirable that the missing conditions for reproducing the LTD in vitro be discovered. It is now apparent that the LTD is the physiological counterpart of the synaptic plasticity postulated theoretically as the memory device of the cerebellar neuronal network. However, properties of the LTD deviate somewhat from the initial theoretical assumptions. In particular, the timing of effective conjunc- tions of parallel fiber and climbing fiber stimulation is allowed a relatively wide latitude, as contrasted with the critical timing postulated by MARK[35]. Stimulated parallel fiber impulses during the period between 20 msec prior and 150 msec subsequent to the stimulation of climbing fibers are all nearly equally potent in inducing the LTD. Even those occurring at 250 msec after a climbing fiber im- pulse induced the LTD, though with less probablity (Ekerot and Kano, personal communication). Therefore, the conjunctive stimulation of parallel fiber and climbing fiber impulses does not need to be critically timed; rather, the LTD may depend on some variable factor such as enhancement of the correlation between the firing of parallel fibers and that of climbing fibers [14]. The latter idea fits the characteristically irregular pattern of climbing fiber discharge with which critical timing for collision with parallel fiber discharge seems to be unrealistic. The mechanism of the LTD also appears to be different from the initial theo- retical assumptions. MARK [35] considered two possibilities. First, coinciding presynaptic and postsynaptic impulse activity may lead to a changed synaptic transmission efficacy, as originally postulated by Hebb. However, the Hebbian type of mechanism does not seem to apply with the LTD, as repetitive stimulation of parallel fibers does not induce it, in spite of the fact that these stimuli do induce postsynaptic firing of Purkinje cells [27]. The second possibility is that climbing fiber terminals liberate a "change" substance which induces the LTD. The "change" substance might be something like thyrotropin-releasing hormone

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(TRH), which selectively depresses glutamate sensitivity in cerebral pyramidal cells [44]. This second possibility, however, does not seem likely either, because the LTD is prevented by stellate cell inhibition in Purkinje cell dendrites [9], which is difficult to explain if the existence of some "change" factor is assumed. TRH, when iontophoretically applied, indeed depressed the sensitivity of Purkinje cells to simultaneously applied glutamate, but this effect diminished as soon as the TRH was withdrawn, suggesting no long lasting effect to be expected for a "change" factor (Ito and Kano, unpublished). A more likely possibility which has been proposed based on recent experimental evidence is that an inflow of Ca ions into Purkinje cell dendrites, induced by climbing fiber stimulation, increases the intra- dendritic Ca concentration, which interferes in some way with glutamate receptor molecules in the parallel fiber-Purkinje cell synapses. Stellate cell inhibition prevents the LTD presumably because it depresses the plateau potentials in Purkinje cell dendrites, which represent Ca inflow provoked by stimulation of climbing fibers [10]. How, then, does the dendritic Ca-inflow interfere with parallel fiber synapses? It may induce a desensitization of receptor molecules [12]. Or, it may cause a change in the shape of dendritic spines which are the sites of parallel fiber-Purkinje cell synapses. These spines are 1.5 to 2.0 um long with a head diameter of 0.4- 0.5 ,um. If the neck of a spine undergoes a constriction, there will be an increase in the electrical resistance through the shaft of the spines. This could, in certain conditions, effectively reduce the synaptic current flowing into the dendritic shaft. This possibility is analogous, though the direction of the postulated change in the spine shape is the opposite, to what has been assumed for plastic enhancement of synaptic efficacy: if the shaft of a spine shortens, there will be an increased efficacy of the postsynaptic currents in influencing the membrane potential in the dendritic shaft and the cell soma [29, 30]. Thus, the mechanism of the LTD should be further investigated with these various possibilities in mind. It is noteworthy that the three different types of synaptic plasticity so far discovered in the cerebellar cortex, the hippocampal cortex, and the red nucleus are all glutaminergic. This is interesting in connec- tion with the suggestion that glutaminergic synapses are involved in cognitive memory functions [43]. Therefore, despite the unique features of the parallel fiber-climbing fiber interaction in the cerebellar cortex, there may be a common glutaminergic mechanism that underlies synaptic plasticity in the central nervous system in general.

C. OPERATION OF THE CEREBELLAR NEURONAL NETWORK

A small piece of the cerebellar cortex is connected to a small group of neurons in the vestibular or cerebellar nuclei. While the former receives climbing fibers from a small group of inferior olive neurons and mossy fibers from multiple

