ANATOMICAL AND PHYSIOLOGICAL FOUNDATIONS OF CEREBELLAR INFORMATION PROCESSING

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1 ANATOMICAL AND PHYSIOLOGICAL FOUNDATIONS OF CEREBELLAR INFORMATION PROCESSING Richrd Apps* nd Mrtin Grwicz Abstrct A coordinted movement is esy to recognize, but we know little bout how it is chieved. In serch of the neurl bsis of coordintion, we present model of spinocerebellr interctions in which the structure functionl orgnizing principle is division of the cerebellum into discrete microcomplexes. Ech microcomplex is the recipient of specific motor error signl tht is, signl tht conveys informtion bout n inpproprite movement. These signls re encoded by spinl reflex circuits nd conveyed to the cerebellr cortex through climbing fferents. This orgniztion revels slient fetures of cerebellr informtion processing, but lso highlights the importnce of systems level nlysis for fuller understnding of the neurl mechnisms tht underlie behviour. PARAVERMIS A region on either side of the midline of the cerebellum tht lies lterl to the vermis nd medil to the hemisphere. It contins the cerebellr corticl zones C1, C2 nd C3 nd receives climbing input from the inferior olive nd projects to the nucleus interpositus. Here, the term is used to denote the functionlly relted C1, C3 nd Y (but not the C2) zones. *Sensorimotor Control Group, Deprtment of Physiology, University of Bristol, University Wlk, Bristol BS8 1TD, UK. Division of Neuroscience, Deprtment of Experimentl Medicl Science, BMC F10, Lund University, Tornv. 10, , Sweden. Correspondence to M.G. e-mil: mrtin.grwicz@mphy.lu.se doi: /nrn1646 Published online 15 Mrch 2005 One of the mjor chllenges of systems neuroscience is to understnd the neurl bsis of perception nd behviour. Considerble progress hs been mde, for instnce, with regrd to the nlysis of the neurl mechnisms tht underlie visul perception. In lrge prt, this hs been chieved by using combintion of ntomicl trct trcing nd physiologicl chrcteriztion of neuronl receptive fields 1.By comprison, our understnding of movement control remins rther less complete. Nevertheless, over the pst decde or two, similr combintion of systems level ntomicl nd physiologicl pproches hs been used to unrvel some of the intriccies of n importnt sensorimotor control system, nmely the cerebellum. Fundmentl to the opertion of ny CNS structure is the informtion processing tht it ccomplishes. The cerebellum receives wide vriety of sensory inputs nd genertes motor-relted outputs ccording to internl rules of computtion. These rules re determined by the internl connectivity of cerebellr neuronl networks nd the intrinsic properties of cerebellr neurons. Consequently, the informtion content of its inputs together with the structurl orgniztion of the internl circuitry of the cerebellum imposes constrints on theoreticl models of cerebellr function. Effective communiction between ntomists, physiologists nd modellers is therefore essentil for understnding how the cerebellum contributes to the control of movement nd other processes. With this outlook in mind, the im of the present review is to summrize recent dvnces in our understnding of the ntomy nd physiology of n importnt region of the cerebellum the PARAVERMIS nd its influence on voluntry limb movements. The prvermis hs bundnt connections with the spinl cord, nd we present evidence to indicte tht key orgnizing principle is its subdivision into n rry of multizonl microcomplexes (MZMCs). The functionl orgniztion of these microcomplexes is thought to reflect spinl withdrwl reflex orgniztion. As result, individul cerebellr microcomplexes could be kept informed bout inpproprite movements tht is, MOTOR ERRORS tht re relted to elementry movements of limb, such s those tht result from contrctions of single muscles. By incorporting recent findings on intrinsic cerebellr corticl connectivity, we lso speculte on how this modulr rrngement might hve role in cerebellr contributions to movement control. It is importnt to emphsize, however, tht the model presented here is derived minly from studies of the NATURE REVIEWS NEUROSCIENCE VOLUME 6 APRIL

2 Prllel Prllel Moleculr lyer Moleculr lyer lyer Grnulr lyer Grnule lyer Climbing Mossy Grnulr lyer Grnule Mossy Cerebellr nucler Stellte Bsket xon Climbing Golgi To thlmus nd descending motor trcts From inferior olive From brin stem nuclei nd spinl cord MOTOR ERROR In the cse of motor commnds, the difference between the ctul motor commnd nd the correct commnd, or between the intended nd chieved movement. A simple exmple is the retinl slip signl, in which this difference is detected directly t the sensory surfce by specilized retinl gnglion s. GAIN The mplifiction fctor tht regultes the reltionship between input nd output, for instnce, in reflex circuit. TIMING THEORY Here, the term refers to Britenberg s ide tht prllel s provide dely lines for converting sptil ptterns into temporl ptterns. LEARNED PATTERN RECOGNITION THEORIES Here, the term refers to the theories of Mrr nd Albus, in which the cerebellum is viewed s sptil pttern recognition device with lerning cpcity. CONTROL THEORY Here, the term refers to conceptul frmework wherein engineering control principles re pplied to the modelling of CNS functions. Figure 1 Bsic structure of the cerebellr cortex. There re two min fferents to the cerebellr cortex: climbing s, which mke direct excittory contct with the s, nd mossy s, which terminte in the grnulr lyer nd mke excittory synptic contcts minly with grnule s, but lso with Golgi s. In some cses, the stem xons of climbing nd mossy s lso provide collterls to the cerebellr nuclei en route to the cerebellr cortex. The scending xons of the grnule s brnch in T-shped mnner to form the prllel s, which, in turn, mke excittory synptic contcts with s nd moleculr lyer interneurons tht is, stellte s nd bsket s. Typiclly, prllel s extend for severl millimetres long the length of individul cerebellr foli 134,135. With the exception of grnule s, ll cerebellr corticl neurons, including the s, mke inhibitory synptic connections with their trget neurons. Modified, with permission, from REF. 1 (2004) Sinuer Assocites. prverml cerebellum nd its connectivity with the spinl cord. The mnner in which cerebellr control systems re connected to other structures in the CNS might vry, nd this, in turn, might influence the role of ny given cerebellr region 2.Nevertheless, it is generlly ccepted (for resons given below) tht findings bsed on the investigtion of one prticulr region of the cerebellum should be pplicble to the cerebellum s whole. Concepts nd models of cerebellr function The importnce of the cerebellum in the coordintion of movement is undisputed 3 8, nd growing body of evidence