Behavioural Significance of Cerebellar Modules

Authors: Nadia L Cerminara Richard Apps

Publish Date: 2010/09/14

Volume: 10, Issue: 3, Pages: 484-494

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Abstract

A key organisational feature of the cerebellum is its division into a series of cerebellar modules Each module is defined by its climbing input originating from a welldefined region of the inferior olive which targets one or more longitudinal zones of Purkinje cells within the cerebellar cortex In turn Purkinje cells within each zone project to specific regions of the cerebellar and vestibular nuclei While much is known about the neuronal wiring of individual cerebellar modules their behavioural significance remains poorly understood Here we briefly review some recent data on the functional role of three different cerebellar modules the vermal A module the paravermal C2 module and the lateral D2 module The available evidence suggests that these modules have some differences in function the A module is concerned with balance and the postural base for voluntary movements the C2 module is concerned more with limb control and the D2 module is involved in predicting target motion in visually guided movements However these are not likely to be the only functions of these modules and the A and C2 modules are also both concerned with eye and head movements suggesting that individual cerebellar modules do not necessarily have distinct functions in motor controlThe cerebellum has long been compartmentalised in order to aid the understanding of cerebellar function for review see 1 2 In particular a longitudinal organisation was first suggested by Jansen and Brodal 3 who divided the cerebellar cortex into lateral hemispheral intermediate paravermal and vermal compartments on the basis of their corticonuclear targets This tripartite division of the cerebellum was based upon the finding that Purkinje cells in each longitudinal division project topographically to a distinct cerebellar nucleus with the efferent connections of each nucleus in turn projecting to different descending pathways thereby controlling different aspects of movement both acquisition and execution In brief the vermal cortex projects preferentially to the fastigial medial and vestibular nuclei the paravermal cortex to the interpositus nucleus anterior and posterior subdivisions and the lateral cortex to the dentate nucleus That these different regions are to an extent functionally distinct was first suggested by Chambers and Sprague 4 5 who determined the classes of motor deficits that occurred after different cortical lesions For example lesion of the vermal cortex and the fastigius nucleus resulted in severe disturbance of axial muscle control and balance while ablation of the paravermal cortex and the underlying interpositus nucleus resulted in the impairment of voluntary goaldirected movements and disturbances of the postural ‘base’ for such tasksSimplified block diagram of cerebellar modules Each module is defined by its inferior olive climbing fibre input and Purkinje corticonuclear output From the medial to the lateral plane right to left in the figure are shown the A AX X B and A2 zones in the vermis the C1 CX C2 and C3 zones in the paravermis and the D1 D0 and D2 zones in the hemisphere Longitudinal zones in the paraflocculus and flocculus are not shown Note that some longitudinal zones are not necessarily present in all cerebellar lobules in the adult animal for example the X and B zones cMAO subnuc a subnucleus a of caudal medial accessory olive cMAO subnuc b subnucleus b of caudal medial accessory olive cMAO subnuc b 1 /c subnucleus b1 and c of caudal medial accessory olive dfDAO dorsal fold of dorsal accessory olive DLH dorsolateral hump DLP dorsolateral protuberance of medial nucleus dlPO dorsal lamella of the principal olive dmPO dorsomedial subnucleus of the principal olive ICG interstitial cell group iMAO lat lateral part of intermediate medial accessory olive iMAO med medial part of intermediate medial accessory olive LVN lateral vestibular nucleus MedN lat lateral part of medial nucleus MedN med medial part of medial nucleus NIA nucleus interpositus anterior NIP nucleus interpositus posterior NL lateral nucleus PML paramedian lobule rMAO rostral medial accessory olive vfDAO ventral fold of dorsal accessory olive vlPO ventral lamella of the principal olive Adapted from 7Many regard modules as a fundamental feature of cerebellar contributions to motor control and indeed other functions see for example 10 11 and it is now generally accepted that investigations of cerebellar function can be framed usefully in terms of their organisation 2 6 12 However despite detailed knowledge of the neuronal wiring of individual olivocorticonuclear modules and their recurrent connections for reviews see 13 14 the functional significance of these relationships remains far from clear The aim therefore of this short review is to consider some of the more recent evidence that cerebellar modules have differing behavioural