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sources, the latter receive collaterals of these climbing and mossy fibers. The cerebeluar corticonuclear microcomplex thus formed would represent a functional unit of the cerebellum which is incorporated into an extracerebellar motor or autonomic system to endow subtle control capabilities [23]. This model of the corticonuclear microcomplex has been postulated on the basis of accumulated anatomical and electrophysiological data, and a representative example has been found in an area of the cerebella that is specifically related to the hori- zontal vestibulo-ocular reflex (HVOR). A small zone of the flocculus, called the H-zone, projects Purkinje cell axons to relay cells of the HVOR in the , while these Purkinje cells receive vestibular signals through mossy fiber afferent pathways and visual signals through a climbing fiber pathway. This neuronal diagram, originally proposed early in the 1970s [17-19], suggests that the H-zone Purkinje cells adaptively modify the dynamic characteristics of the HVOR by changing the vestibular mossy fiber re- sponse under the influence of retinal error signals conveyed by the visual climbing fiber pathway. In other words, the H-zone Purkinje cells act as the adaptive con- trol center of the HVOR for which the visual climbing fiber pathway serves as an error-detecting system. Thus, the structure of the flocculo-HVOR system closely conforms to the proposed modifiable neuronal network model of the cerebellum. Demonstration of the remarkable adaptiveness of the HVOR by GoNSHOR and MELVILL-JONES[16] at about the same time that the flocculus H-zone control of vestibulo-ocular reflex was hypothesized, opened the way for experimental testing of that hypothesis. The HVOR undergoes an adaptive change in gain when a subject experiences sustained visual-vestibular interaction. In human subjects wearing dove prism goggles, which reverse the right-left relationship of the visual field, the HVOR is progressively reversed in polarity [16]. Monkeys wearing magnifying lenses exhibit an increase in the HVOR gain [37]. Sinusoidal rotation of an animal on the horizontal plane in combination with rotation of the surround- ing screen causes similar adaptive modification of the HVOR in various species [15, 28, 40, 47]. Outphase rotation of the screen causes an increase, while in- phase screen rotation causes a decrease of the HVOR gain. The "flocculus hypothesis of the vestibulo-ocular reflex control" is supported by lesion studies. Ablation of the flocculus or chemical destruction of floccular neurons with local application of kainic acid abolishes the adaptiveness of the HVOR, as demonstrated in rabbits [20, 40], cats [45], and monkeys [37]. Lesions of the dorsal cap of the inferior olive, i.e., the source of climbing fibers to the floc- culus, or severance of the visual pathway to the dorsal cap also lead to abolition of the HVOR adaptivenss [6, 26]. In microelectrode recordings from Purkinje cells in alert animals, the H-zone can be specified after local electrical stimulation that causes abduction of the ipsilateral eye, and also by the climbing fiber responses of Purkinje cells in this zone to horizontally moving optokinetic stimuli [7, 47]. Thus, the events described in H-zone Purkinje cells closely conform to the flocculus

Japanese Journal of Physiology NEURONAL NETWORK OF CEREBELLUM 787 hypothesis. I) Simple spike discharge from H-zone Purkinje cells is modulated by sinu- soidal head rotation [13, 31], and this modulation changes its pattern in parallel with the HVOR adaptation [7, 47]. The change confirms the expectation derived from the flocculus hypothesis that modification of vestibular responsiveness of flocculus Purkinje cells is the primary cause of the HVOR adaptation [22]. II) Complex spike discharge from H-zone Purkinje cells is also modulated by optokinetic stimuli involved in the visual-vestibular interaction [16, 47]. The modulation of complex spike discharge is reciprocal with the change in simple spike modulation. For example, when complex spike discharge from a Purkinje cell is modulated out of phase with the head rotation during sustained visual-ves- tibular interaction, the simple spike modulation of the same Purkinje cell progres- sively becomes less outphase or more inphase. These observations are consistent with the flocculus hypothesis that the retinal error signals conveyed by the visual climbing fiber pathway act to modify the simple spike activity by producing the LTD in the parallel fiber-Purkinje cell synapses that are simultaneously activated. Moreover, a simulation study with an adaptive filter model of the cerebellar neuronal network, which is based on the plasticity assumptions, was able to suc- cessfully reproduce with fidelity the adaptive modification of the HVOR, when the model was incorporated in the position of the flocculus in the block diagram of the oculomotor system [12]. Despite these positive lines of evidence, several objection have been raised against the flocculus hypothesis, which can be removed by careful reexamination. 1) In an early experiment on the flocculus of the monkey, changes in simple spike activity, as shown above in I), could not consistently be detected. This nega- tive observation was taken to indicate that the primate flocculus is devoted to a different function than the rabbit flocculus [38]. It is now evident, however, that the failure of the early experiment was due to an ignorance of the corticonuclear microcomplex structures of the cerebellum. Reexamination with specification of the H-zone revealed prominent changes in the simple spike modulation, similar to those reported in the rabbit flocculus [47]. 2) Data have been collected using albino rabbits as experimental subjects [7, 13, 24, 26]. Since an anomalous optokinetic responsiveness was discovered in albino rabbits [5], the general applicability of albino rabbit data has been ques- tioned. However, reexamination using pigmented rabbits as experimental sub- jects revealed an essential similarity between the data obtained from these two strains, except for certain quantitative differences [39-41]. 3) The initial assumption that simple spike modulation caused by head rota- tion represents vestibular mossy fiber responsiveness of Purkinje cells has been ques- tioned since mossy fiber signals representing eye velocity were also found to reach the flocculus. It might happen that a change in the simple spike modulation par- alleling an adaptive change of the HVOR is a mere reflection of the changed eye