indictes tht it might lso be involved in certin cognitive processes 9,10.Cerebellr networks show long-term synptic plsticity 11 14,which indictes tht experience-dependent dptive nd lerning processes re lso slient feture of cerebellr function Such dptive cpcity is key feture of mny current theories of cerebellr function. Indeed, modelling hs long trdition in cerebellr studies nd models differ in mny respects (see REF. 18 for review). Some models ddress the involvement of the cerebellum in specific reflex behviours, such s the dptive regultion of GAIN in the vestibulo oculr reflex (see REF. 19 for recent review), or the role of the cerebellum in clssicl conditioning of eye-blink reflexes (see REF. 20 for recent review). More generl cerebellr models rnge from those inspired chiefly by cerebellr cytorchitecture nd the physiologicl properties of its constituent neurons (historiclly strting with the TIMING THEORY 21 nd the LEARNED PATTERN RECOGNITION THEORIES 22,23 ) to those motivted more by CONTROL THEORY The model presented here builds on specific trdition tht emphsizes the division of the cerebellum into collection of modules defined by structure function reltionships. These modules re thought to form the bsis for informtion processing performed by the cerebellum 2,27,28. Bsic structure of the cerebellr cortex Throughout its highly convoluted extent, the cerebellum cn be divided into three corticl lyers with the sme bsic neuronl circuitry everywhere, which involves five min types (FIG. 1).The most conspicuous of these re the s, which form n orderly monolyer interposed between the grnulr nd moleculr lyers, extending their plnr dendritic trees into the moleculr lyer bove. As these s re the sole output neurons of the cerebellr cortex they re centrl to cerebellr corticl informtion processing. The grnulr lyer below the s derives its nme from the smll, densely pcked grnule s tht send their xons into the moleculr lyer, where they bifurcte to become prllel s (FIG. 1). These course prllel to the long xis of ech folium nd s result they intersect the fn-like dendritic trees of mny s. Mossy fferents trget grnule s nd, therefore, excite the s indirectly through the grnule prllel pthwy, which cuses the 298 APRIL 2005 VOLUME 6

3 Olivocerebellr rpml Cerebellr corticl sgittl zones Hemisphere Prvermis Vermis D2 Y D1 C3 C2 C1 B X A Inferior olive Cerebellr nuclei dipo vipo rdao cdao rmao mmao cmao D D/NIA NIA NIP LVN NIP/FN FN Spino olivry pthwys Rostrl V Corticonucler Descending motor trcts Figure 2 Connectivity of the cerebellum. The top pnel shows dorsl view of the ct cerebellum, indicting the pproximte loction of different sgittl zones on the cerebellr surfce. In the simplified block digrms below, mtching colours show, for individul cerebellr corticl zones, the sites of origin of climbing s in the contrlterl inferior olive, nd the corresponding corticonucler output trgets in the ipsilterl cerebellr nuclei. Different regions of the inferior olive receive signls from the spinl cord through n rry of spino olivry pthwys, nd individul cerebellr nuclei influence descending motor pthwys with different responsibilities in motor control. As result, zones locted in different regions of the cerebellr cortex re thought to be ssocited with different spects of motor control. For exmple, the C1, C3 nd Y zones receive input from the postsynptic dorsl column pthwy 58 through the rostrl prt of the dorsl ccessory olive nd output through the nucleus interpositus nterior (NIA) to the rubrospinl nd corticospinl trcts. These trcts re especilly concerned with the control of voluntry limb movements, such s wlking nd gol-directed reching 136,137. Lesions in experimentl nimls indicte tht the prvermis is importnt for precision limb movements such s skilled wlking 7,138 nd gol-directed reching An importnt principle seems to be tht coordintion is chieved by nticiptory control nd compenstion of inter-joint interctions chrcteristic of multi-joint limb movements 141. A diminished cpcity to generte such compenstory ctivity in predictive mnner seems to be crdinl cerebellr symptom in ll species studied, including mn 144,145. Conspicuously, cerebellr lesions result in deficits both of isolted rech nd isolted grsp, nd of the coupling between these two components of gol-directed movement 146. cdao, cudl prt of dorsl ccessory olive; cmao, medil ccessory olive; D, dentte nucleus; dlpo, dorsl lmell of the principl olive; FN, fstigil nucleus; LVN, lterl vestibulr nucleus; mmao, middle prt of medil ccessory olive; NIP, nucleus interpositus posterior; rdao, rostrl prt of dorsl ccessory olive; rmao, rostrl medil ccessory olive; rpml, rostrl foli of the prmedin lobule of the posterior lobe; V, lobule V c of the nterior lobe; vlpo, ventrl lmell of the principl olive. s to dischrge simple spikes (conventionl ction potentils). They lso contct vrious types of interneuron in the cerebellr cortex, both directly nd indirectly through the prllel s (not shown in FIG. 1). The other min clss of cerebellr fferent is the climbing s, which rise exclusively from the inferior olive, well-defined complex of sub-nuclei in the ventrl prt of the cudl brin stem (for further detils, see REFS 29 31). In mrked contrst to the indirect influence of mossy s, the climbing s mke direct synptic contct with s (FIG. 1). Moreover,ech receives input from just one climbing, but the contct is so extensive tht climbing s generte the lrgest depolrizing event seen in ny neuron: highly chrcteristic burst of impulses known s climbing response 32 or complex spike 33. Functionl microntomy of cerebellr circuitry Given the uniform structure of the cerebellr cortex, the bsic neurl computtion performed is ssumed to be similr throughout, whether used for the control of utonomic functions, limb movements or higher functions such s lnguge. Notwithstnding regionl differences in chemorchitecture (for exmple, in the cerebellr corticl distribution of moleculr mrkers such s zebrin ), it follows tht functionl differences between vrious prts of the cerebellr cortex must rise primrily, if not exclusively, from locl differences in input nd output connectivity. It is, therefore, understndble tht considerble emphsis hs been plced on the study of cerebellr corticl input nd output pthwys (for historicl references, see REFS 37,38). Levels of resolution hve been grdully refined, nd the modern key orgnizing principle, on the bsis of detiled studies minly in cts nd rts, is division of the cerebellr cortex into series of longitudinlly oriented strips or sgittl zones. Individul zones re typiclly 1 2 mm in width, running cross the cerebellr lobules for mny millimetres in the rostrocudl plne 28,37,39,40 (FIG. 2).The s in ech zone receive climbing input from circumscribed