This manuscript reviews a series of experiments which support the notion that the cerebellum and more specifically the cerebellar cortex is principally involved in real time operations required for the regulation of coordinated motor activity. Experiments are reviewed which illustrate: (1) that the climbing fiber inputs to Purkinje cells can induce a short-lasting enhancement of their responses to mossy fiber-granule cell-parallel fiber inputs, (2) that the cerebellum is not essential for the acquisition and performance of the classically conditioned nictitating membrane reflex (NMR) of the rabbit, and (3) that the observations resulting from the microinjection of lidocaine and multiple single unit recordings within the brainstem support the notion that cell populations in this region may participate in establishing the modifications in neuronal interactions required for the acquisition of the conditioned NMR. In addition, preliminary data are shown comparing the capacity of a normal subject and a patient with a massive ipsilateral cerebellar stroke to learn certain tracing tasks and to redraw these learned tracing movements 90° to the orientation of the original image. The data support the notion that the cerebellum is essential, not for the initial learning of the tracing movement, but rather for performing the learned movement with the required rotation of the original image.

Intracellular recording was made from dentate nucleus neurons (DNNs) in anesthetized cats, to investigate cerebral inputs to DNNs and their responsible pathways. Stimulation of the medial portion of the contralateral pericruciate cortex most effectively produced EPSPs followed by long-lasting IPSPs in DNNs. Stimulation of the pontine nucleus (PN), the nucleus reticularis tegmenti pontis (NRTP) and the inferior olive (IO) produced monosynaptic EPSPs and polysynaptic IPSPs in DNNs. The results indicate that the excitatory input from the cerebral cortex to DNNs is at least partly relayed via the PN, the NRTP and the 10. Intraaxonal injection of HRP visualized the morphology of mossy fibers from the PN to the DN and the cerebellar cortex. The functional significance of the excitatory inputs from the PN and the NRTP to the DN is discussed in relation to the motor control mechanisms of the cerebellum.

Most descriptions treat the cerebellum as a uniform structure, and the possibility of important regional heterogeneities in either chemistry or physiology is rarely considered. However, it is now clear that such an assumption is inappropriate. Instead, there is substantial evidence that the cerebellum is composed of hundreds of distinct modules, each with a precise pattern of inputs and outputs, and expressing a range of molecular signatures. By screening a monoclonal antibody library against cerebellar polypeptides we have identified antigens – zebrins – that reveal some of the cerebellum’s covert heterogeneity. This article reviews some of these findings, relates them to the patterns of afferent connectivity, and considers some possible mechanisms through which the modular organization may arise.

Quantitative immunogold cytochemistry at the electron microscopic level was used to assess the endogenous contents of glutamate, aspartate, homocysteic acid, and glutamine (a precursor of glutamate) in the cerebellar climbing fiber terminals. Of the three excitatory amino acids, only glutamate appeared to be enriched in these terminals. The climbing fiber terminals also displayed immunoreactivity for glutamine. The level of aspartate immunoreactivity was far higher in the nerve cell bodies in the inferior olive than in their terminals in the cerebellar cortex. Homocysteic acid immunolabelling was concentrated in glial cells including the Golgi epithelial cells in the Purkinje cell layer. Our immunocytochemical data indicate that glutamate is a more likely climbing fiber transmitter than aspartate and homocysteic acid.

The results obtained with neuronal grafting in an animal model of heredo-degenerative ataxia (the pcd mutant mouse) have been extremely useful to unmask new aspects of neural plasticity. The grafted embryonic Purkinje cells invade the deficient molecular layer of the host by migrating radially through adult Bergmann fibers. There, they start building their dendritic trees and, by promoting the axonal sprouting of specific adult neuronal population in a timed sequence, they receive appropriate synaptic contacts, starting ten days after grafting. Twenty-one days after grafting, the grafted Purkinje cells have acquired their adult dendritic pattern and synaptic investment. Both the detailed timetable and the nature of the cellular interactions between embryonic and adult neural cells are remarkably similar to those occurring during normal development. These results raise the possibility that embryonic Purkinje cells can induce in adult neural cells a new type of plasticity, that of recreating a permissive microenvironment for the synaptic integration of the grafted neurons, leading to the anatomical restoration of the cortical circuit of the mutant cerebellum.