Vol. 34, No. 5, 1984 788 M. ITO velocity, and has nothing to do with the vestibular responsiveness of Purkinje cells. This suspicion, however, has diminished with the results of the following two lines of experimentation. First, the actual eye velocity responsiveness of H- zone Purkinje cells was measured in the flocculus of the rabbit by eliciting eye movements uncontaminated with vestibular or visual mossy fiber signals, using electrical stimulation of the optic tract at a relatively low frequency [39]. It was discovered that the actual eye velocity responsiveness of H-zone Purkinje cells accounts for only a minor fraction of the simple spike responsiveness to head rota- tion and its adaptive alteration. Second, even when eye velocity was nullified by a chronic lesion of the rostra! vestibular nuclei in monkeys, the simple spike modulation and its adaptiveness in the H-zone Purkinje cells were preserved as in normal monkeys [47].

D. ROLES OF THE CEREBELLARNEURONAL NETWORK The applicability of the modifiable neuronal network model to the flocculo- VOR system now appears to be well supported. A similar model has been sug- gested for the floccular control of the optokinetic eye movement response (OKR). The nucleus reticularis tegmenti pointis mediates visual signals to the flocculus via mossy fibers [33] and at the same time relays them to vestibular nuclei, either directly [2] or indirectly [34]. The H-zone of the flocculus thus forms sidepaths to both the VOR and OKR brain stem pathway, and acts to modify either the VOR or OKR by referring to visual climbing fiber signals. Optokinetic stimuli-induced modification of the simple spike modulation of H-zone Purkinje cells has recently been shown to be effective under sustained optokinetic stimulation that causes an adaptive increase of the OKR gain [41]. The fruitful outcome of studies of the flocculo-VOR and -OKR systems is encouraging, reinforcing efforts to dissect complex cerebellar systems into a number of unit organizations, each of which consists of a cerebellar corticonuclear micro- complex and an associated extracerebellar control system, either motor or auto- nomic. A climbing fiber pathway may convey error signals which provoke re- organization of the neuronal network in the cerebellar cortex and consequently adaptive modification of the overall performance of the control system. In other words, a cerebellar corticonuclear microcomplex incorporated into any bodily control system acts as a central calibrator to minimize errors in the system's per- formance. This view fits the classic description of the orthometric cerebellar function, represented by "dysmetria" in patients with cerebellar diseases. When two or more control systems act in concert, a corticonuclear complex might serve as a common calibrator for the combined systems, just as the floccular H-zone serves for adaptive control of both the VOR and OKR. This situation suggests a model of coordination, another classic concept of cerebellar function. Modeling of coordination with multiple reflex systems operating under the control

Japanese Journal of Physiology NEURONAL NETWORK OF CEREBELLUM 789 of a common cerebeller corticonuclear microcomplex seems a promising subject for both experimental and theoretical investigations in the future. The control models developed for reflexes must also be expanded to apply to voluntary motor control problems. A corticonuclear microcomplex may act as a central calibrator for a voluntary control system that involves the . It is necessary to isolate a suitable model from the complex cerebral- cerebellar relationships for such investigation. Moreover, it is important to discover a neuronal process that accounts for the motor learning which implies more than adaptation. The former is supported by memory of preceding experi- ences, while the latter is based only on experiences within the same trial [20]. An adaptive system thus modifies its performance in the same way no matter how many times the trials are repeated, while a learning system progressively improves its performance from trial to trial. The HVOR adaptation in fact takes a similar time course in each of repeated trials of visual-vestibular interaction. A neuronal correlate for the memory of preceding experiences is unknown at present, but it will be a major theme for investigation of the cerebellum and related structures. From this point of view, I would draw attention to the long-known dentato-rubro- olivary triangle as a likely candidate [23]. In this triangle, climbing fiber afferents which would act as an error detecting system are afforded a prominent supply of inputs from cerebellar nuclei. This may suggest that the error-detecting and parameter-setting device of the cerebellar control system, represented by the in- ferior olive, is by itself under control of the cerebellum. This arrangement seems to be similar to the design of a learning control system in which the error-detecting and parameter-setting device of an adaptive control system is attached to itself for modification.

SUMMARY Recent data of neuronal network structures of the cerebellum are reviewed and experimental evidence is presented for the hypothesis that parallel fiber synapses on Purkinje cells retain plasticity which provides a memory device to the cerebellar cortical network. A corticonuclear microcomplex, consisting of a small area of the cerebellar cortex, a small group of cerebellar and vestibular nu- clear neurons, and a small group of inferior olive neurons, which are interconnected, is proposed to form a functional unit of the cerebellum. The idea that a corti- conuclear microcomplex endows an extracerebellar system with subtle control capabilities such as coordination, prediction, and adaptation-learning is supported with experimental data on the cerebellar control of the vestibulo-ocular reflex.

Key Words: cerebellum, Purkinje cell, plasticity, adaptation, motor control.

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