region of the inferior olive nd, in turn, send output to circumscribed region in the cerebellr nuclei, thereby forming discrete olivo cortico nucler complexes 2 (FIG. 2). For the olivocerebellr climbing input to ech cerebellr corticl zone, there is corresponding detiled topogrphy. In brief, rostrl nd cudl subdivisions of the contrlterl inferior olive mp onto zones locted in the lterl (prverml nd hemispherl) nd medil (verml) prts of the ipsilterl cerebellr cortex. More detiled ntomicl trct trcing studies in rts nd cts indicte tht given cerebellr corticl zone receives climbing input from discrete cluster of olive s tht often form rostrocudlly elongted column in the olive Also, olivocerebellr xons brnch preferentilly in the rostrocudl xis so tht individul olive s typiclly provide single climbing to ech of severl s t different points long the length of single cerebellr corticl zone 47.Climbing s therefore impose very precise order on cerebellr corticl orgniztion, which presumbly hs importnt implictions for function. Therefore, it is perhps not surprising tht the integrity of the climbing projection is vitl to norml cerebellr contributions to movement control. If the cerebellum is deprived of its climbing input, severe disorders to movement result tht re similr in mny respects to those tht rise fter dmge to the cerebellum itself So, understnding the functionl orgniztion of climbing s is likely to be essentil to estblishing how the cerebellum ccomplishes its vrious roles. NATURE REVIEWS NEUROSCIENCE VOLUME 6 APRIL

4 b c 1 Lterl V 1 mm Vb C3 1 1 Vc 6 C C2 C1 pv pf Medil Figure 3 Mpping of cerebellr corticl microzones. A dorsl view of the ct prverml cerebellum in the region of lobules V c. The boundries of individul zones re delimited by dshed lines. A mediolterl sequence of recordings ws mde t two different rostrocudl levels in the C3 zone, nd the climbing receptive fields on the ipsilterl forelimb were mpped using quntifible nociceptive input. b,c Ech set of figurines of the dorsl nd ventrl spects of the ipsilterl forelimb shows the receptive fields on the skin obtined from the two corresponding colour-coded sequences of recording trcks. Drk blue res denote regions of skin tht generted mximl response; light blue res denote totl extent of receptive field. Note the trnsition of receptive fields within ech mediolterl sequence, defining the boundry between djcent microzones (boxed), nd tht individul microzones tht re present t both rostrocudl levels re rrnged in the sme mediolterl order (linked by dshed lines). See min text for further detils. pv; prverml vein; pf, primry fissure. Dt from REF MZMCs re fundmentl cerebellr processing units. In terms of functionl orgniztion, different prts of the olive convey informtion from one or severl specific spino olivo cerebellr pthwys nd, consequently, ech zone cn be redily identified with electrophysiologicl mpping techniques 39,40,51.Within ech zone, smller units known s microzones cn lso be redily identified electrophysiologiclly These re defined by the specific functionl chrcteristics of their climbing input. Therefore, microzone is nrrow longitudinl strip of cerebellr cortex within which ll s receive climbing -medited input with similr receptive field identity. In the cse of the prverml cerebellum, ech climbing hs prticulr receptive field on the skin, usully locted on one of the ipsilterl limbs (FIG. 3). This results in n intricte but highly reproducible mp within the cerebellr cortex tht is prticulrly well studied in the forelimb re of the prverml C3 zone of the ct 54,56 58.Microzones re lso the defining components of olivo cortico nucler microcomplexes 2,27,which might be thought of s the cerebellr counterprts of cerebrl corticl columns. Both electrophysiologicl nd ntomicl studies in cts hve shown tht the stem xons of olive s cn brnch to innervte microzones in different cerebellr corticl zones nd/or in different prts of the sme zone 57,59.For exmple, some xons brnch widely to innervte microzones locted in the nterior nd posterior lobes 45,60.This olivocerebellr divergence hs two importnt implictions. First, it provides structurl bsis for functionl linkge of two or more microzones with the sme climbing receptive field, but with n independent cerebellr corticl loction. Second, it indictes tht the mp relted to the ipsilterl body surfce generted by climbing input tht termintes in the C3 zone is t lest prtly repeted in the cerebellr corticl C1 nd Y zones (FIG. 2). The functionl orgniztion of climbing input to the C1 zone supports this ssumption 61. An importnt dditionl finding is tht the multiple prverml cerebellr corticl representtions defined by climbing input to the C1, C3 nd Y zones pper to converge onto single representtion in one of the prverml output nuclei: the nterior division of nucleus interpositus (NIA) 62.This convergence seems to occur between prts of zones with common climbing input, regrdless of whether they re seprted mediolterlly or rostrocudlly in the expnse of the cerebellr corticl sheet. Tken together, these observtions led to the hypothesis tht mny, if not ll, of the bsic structurl functionl units of the prverml cerebellum re multizonl microcomplexes (MZMCs) 62,63.Such n rrngement, whereby strict correspondence is mintined between input nd output in sptilly seprte microzones, is n extension of the ides originlly put forwrd by Oscrsson 27 nd elborted by Ito 2.The modifiction here is tht there is specific convergence of informtion to the sme region of cerebellr nucleus tht rises from multiple similr microzones in the cerebellr cortex. 300 APRIL 2005 VOLUME 6

5 More specificlly, ech MZMC cn be defined s two or more microzones locted in different prts of the prverml cerebellr cortex tht receive climbing input with similr receptive field chrcteristics (olivocerebellr divergence), nd tht provide cerebellr corticonucler output to common group of cerebellr nucler neurons (cerebellr corticonucler convergence; FIG. 4). The most direct evidence to support this rrngement so fr hs been obtined from cts by using electrophysiologicl techniques in combintion with bidirectionl double-trcer method 64.Injections of trcer were mde into two cerebellr corticl regions in the prverml C1 nd C3 zones with similr climbing receptive field chrcteristics. The degree of overlp in NIA between the two territories occupied by nterogrdely lbelled cerebellr corticonucler terminls ws in strict proportion to the number of olive s tht were double-lbelled with retrogrde trcer. This shows close correspondence between olivocerebellr divergence nd cerebellr corticonucler convergence from functionlly similr but sptilly seprte cerebellr corticl res, which is entirely in greement with the proposed MZMC orgniztion of the