The activity of single cells in the cerebellar and motor cortex of awake monkeys was recorded during separate studies of whole-arm reaching movements and during the application of force-pulse perturbations to handheld objects. Two general observations about the contribution of the cerebellum to the control of movement emerge from the data. The first, derived from the study of whole arm reaching, suggests that although both the motor cortex and cerebellum generate a signal related to movement direction, the cerebellar signal is less precise and varies from trial to trial even when the movement kinematics remain unchanged. The second observation, derived from the study of predictable perturbations of a hand-held object, indicates that cerebellar cortical neurons better reflect preparatory motor strategies formed from the anticipation of cutaneous and proprioceptive stimuli acquired by previous experience. In spite of strong relations to grip force and receptive fields stimulated by preparatory grip forces increase, the neurons of the percentral motor cortex showed very little anticipatory activity compared with either the premotor areas or the cerebellum.

This review describes some characteristics of patients with cerebellar lesions, including limb movements, changes in motor planning and disturbances in time-dependent perception. The delay in movement initiation can be explained by a delay in onset of movement-related discharge of neurons in motor cortex. Disorders of movement termination (hypermetria) are accompanied by asymmetric velocity profiles and by prolonged agonist and delayed antagonist EMG activity necessary to brake the movement. During complex movements in three-dimensional space, the cerebellum contributes to timing between single components of a movement, scales the size of muscular action, and coordinates the sequence of agonists and antagonists. The basic structure of motor programs is not generated exclusively within the cerebellum and patients with cerebellar lesions can use precuing information to improve their motor performance. Time-dependent perception in the auditory and visual domains are disturbed in patients with cerebellar lesions.

Synaptic plasticity plays a role in the learning capability of brain tissues. Long-term depression (LTD) of parallel fiber synapses in cerebellar Purkinje cells occurs when these synapses are activated in conjunction with climbing fiber synapses. Signal transduction mechanisms underlying LTD have recently been investigated extensively. It has also become apparent that climbing fiber signals encode errors in the motor performance of an animal. It is therefore hypothesized that learning proceeds in cerebellar tissues in such a way that error signals of climbing fibers act to depress by LTD those parallel fiber synapses responsible for the errors. The cerebellum contains a large number of corticonuclear microcomplexes. Each microcomplex is connected to an extracerebellar system and is presumed to endow the system with learning capability. The hypothesis accounts for the adaptation of the vestibuloocular reflex and probably also for other forms of motor and cognitive learning.

The circuitry of the cerebellum is quite well understood. The computation takes place in the cerebellar cortex, which functions in synchronized strips to provide excellent timing signals to the cerebral cortex and the spinal cord. The cerebellar cortex is also the site where error signals from other parts of the central nervous system are incorporated. For voluntary limb movements the cerebellular cortex is important for the timing of the innervation of the agonist and antagonist anterior horn neurons. It is also important for the temporal order of and precision in the execution of motor programs. As will be apparent, the cerebellum is not only a computer taking care of motor programs.

A review concerning the characteristics of the cerebellar serotoninergic system is presented. In rat, cat and oppossum, the perikarya of origin are located in the brain stem raphe nuclei and in other brainstem structures. The projections to the cerebellar layers and deep nuclei include synaptic connections, but also non synaptic terminals, espedaily in a diffuse cortical plexus. Serotoninergic receptors have been described: 5-HT1B in the molecular layer and 5-HT2 in the inferior olive. Serotonin exerts neurophysiological effects on several target cells, directly or indirectly, presynaptically or postsynaptically. A modulatory effect on Purkinje cells is well documented. In thiamine deprived animals, a specific serotoninergic cerebellar syndrome includes a selective degeneration of the serotoninergic cerebellar system, an increase of the 5-HIAA cerebellar values and an exaggerated serotoninergic turnover. In human here-doataxias (Friedreich’s ataxia and cerebellar cortical atrophy), serotoninergic disturbances have been observed in the CSF, including low 5-HIAA values and an increased serotoninergic turnover. Therapeutic results have been obtained with L-5-HTP, a precursor of serotonin, in several conditions presenting cerebellar ataxia. L-5-HTP resistance of olivo-pontocerebellar atrophies may be explained by the destruction of serotonin-sensitive target cells, especially Purkinje cells.

A feature of cerebellar ataxia is dysmetria, which is characterized by inaccurate movements. Studies of rapid movements at a single joint show prolonged acceleration phases and prolonged initial bursts of EMG activity in the agonist muscle. These two features correlate with each other, suggesting that the prolongation of the neural signal is responsible for the kinematic abnormality. This explains a tendency to hypermetria. Studies of multijoint movements show abnormalities in relative timing of the different joints. During locomotion, knee and ankle motions can be delayed differentially with respect to the gait cycle. Subjects attempting straight-line movements with the arm have systematic deviations that reflect incoordination of the shoulder and elbow with respect to each other. A possible explanation of dysmetria is a failure of sufficient force generation within the necessary time to accomplish a coordinated movement. Another possible explanation is that the cerebellum is responsible for timing of brain functions.