significance We will focus on three modules each located in a different cerebellar compartment the vermal A module the paravermal C2 module and the lateral D2 module and with an emphasis on the olivocerebellar climbing fibre systemThe A module extends over the entire rostrocaudal length of the cerebellar vermis and is defined by its climbing fibre input originating from the caudal half of the medial accessory olive caudal MAO and its Purkinje cell corticonuclear projections to the fastigial nucleus The A module includes what is commonly referred to as the ‘oculomotor vermis’ lobules VI and VII of the posterior lobe 15 The caudal MAO primarily receives inputs from ascending somatic sensory pathways including direct inputs from the spinal cord dorsal column trigeminal vestibular optokinetic and tectal nuclei see 16 for a review Outputs from the fastigial nucleus involve connections with both ascending and descending motor pathways with the former including terminations in the contralateral superior colliculus 17 and visual structures of the midbrain and the latter including terminations in the vestibular nuclei and pontomedullary reticular formation 18 19 20 21 22 23 Mossy fibre inputs to the A module include the pontine nuclei and the nucleus reticularis tegmenti pontis NRTP which in turn receive afferents from amongst other structures the superior colliculus pretectum nucleus of the optic tract and subcortical visual and oculomotor centres see 19 for references 24Given the pattern of precerebellar sources and output targets of the A module its function is likely to be involved in the control and regulation of posture and balance as well as head and eye movements see 25 for a review Electrophysiological studies support such a tenet Purkinje cells in the oculomotor vermis discharge both simple spikes and complex spikes in relation to eye movements and head rotation whereas microstimulation evokes eye movements 26 27 28 29 30 31 32 33 34 see 35 for a review Chemical and mechanical lesions of the vermis and fastigial nucleus in monkeys have been shown to produce disturbances in balance and deficits in eye and head movements 36 37 38 39 40 41 Similarly in cats inactivation of caudal MAO or fastigius severely impairs balance head and trunk control with little or no deficits on voluntary limb movements such as reaching and grasping 42 43 In humans focal lesions to the cerebellar vermis causes balance impairments 44 45 and disturbances to smooth pursuit eye movements eg 46 The deficits produced by inactivation or lesion studies in both animals and humans are thus in agreement with the anatomical evidence suggesting a role for the A module in balance head and eye movement controlSurgical or localised delivery of pharmacological agents to induce lesions are unlikely however to be confined exclusively to discrete parts of a complexshaped nucleus such as the inferior olive without concurrent disturbance of neighbouring structures or fibres of passage An alternative approach to study the function of a whole module without affecting its neighbouring modules is by cortical injection of the retrogradely transported neurotoxin cholera toxin B conjugated to saporin 47 A related method is a systemic treatment with neurotoxins Llinas and coworkers 48 found that rats treated intraperitoneally with the pharmacological agent 3acetylpyridine 3AP resulted in destruction of the inferior olive and caused ataxic behavioural disturbances although some recovery of motor competence was observed after the initial acute loss Nevertheless even 6 months after the administration of 3AP the animals movements remained sluggish and a distinctive gait persisted termed ‘mudwalking’ characterised by exaggerated flexion of the limbs and an abnormal shift of body weight from one side to the otherRemoval of the olivocerebellar climbing fibre projection either acutely or chronically is also known to have a profound influence on Purkinje cell activity causing simple spikes to exhibit highly abnormal firing patterns eg 49 50 51 52 53 which may explain the severe motor deficits that occur after the inferior olive is damaged Global removal of the olivocerebellar projection therefore demonstrates that climbing fibre inputs to cerebellar modules are critical for normal cerebellar operation However an important limitation of 3AP is that it has been shown to cause the degeneration of neurones and fibres in areas of the brain besides the olive including the nucleus ambiguus hypoglossal nuclei substantia nigra dorsal motor nucleus X see 54 even when used in conjunction with the antidote nicotinamide which when administered 45 h following 3AP limits its CNS exposure and thus restricts the extent of neuronal degeneration 54 55 Thus the motor deficits observed with the use of 3AP may occur as a result not only of the removal of climbing fibre input to multiple if not all cerebellar modules but also due to neuronal degeneration in other brain structures that are implicated in motor function

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