prvermis. MZMC structure llows prllel informtion processing. Wht is the functionl significnce of the distributed nture of the MZMCs? Besides climbing s, the other min input to the cerebellum is the mossy projection (FIG. 1),which rises from wide vriety of sources, including the spinl cord 65,numerous brin stem nuclei (especilly the pons; see REF. 66 for review) nd the cerebellum itself The orgniztion of mossy s in reltion to cerebellr corticl microzones is of prticulr interest with regrd to the sptil distribution of individul prverml MZMCs. At lest hypotheticlly, microzones in different prts of the cerebellr cortex tht re ssocited with n individul MZMC could process in prllel nd integrte informtion derived from mossy inputs tht rise from different origins. But is there ny evidence for such n rrngement? So fr, the most detiled ntomicl trcer studies tht ddress this possibility hve been confined to investigting differences in mossy inputs t the zonl level of resolution. For exmple, the C1 nd C3 zones in cts hve been found to hve significnt quntittive differences in the density of their mossy projections from the bsilr pontine nuclei, the lterl reticulr nucleus nd the nucleus reticulris tegmenti pontis 71,72.This indictes tht different mossy medited informtion might be processed in these two zones, potentilly by microzones tht belong to the sme MZMC. However, perhps the most striking distinction found so fr is tht ll of the prverml zones differ in the extent to which they re trgets for corticlly directed xons of cerebellr nucler s, which probbly terminte s mossy s in the grnulr lyer. The nucleus interpositus posterior (NIP) seems to be the most importnt source of these nucleocorticl projections, nd there is degree of non-reciprocity in the Corticonucler convergence b Cerebellr cortex Cerebellr nuclei Posterior lobe C1 zone rpml D NIA NIP Cerebellr cortex Olivocerebellr divergence rdao Anterior lobe C1 zone lobule V NIA Figure 4 Prllel processing in cerebellr microcomplexes. The bsic structurl design of prverml multizonl microcomplex (MZMC) s deduced from electrophysiologicl mpping studies 62 nd supported by neurontomicl trct trcing experiments 64,147. Ech prverml MZMC is defined by divergence of informtion in the olivocerebellr projection nd convergence of informtion in the corresponding corticonucler projection (see text for further detils). b Schemtic digrm summrizing the cerebellr corticonucler nd nucleocorticl connections of the C1 zone in the forelimb-receiving prts of the nterior nd posterior lobes of the ct cerebellum. Downwrd rrows indicte the corticonucler projections tht trget the cerebellr nuclei. Upwrd rrows indicte the corresponding nucleocorticl projections. For the ltter, the depth of shding of ech rrow indictes the density of the projection from ech of the cerebellr nuclei; drker rrows indictes greter density. Note tht the C1 zone in the forelimb-receiving prt of the nterior lobe (lobule V) receives no nucleocorticl projection, wheres the sme zone in the homologous prt of the posterior lobe receives n extensive nucleocorticl projection. This is consistent with the possibility tht individul microzones tht belong to the sme MZMC, but re locted in different prts of the cerebellr cortex, receive distinct ptterns of mossy inputs (see text for further detils). D, Dentte nucleus; NIA, nucleus interpositus nterior; NIP, nucleus interpositus posterior; rdao, rostrl prt of the dorsl ccessory olive; rpml, rostrl foli of prmedin lobule; lobule V, lobule V c. Pnel modified, with permission, from REF. 148 (1998) Americn Physiologicl Society. Pnel b dt from REFS NATURE REVIEWS NEUROSCIENCE VOLUME 6 APRIL

6 c ERROR-DETECTION HYPOTHESIS The generl ide tht climbing s (detect nd) convey signls tht reflect errors in motor performnce (posture s well s overt movement) b 100 5b 5e 5e 5g 5h 2d 7d FCR FDP PL FCU ECU ECRL SNWR receptive field (%) Figure 5 Quntittive comprison of receptive fields. Smples of electromyogrphic (EMG) ctivity evoked by noxious mechnicl stimultion of skin sites with different sensitivity (left). A smple receptive field mp of single plmr flexor muscle constructed by quntifiction of EMG responses shown on the ventrl side of the left forelimb of the ct (right). Numbers indicte response mgnitude s percentge of mximl response. Dshed lines indicte mthemticlly derived iso-response levels. This procedure ws used to determine the receptive fields tht re shown in simplified form in c (bottom row) such tht drk blue res denote the receptive field res with mximl response nd light blue res denote the totl extent of receptive fields. b Exmple grph plotting the quntittive dt on receptive field sensitivity (expressed s percentge of mximl response) of climbing input to prverml multizonl microcomplex (MZMC) s function of the equivlent dt for the corresponding spinl nociceptive withdrwl reflex (SNWR). The correltion coefficient obtined provides n objective mesure of the degree of similrity between receptive fields in the two systems. c Smple nociceptive climbing receptive fields of individul s (top, bsed on complex spike ctivity) nd individul forelimb muscles (bottom, bsed on EMG ctivity) both using the method described in. Correltion coefficients for the exmples shown were, on verge, The close correspondence indictes tht individul climbing fferents convey informtion bout the skin surfce representing n imprint of withdrwl efficcy of single muscle. In ddition, the sme climbing receives convergent input from group II muscle fferents, originting minly in the sme muscle 84. Therefore, n individul climbing monitors both the input nd the output element of n individul SNWR module (compre with FIG. 10). The functionl significnce of the muscle fferent input is not known, s cutneous nd muscle fferent input interctions hve not been investigted. However, the convergence emphsizes the integrted sensorimotor nture of the prverml climbing input. 