A patient with an infarct in the distribution of the right superior cerebellar artery was studied with regard to his ability to make simple movements (visually triggered, self-terminated ballistic wrist movements), and compound movements (reaching to a visual target and precision pinch of a seen object). Movements on the right side of the body alone were affected. Control movements were made by the normal left upper extremity. Wrist movement on the right side was normal in reaction time, direction, peak velocity, and end-point position control ascompared to the left. By contrast, both reaching and pinching movements on the right were impaired. Reaching movements showed marked decomposition of the compound elbow-shoulder movement into seriatim simple movements madealternately at elbow and shoulder. Pinching movements were not made, and instead winkling movements (a movement of index alone) were substituted. These results are compared to similar results of controlled inactivation of the cerebellar dentate nucleus in monkeys. We conclude that one function of the cerebellum may be to combine elements in the movement repertoires of downstream movement generators. When that ability is lost, a strategy may be voluntarily adopted of using the preserved simple movements in place of the impaired compound movements.

In recent years, substantial progress has been made in understanding the organization and function of the cerebellum at the neuronal, synaptic, and molecular level. More than any other region of the brain, the cerebellum utilizes amino acids as its main excitatory and inhibitory transmitters. Excitatory amino acids, such as glutamate and aspartate, in addition to serving as chemical messengers, may also mediate neurodegenerative processes in human ataxic disorders. Of the monoamines, serotonin has been proposed as a neuromodulator in the cerebellum and is thought to play a role in the pathophysiology of ataxia in animal models, and human cerebellar disorders. These considerations raise the possibility that pharmacologic modification of amino acid and serotonergic transmission may provide a means for therapeutic intervention in ataxia.

Glutamate dehydrogenase (GDH), an enzyme central to glutamate metabolism, is significantly reduced in patients with heterogenous neurological disorders characterized by multiple system atrophy (MSA) and predominant involvement of the cerebellum and its connections. In human brain, GDH exists in multiple isoforms differing in their isoelectric point and molecular mass. These are differentially reduced in quantity and altered in catalytic activity in patients with clinically distinct forms of MSA, thus suggesting that these GDH isoproteins are under different genetic control. Dysregulation of glutamate metabolism occurs in patients with GDH deficiency and is thought to mediate the disease’s neurodegeneration via neuroexcitotoxic mechanisms. This possibility is supported by additional data showing that glutamate binding sites are significantly decreased in cerebellar tissue obtained at autopsy from MSA patients. At the molecular biological level, several cDNAs specific for human GDH have been isolated recently and cloned. Northern blot analysis of various human tissues, including brain, has revealed the presence of multiple GDH-specific mRNAs. In addition, multiple GDH-specific genes are present in humans and these data are consistent with the possibility that the various GDH isoproteins are encoded by different genes. These advances have laid the groundwork for characterizing the human GDH genes and their products in health and disease.

Paraneoplastic cerebellar degeneration is a rare complication of a number of cancers, particularly small cell lung cancer, gynecologic cancers and Hodgkin’s disease. The disorder is clinically characterized by rapid development of pancerebellar dysfunction, which usually does not improve, and pathologically characterized by loss of Purkinje cells with or without inflammatory infiltrates. In some but not all patients, an autoantibody that reacts with the tumor and Purkinje cells can be found in the serum and spinal fluid of patients with paraneoplastic cerebellar degeneration. The presence of the autoantibody suggests, but does not prove, that the disorder has an autoimmune mechanism for its pathogenesis.

Cerebellar ataxia is a common presenting sign in the Wernicke-Korsakoff syndrome (WKS). Recovery from ataxia following thiamine treatment is rarely complete, suggesting the existence of both a reversible (“biochemical”) lesion as well as irreversible, neuropathological damage. Cerebellar pathology in WKS includes severeloss of Purkinje cells in superior cerebellar vermis as well as neuronal loss from the granular layer. In addition, damage to inferior olivary nucleus could result in loss of climbing fibre input to cerebellum in this condition. Experiments using an animal model of WKS, the pyrithiamine-treated rat, reveal selective reversible decreases of α-ketoglutarate dehydrogenase (αKGDH) in cerebellum. Decreased enzyme activities are associated with decreased cerebellar content of GABA and aspartate. Thiamine reversal of neurological symptoms results in normalization of cerebellar enzyme activities and GABA content suggesting that reduced activities of αKGDH constitute “the biochemical lesion” in these animals. Possible mechanisms implicated in neuronal cell death in cerebellum include impaired cellular energy metabolism, focal lactic acidosis and excitotoxic damage resulting from excess glutamate release mediated by Nmethyl-D-aspartate (NMDA) receptors. Similar mechanisms could be involved in the reversible and irreversible neurological symptoms of WKS in humans.