5b, e, g, h, 2d nd 7d, denote clssifiction of different climbing microzones (see REF. 54 for detils). ECRL, extensor crpi rdilis longus; ECU, extensor crpi ulnris; FCR, flexor crpi rdilis; FCU, flexor crpi ulnris; FDP, flexor digitorum profundus; PL, plmris longus; TRI, triceps. Pnels nd c modified, with permission, from REF. 84 (2002) Blckwell Publishing Ltd. MZMC receptive field (%) 100 TRI topogrphy of the projection For exmple, in the nterior lobe of the ct cerebellum, the C1 zone receives little or no such projection, wheres in the posterior lobe, the sme zone hs n pprecible nucleocorticl projection, minly from NIP, but lso, to lesser extent, from NIA nd dentte nucleus (FIG. 4b). This implies tht output from different cerebellr corticl zones (the C2 zone nd lso the C1 nd D zones to some extent; see FIG. 2) is fed bck to the grnulr lyer of one portion of the C1 zone, but not to nother. Such findings re consistent with the notion tht the structurl orgniztion of the prverml cerebellr cortex llows similr climbing inputs to integrte with mossy signls tht rise from different sources. Functionl significnce of climbing s Mny different functions hve been suggested for climbing s (see REF. 73 for review), but two concepts remin centrl in the context of movement control. First, tht climbing s medite motor error signls 2 nd, second, tht climbing ctivity is instrumentl in the induction of synptic plsticity underlying motor dpttion nd motor lerning 74.These concepts re often linked to one nother, nd both re supported, nd were, in fct, inspired, by theoreticl considertions of cerebellr corticl infrstructure 22,23. Types of informtion medited by climbing s. Experimentlly, more or less strightforwrd reltionships between the occurrence of climbing signls nd vrious types of unexpected perturbtion of movement hve been described (however, see REF. 78 for n lterntive view). Although these nd similr findings hve been tken s support for the ERROR- DETECTION HYPOTHESIS, theorists hve rised concerns s to the plusibility nd physiologicl origin of true motor error signl. In prticulr, the nture of such signl does not seem comptible with the sensory chrcteristics of climbing responses 24,79.A key issue, therefore, concerns whether climbing signls should insted be thought to signl sensory errors (defined s the sensory consequences of motor error), nd, if so, how these might be trnsformed into motor error signls. According to some theories of cerebellr function, such trnsformtion is prerequisite for the use of sensory informtion to form nd updte internl cerebellr models of movements or movement components 25,26 (but see REFS 79,80 for n lterntive view). As possible solution to this motor error problem, it hs been proposed tht climbing signls encode sensory informtion in motor frme of reference 24,81,82.Ifthis were the cse, then it might be expected tht climbing responses would hve both sensory nd motor chrcteristics. Experimentl evidence consistent with this possibility hs been obtined in the cerebellr ventrl PARAFLOCCULUS 83.In this system, ptterns of climbing ctivity during the oculr following response indicte not only tht climbing signls represent sensory input (visul stimuli ssocited with RETINAL SLIP), but lso tht their ctivtion seems to relte to the direction of eye movements, nd in prticulr, to the xis of contrction of individul eye muscles. This indictes tht the climbing input to the cerebellr ventrl prflocculus is conveyed by sensorimotor brin stem system tht 302 APRIL 2005 VOLUME 6

7 A b B Z Stim. Y X Z X Y c V d e t V α V n N Plntr V n = V cos α Medil C Gstrocnemius Peroneus longus Tibilis nterior Motor output: withdrwl field Sensory input: receptive field Figure 6 Sensorimotor trnsformtions in spinl nociceptive withdrwl reflex modules. A A method to document nd nlyse how movements cused by the contrction of single muscles move skin surfce in three dimensions. Movements of the right hind pw of the rt were elicited by intr-musculr stimultion (stim.) of individul muscles nd documented with two cmers plced t right ngles to ech other. Dots indicte the points on the skin tht were trced by motion nlysis. b The shpe of ech pw segment ws determined by photogrphing sections of hrdened wx model of the entire pw. c Cross-section of digit segment: the movement of the skin surfce ws decomposed to determine the ctul withdrwl of the skin surfce, defined s the inwrd vector indicted by V n. N, norml; V t, tngentil vector. d Smple of withdrwl vectors V n long the skin surfce of the proximl phlnx of digit V on contrction of given muscle. e Distribution of V n on the whole hind pw on contrction of the sme muscle. Shding indictes res of low (light blue), medium (mid blue) nd high (drk blue) degrees of withdrwl. B Simplified digrm of spinl nociceptive withdrwl reflex module in the ct. The skin receptive field on the left forelimb s determined by recording nd quntifiction of the electromyogrphic response in single muscle on nociceptive stimultion of the skin (see FIG. 5) is shown on the right (drk blue re denotes the receptive field re with mximl response nd light blue re denotes the totl extent of the receptive field). Arrows indicte schemticlly the mgnitude of withdrwl of the different prts of the receptive field on contrction of the muscle depicted to the left. C Comprison of quntified withdrwl fields (s in A) nd quntified skin receptive fields (s in B) for three muscles in the rt hindlimb shows high levels of similrity (correltion coefficients rnging ). Pnels A nd C modified, with permission, from REF. 86 (1994) Springer. Pnel B dt from REF PARAFLOCCULUS In experimentl nimls, the dorsl nd ventrl prflocculus re the two most cudl lobules of the cerebellr hemisphere. RETINAL SLIP An unwnted movement of the visul imge on the retin tht occurs, for instnce, when the movement of the eyes is indequte to follow moving object. pre-processes the sensory input, thereby generting climbing signls with properties tht re trnsitionl between sensory nd motor informtion. Spinl reflex nd climbing reltions. Despite their explntory vlue for the regultion of eye movements, the findings on the ventrl prflocculus re not esily extrpolted to other prts of the motor system. This is becuse eye movements re reltively simple: they re limited to motion in two dimensions nd involve movement of constnt mss. Recently, however, progress hs been mde with regrd to understnding the nture nd origin of climbing signls tht re relevnt to the more complex issue of limb movement control. Quntittive techniques hve been used to compre the sptil encoding of sensory informtion medited by climbing s tht terminte in the prverml cerebellum with sensory encoding in previously well-chrcterized sensorimotor system tht medites spinl nociceptive withdrwl reflexes (SNWR; FIG. 5). In brief, correltion nlysis of quntified receptive field mps 84 showed tht the skin receptive fields of climbing s tht terminte in individul microzones in the prverml cerebellr cortex 54 nd the receptive fields of individul modules of the SNWR system 85 NATURE REVIEWS NEUROSCIENCE VOLUME 6 APRIL

8 WITHDRAWAL EFFICACY The motor effect of muscle in terms of its movement wy from n externl reference point, which cn be represented s quntittive topogrphicl mp bsed on n nlysis of the displcement of mny points on the skin during the contrction of single limb muscle. IMPRINT In the SNWR system there is, for ech individul muscle, close reltionship between the distribution of sensitivity in the receptive field on the skin nd the pttern of skin withdrwl cused by muscle contrction. Therefore, the output of the single muscle reflex component ppers to be imprinted on the spinl reflex circuitry tht crries out the input output trnsformtion. CEREBELLAR FEEDBACK-ERROR- LEARNING MODEL A cerebellr model proposed by Kwto nd collegues tht specificlly ddresses the issue of how sensory errors might be trnsformed into motor errors. were highly similr. Therefore, climbing signls tht rise from the spinl cord might be pre-processed by SNWRs. The ltter system consists of seprte modules, ech comprising specific skin receptive field, segmentl multi-synptic reflex rc nd specific output muscle 85.Ech module performs detiled sensorimotor trnsformtion tht results in grded withdrwl of the limb (or prt of the limb), such tht its prticulr receptive field on the skin is moved wy from the stimulus. For ny given SNWR module, the input strength hs chrcteristic pttern on the skin tht mimics the pttern of WITHDRAWAL EFFICACY when the output muscle of the module contrcts 86 (FIG. 6). The similrity between the receptive fields of climbing s nd SNWRs might explin why the cerebellr prvermis is divided into microzones in the first plce tht is, why it is modulr in functionl orgniztion. An ction-bsed representtion of sensory informtion should yield highly processed (computtionl) mp in the cerebellr cortex rther thn fithful representtion of the body surfce with n orderly sequence of receptive fields, s in conventionl sensory mp tht is somtotopicl in the strict sense of the word 87.In fct, skin res displced by the ction of single muscles do not necessrily form continuum on the body surfce. On the contrry, system orgnized on the bsis of movement-relted representtion of the skin is inherently modulr if such system opertes through n rry of individul muscles. The implictions of this orgniztion for cerebellr informtion processing re considered below. However, before returning to this issue, it is of interest to note tht the close correspondence between SNWR modules nd prverml climbing s might lso be relevnt to the observtion tht climbing pthwys tht rise from the spinl cord re subject to substntil centrl control, especilly during ctive movements such s wlking or reching for n object 92,93.The gting of trnsmission occurs only t certin times, specific to the prticulr movement. During locomotion, for instnce, skin fferents from the ipsilterl forepw re most likely to trnsmit informtion through scending climbing pthwys to the C1 nd C3 zones in lobule V of the cerebellr cortex in the swing phse of the step cycle Although gting nd its temporl pttern seem to be fundmentl chrcteristics of climbing pthwys in generl, its mechnisms nd functionl significnce re not well understood 94,95. Notbly, however, similr phenomenon hs been reported for spinl reflex pthwys: the swing phse of the step cycle is lso the time when ctivtion of the sme skin fferents is most likely to elicit reflex withdrwl of the limb 96.This similrity in the pttern of modultion provides dditionl evidence for the possibility of close functionl link between scending climbing pthwys nd spinl reflex circuits, nd indictes tht the movement-relted gting might hve common origin, presumbly t the level of the spinl cord. Both SNWRs nd climbing s signl motor errors. To better understnd the ction-bsed nture of sensory encoding in SNWR modules, it is useful to consider their postntl development The sensorimotor trnsformtions performed in ech module re not innte but insted re functionlly dpted by postntl lerning process tht occurs during ctive sleep. Specificlly, s individul muscles re brought to twitch by spontneous ctivity in spinl sensorimotor circuits, the ensuing tctile feedbck is used to tune the connection strengths in individul SNWR modules 100.The chnge of tctile input from the withdrwn skin re tht occurs in conjunction with the spontneous single muscle movements hs n dptive effect on the reflex module 101.By this process, ech skin receptive field becomes sensory IMPRINT of the withdrwl efficcy of n individul muscle (FIG. 7). In individul SNWR modules, the precise sensorimotor reltionship between the distribution of sensitivity on the skin of noxious (or tctile 102 ) inputs nd the withdrwl efficcy of the muscle 86 provides theoreticl foundtion for the detection of motor errors. First, the probbility tht the skin receptive field of prticulr reflex module will be stimulted (for exmple, by hitting n externl object), nd therefore be ctivted t given point in time, is inversely proportionl to the level of contrction of the muscle of tht module (s muscle contrction will tend to withdrw the relevnt skin re from the stimulus). Second, if point in the receptive field does encounter noxious stimulus, the degree of ctivtion of the module for given stimulus intensity is in direct proportion to the extent to which the muscle hs the cpcity to withdrw the stimulted point from the stimulus. Therefore, the more indequte the contrction of muscle is tht is, the lrger the motor error of tht specific muscle the stronger the receptive field ctivtion will be. In other words, the degree to which the sensory receptive field is ctivted during movement provides precise informtion bout the extent to which n elementl prt of the motor system hs mde n error. By nlogy to input to individul SNWR modules, signls conveyed to the prverml MZMCs through scending climbing pthwys 84 would seem to be encoded in wy tht is directly relted to motor output 86.The informtion contined in climbing signls rising from the spinl cord does not represent n error signl in sensory coordintes tht must be converted from sensory into motor error. Tht conversion hs lredy tken plce in the spinl cord. As result, climbing s tht terminte in individul prverml MZMCs seem to provide informtion bout motor errors tht relte to the ction of single muscles. Overll, the ctionbsed fetures of climbing sensory signls seem to be brodly consistent with those stted by the CEREBELLAR FEEDBACK-ERROR-LEARNING MODEL 24,81,82.Despite differences with respect to phylogenetic ge nd the complexity of motor control crried out, both limb nd eye movement 83 cerebellr control systems seem to involve similr principles of sensory encoding, which indictes tht these principles might pply more generlly. 304 APRIL 2005 VOLUME 6

9 P1 3 PL EDL n = 8 n = 19 c Nociceptive Tctile () Skin pressure () P20 25 b SNWR error rte (%) n = 6 n = 5 W S Reflex encoder 4 1 ( ) Skin pressure ( ) Postntl dy Motor neuron Muscle Figure 7 Postntl developmentl tuning of sensorimotor trnsformtions in rt spinl nociceptive withdrwl reflex modules. Quntified receptive fields of two hindlimb muscles t postntl dys (P) 1 3 (top) nd (bottom) show developmentl tuning of sensorimotor trnsformtions. The number of individul receptive fields used to crete the verge is shown below ech figurine. EDL, extensor digitorum longus; PL, peroneus longus. b Developmentl tuning curves of til withdrwl on nociceptive stimultion of the skin in one litter of rt pups. Error rtes (defined s inpproprite til movements towrds noxious stimulus) re round chnce level (50%) or worse during the first two postntl weeks nd then decrese rpidly to rech dult level by the end of the third postntl week. c A proposed self-orgnizing circuitry tht uses tctile informtion relted to withdrwl efficcy to djust the strength of nociceptive connections. One lerning cycle consists of the following chin of events: spontneous bursts in reflex encoders (tht is, neurons tht encode the mgnitude of the reflex response) (1); motor neuron ctivtion by the reflex encoder leds to muscle twitch (2); the twitch produces either n increse or decrese in non-noxious skin pressure on the til (3), resulting in ltered sensory input to pre-reflex encoder interneurons (sterisk). Pink nd blue lines represent fferents from skin res on the til from where n increse () or decrese ( ), respectively, in low-threshold mechnoreceptor (tctile) input would occur. Dshed lines symbolize the rre occurrence of nociceptive input. Finlly, the strength of erroneous connections (receiving incresed tctile input) between pre-reflex-encoder interneurons nd the reflex encoder is wekened (W) nd tht of pproprite ones (receiving reduced tctile input) is strengthened (S) (4). Once the tuning is estblished, ctivtion of the skin receptive field of the muscle will led to tht prticulr skin re being moved wy from the stimulus. Pnel modified, with permission, from REF. 97 (1996) Blckwell Publishing Ltd. Pnels b nd c modified, with permission, from REF. 101 (2003) Society for Neuroscience. Informtion processing in prverml MZMCs From the point of view of informtion processing, fundmentl issue to understnding the function of the prverml cerebellum is the wy in which input nd output in individul MZMCs is modified over time. Indeed, the importnce of the cerebellum s storge site of internl models of the motor pprtus 25,26 depends entirely on its cpcity to dptively chnge input output trnsformtions. The neuronl mechnisms tht underlie this dptive cpcity include synptic plsticity influencing trnsmission from prllel s to s nd lso from prllel s to cerebellr corticl interneurons. An importnt fctor in regulting cerebellr synptic plsticity seems to be the interctions between climbing nd mossy prllel inputs 103.Ptterns of convergence between the climbing nd mossy fferent systems re thought to be fundmentl to these interctions (FIG. 8). Climbing nd mossy reltionships re specific. With regrd to functionl orgniztion, there re both similrities nd differences between climbing nd mossy prllel inputs to the prverml cerebellum. This issue cn be broken down into two levels tht correspond to two stges of informtion processing. The first level is the reltionship between climbing receptive fields tht define given cerebellr corticl microzone nd receptive fields of individul mossy s in the underlying grnulr lyer. Mossy s with given peripherl receptive field hve wider res of termintion thn climbing microzones, with certin degree of overlp between neighbouring res 104.As result, ech microzone receives input from severl mossy receptive fields. Nevertheless, the overll mossy input is similr to the climbing input (FIG. 8c;complex spike in FIG. 8), nd is feture tht seems to be conserved cross species nd other prts of the cerebellr cortex (for exmple, crus II in the rt 105 ). The high level of similrity between individul mossy nd climbing receptive fields 104 implies tht t lest some mossy input, like climbing input, is encoded in motor frme of reference 106,107. However, climbing input from the periphery is multi-modl, with convergence between tctile nd nociceptive skin fferents 108,109 nd muscle fferents 110. By contrst, input conveyed by t lest some spinl pthwys tht terminte s mossy s is usully NATURE REVIEWS NEUROSCIENCE VOLUME 6 APRIL

10 A Prllel Interneuron Mossy c Climbing b B b c CS SS IN MF n = 17 n = 8 n = 18 n = 9 n = 15 n = 5 n = 36 n = 10 Figure 8 Receptive fields in the cerebellr cortex. A Schemtic digrm of recording sites in s, interneurons (IN) nd mossy s (MF) t right ngles to the surfce through the C3 zone in the prverml cerebellr cortex. Mossy input ws provided by the externl component of the cuneo cerebellr trct 104,149. B Typicl receptive field chrcteristics of neuronl elements in two microzones (left nd right columns) re depicted on the ventrl nd dorsl surfce of the left ct forelimb. Complex spike (CS) nd simple spike (SS) receptive fields of s. b Receptive fields of nerby interneurons. c Receptive fields of mossy terminls immeditely below the lyer. Note tht in ech microzone, the CS response (due to climbing ctivity) of individul s hs similr receptive field on the skin of the ipsilterl forelimb s locl inhibitory interneurons nd mossy terminls in the subjcent grnulr lyer. By contrst, the excittory SS receptive field of the sme s (due to mossy grnule prllel input) is different. Vlues shown with ech pir of limb figurines denote the numbers of units tht contributed to producing the verge receptive field mp. Pnel B modified, with permission, from REF. 112 (2001) Blckwell Publishing Ltd nd REF. 150 (2003) Tylor nd Frncis. modlity specific tht is, it is either tctile or muscle fferent-relted 104.Consequently, lthough the sptil encoding of informtion is similr in the two systems, the informtion does not seem to be derived from the sme spinl circuits. Rther, similrities between climbing nd mossy s might indicte tht ction-bsed encoding of sensory informtion is common principle of spinl networks 111. The second level of climbing nd mossy interctions concerns the reltionship between climbing nd prllel input to individul s nd cerebellr corticl interneurons. At present, opinion is divided s to whether the receptive fields of s generted by trnsmission in prllel s re primrily due to inputs from locl or non-locl grnule s. In the cerebellr prvermis, evidence from cts indictes tht locl mossy s do not, s might be expected, provide excittion to the s directly overlying them 112.Insted, locl interneurons hve excittory receptive fields similr to those of subjcent mossy s (FIG. 8b,c),implying tht the scending brnch of individul grnule xons nd the most proximl prts of their prllel s primrily contct locl inhibitory interneurons. As result, the s in given prverml microzone hve interneuron-medited inhibitory receptive fields tht re similr to those of the underlying mossy s. By contrst, the prllel medited excittory receptive fields of the sme s re different nd therefore seem to be derived from mossy s tht terminte in non-locl regions of cerebellr cortex (simple spike in FIG. 8). The ltter finding contrsts, however, with erlier studies in rts tht indicte tht the scending xons of grnule s mke prticulrly powerful direct connections with s, which results in their prllel -medited receptive fields being similr to those of the underlying mossy s At present, it remins uncler how the discrepncy between these findings might be resolved, lthough differences between species (ct versus rt) nd prts of the cerebellum studied (prvermis versus hemisphere) might be contributory fctors. In the context of informtion processing in cerebellr circuits, this is n importnt issue to resolve, becuse if prllel excittion of s rises from non-locl mossy s, then prllel s could serve centrl role in distributing informtion cross severl cerebellr corticl microzones. As discussed below, this, in turn, could provide neuronl substrte for the control of muscle synergies bsed on sptil nd/or temporl ptterns of prllel inputs to s. Input output reltionships in MZMCs re specific. Microstimultion in different prts of NIA, relting to the output stge of different MZMCs, hs been shown to evoke different limb movements tht re medited through the red nucleus nd the rubrospinl trct In generl, these movements usully involve two or three segments of n ipsilterl limb 116,indictive of control of multi-joint muscle synergies, such s retrction of the limb t the shoulder nd flexion t the elbow (FIG. 9).Antomicl nd physiologicl fetures of the rubrospinl 119,120 nd corticospinl 121 trcts support the existence of such divergence.looking t the system s whole, n importnt consequence of this orgniztion is tht significnt number of limb muscles re likely to be controlled from severl MZMCs. The functionl overlp with regrd to output implied by these ptterns of connectivity is in strk contrst to the highly segregted microzonl climbing input to individul MZMCs. The significnce of this discrepncy is uncler, but it might relte to conflicting demnds plced on the 306 APRIL 2005 VOLUME 6

11 b c NIA Climbing rdao NIA Climbing rdao NIA Climbing rdao Figure 9 Input output reltionships. Microstimultion of individul sites in nucleus interpositus nterior (NIA) relting to the output stge of different multizonl microcomplexes (MZMCs) results in distinct ptterns of multi-joint movements in the ipsilterl limb of the ct. c Reltionships between climbing input nd nucleofugl output re shown for three exmple MZMCs. To the right of ech pnel is shown the skin climbing receptive field of n individul MZMC, depicted on dorsl nd ventrl view of the ipsilterl forelimb. Drk blue res denote regions of skin tht generted mximl response; light blue res denote totl extent of receptive field. To the left of ech pnel is skeleton of the sme forelimb showing schemticlly the groups of muscles ctivted on microstimultion of sites in NIA with receptive fields corresponding to the output stge of tht prticulr MZMC. Wrist dorsiflexors nd plmr flexors re shown on dorsl nd ventrl side of the forerm, respectively; elbow flexors nd extensors on the upper rm; nd shoulder flexors between the upper rm nd scpul. Note tht the experimentl pproch mens tht inhibitory influences on spinl segmentl circuitry go undetected. In view of reciprocl gonist/ntgonist innervtion by some rubrospinl neurons, it might be ssumed tht excittory output to the ntgonist muscle (see lso FIG. 10) is, t lest in some cses, ssocited with inhibitory output to the gonist (not shown). rdao, rostrl dorsl ccessory olive. Dt from REF control system. Efficient lerning, for instnce, might be fcilitted by modulrity, which llows different components of movement to be fine-tuned independently without interference from other components 122. Overll, evoked movements usully lso show preferred direction tht is in close correspondence with the climbing receptive field of given MZMC 116.We rgue bove tht the peripherl receptive field of the climbing input to ech prverml MZMC encodes the withdrwl efficcy of prticulr limb muscle. In terms of excittory cerebellr output from the sme MZMC (see lso FIG. 9 legend), the distl-most muscle in the muscle synergy under control seems to hve roughly ntgonistic ction to the muscle ssocited with the input side of the circuit. For instnce, in the ct, the prverml MZMC receiving its climbing input from the SNWR module tht controls plmr flexor of the wrist (plmris longus) hs receptive field tht hs s its centre n re of skin on the ventrl forepw just proximl to the centrl footpd (FIG. 9).When the limb is in stnding position, the ction of this muscle is to withdrw this prticulr re of skin wy from the stimulus 84 (FIG. 6B). By contrst, the muscle synergy tht constitutes the excittory cerebellr output from this specific MZMC seems to include the pproximte ntgonist of this muscle probbly the extensor digitorum communis, which is dorsl flexor of the wrist 116 (FIG. 9). Implictions for motor coordintion The previous sections drw ttention to severl fetures of the prverml cerebellr system, which, tken together, could provide the bsis for the control of singlend multi-joint movements ( hllmrk of prverml contributions to motor control). First, the climbing nd the min mossy input from the periphery to ny prticulr MZMC hve similr excittory receptive fields 104 (FIG. 8).Second, the mossy input seems to exert its effect primrily on the s in the sme MZMC through locl inhibitory interneurons, wheres the excittory prllel input to the sme s seems to be derived minly from nonlocl mossy s 112 tht might encode the withdrwl efficcy of different muscle (FIG. 8).As consequence of these two ptterns of interconnectivity, we speculte tht ech prverml MZMC might prticipte in two types of interction with the reflex circuitry of the spinl cord (FIG. 10). On the one hnd, mossy input medited through locl grnule s nd moleculr lyer interneurons in prticulr MZMC might provide neuronl substrte for regulting the timing of ctivity in two opposing muscles tht re involved in single-joint movements (follow the pth of signs in white circles in FIG. 10). In prticulr, peripherl feedbck to the MZMC tht is relted to the ction of prticulr gonist muscle nd medited by mossy fferents might ct through the output of the MZMC s cue to the termintion of ctivity in tht muscle (through inhibitory connections not indicted in FIG. 10; FIG. 9 legend) nd influence the onset of ntgonist muscle ctivity. In this respect, it is relevnt to note tht the correct timing of trnsitions between gonist nd ntgonist ctivity ssocited with single-joint movements 123 is disrupted following cerebellr dmge 124. On the other hnd, similr peripherl feedbck could be conveyed through the prllel s to influence the NATURE REVIEWS NEUROSCIENCE VOLUME 6 APRIL