Cerebellar Influences on Descending Spinal Motor Systems

  • Tom J. H. RuigrokEmail author
Living reference work entry


The cerebellar nuclei, and to some extent the vestibular nuclei, mediate the ultimate result of cerebellar processing to the rest of the brain. Cerebellar output is directed to the diencephalon and to a score of brainstem regions. This chapter reviews the cerebellar nuclear projections to the brainstem areas that give rise to descending connections that can influence motor programming at spinal cord level, i.e., the reticulospinal, vestibulospinal, rubrospinal, tectospinal, and interstitiospinal pathways. In addition, cerebellar projections to other areas will be briefly considered. Although cerebellar output is structured by the modular internal organization of cerebellar circuitry and related olivocerebellar connections, it is concluded that the modular output, i.e., output of individual cerebellar nuclei or parts thereof, still reaches many areas in the brainstem and diencephalon. In addition, multiple modules may converge their outputs indirectly to the same muscles. This suggests that multiple modules may each take part in different aspects of control of the same muscle or muscle group. Conversely, individual modules, due to the distributed nature of their outputs, may simultaneously affect several descending motor systems with the same ensuing goal. Tools for detailed anatomical and physiological studies are now available and are expected to enhance our knowledge on the effects of the cerebellum on descending motor pathways.


Cerebellar nuclei Reticulospinal tracts Rubrospinal tract Vestibulospinal tracts Tectospinal tract 

List of Abbreviations


Hypoglossal nucleus


3rd ventricle

4/5 Cb

Cerebellar lobule 4/5


4th ventricle


Facial nucleus


Anterior interposed nucleus


Ambiguus nucleus


Anterior pretectal nucleus




Basal interstitial nucleus


Basilar pontine nuclei




Central gray


Cerebellar nuclei


Cerebral peduncle


Nucleus of Darkschewitsch


Dorsolateral hump


External cuneate nucleus


Fields of Forel


Retroflex fascicle


Gigantocellular reticular nucleus


Inferior colliculus


Interstitial cell groups


Inferior cerebellar peduncle


Interstitial nucleus of Cajal


Inferior olive


Fourth ventricle


Lateral cerebellar nucleus


Lateral geniculate nucleus


Lateral reticular nucleus


Lateral vestibular nucleus


Medial cerebellar nucleus


Middle cerebellar peduncle


Medullary reticular nucleus


Medial geniculate nucleus


Medial lemniscus


Medial longitudinal fascicle


Motor trigeminal nucleus


Medial vestibular nucleus


Facial nerve


Nucleus reticularis tegmenti pontis


Periaqueductal gray


Parvicellular reticular formation


Parafascicular thalamic nucleus




Posterior interposed nucleus


Caudal pontine reticular formation


Oral pontine reticular formation


Pyramidal tract


Red nucleus


Magnocellular red nucleus


Parvicellular red nucleus


Superior colliculus


Superior cerebellar peduncle


Simple lobule


Substantia nigra


Superior olive


Spinal trigeminal nucleus


Spinal vestibular nucleus


Superior vestibular nucleus


Ventral group thalamic nuclei


Zona incerta


The cerebellum, which is dominantly involved in the coordination, adaptation, and learning of motor behavior and, most likely, also participates in visceral, affective, and cognitive functions, exerts its influence on these functions by way of the cerebellar nuclei. In addition, selected sets of Purkinje cells provide a direct input to specific regions of the vestibular nuclei. The specific connections of virtually all regions of the cerebellar nuclei with those parts of the thalamus that are connected to the primary and premotor cortices were already recognized and stressed in the early literature (Allen and Tsukahara 1974). However, the cerebellar nuclei also have a prominent direct impact on a number of premotor centers with connections to the spinal cord or lower brainstem. Here, a brief overview of the cerebellar nuclei will be provided followed by a review of their connections to these descending motor systems. Finally, these connections will be briefly assessed in relation to other regions that receive cerebellar output and their joint impact on cerebellar functioning and dysfunctioning.

The Cerebellar Nuclei

The cerebellar nuclei are divided into four main nuclei: the medial, posterior interposed, anterior interposed, and lateral cerebellar nuclei (Fig. 1). These divisions are essentially based on cytoarchitectonic grounds but also agree with organizational features of the cerebellum. Purkinje cells projecting to each nuclear subdivision are organized into longitudinal strips. Jan Voogd, in his historic work (Voogd 1964, 2011), proposed that the medial cerebellar nucleus (MCN) receives its cortical afferents from the A zone, both interposed nuclei from the C zone, and the lateral cerebellar nucleus (LCN) from the D zone. The B zone, intercalated between A and C zones, targets the lateral vestibular nucleus. Presently, this basic scheme still holds true although the description of multiple subdivisions of the various zones has been refined considerably and has been shown to correspond with the description of several nuclear subdivisions (Apps and Hawkes 2009; Voogd and Glickstein 1998; Sugihara and Shinoda 2007; Cerminara et al. 2013; Ruigrok 2011). The remarkable reciprocal relation between the inferior olive and cerebellar nuclei has been noted by several authors and has been suggested to form the basis of the olivocerebellar organization (Ruigrok 1997; Ruigrok and Voogd 1990, 2000). Here, a short general description of the cerebellar nuclei of the rat, cat, macaque, and man will be presented before detailing the projections from these nuclei to the rest of the brain (see Fig. 1).
Fig. 1

Three-dimensional reconstructions of the left cerebellar nuclear complex of the rat, cat, macaque, and human (from top to bottom). Left hand panels show the nuclear complex from a rostral view. Right-hand panels show the individual nuclei from a dorsorostral view. Note that the general organization of the nuclei in all four species is virtually similar, but especially the size of the human dentate has increased formidably. For abbreviations see “List of Abbreviations.” Reconstructions were made with Neurolucida (MicroBrightfield, Inc., Williston, VT, USA) using serial microscopic sections (rat, cat, human) or sections from the macaque atlas by Paxinos et al. (2000). Segmentation of the human nuclear complex was performed by Jan Voogd

The MCN, in cat, macaque, and human often referred to as the fastigial nucleus as it is positioned directly adjacent to the fastigium (apex, roof) of the fourth ventricle, is the most medially located nucleus. Its rostral half is found directly dorsomedial to the rostral half of the fourth ventricle. Caudally, it is found dorsal to the lateral part of the nodulus. In the rat, as in mice, the MCN is characterized by a prominent outgrowth that reaches up into the white matter, consists of generally large cells, and is known as the dorsolateral protuberance (DLP; Korneliussen 1968). The rostral tip of the MCN is in ventrolateral direction continuous with the medial aspect of the superior vestibular nucleus. Caudally, the MCN is separated from both parts of the interposed nuclei by passing corticovestibular fibers. Located within these fibers are small groups of nuclear cells which are collectively known as the interstitial cell groups (ICG; Buisseret-Delmas et al. 1998). The ICG, based on their cortical and efferent connections, seem to be mostly associated with the posterior interposed nucleus (PIN; Buisseret-Delmas et al. 1993; Pijpers et al. 2005). Although the ICG are not mentioned in the description of the cerebellar nuclei of other mammals, they can also be recognized in the cat. In man, the fastigial nucleus also displays a dorsally extending protuberance; however, it is not known to what extent this is homologous to the DLP of rodents.

The PIN is found directly lateral to the caudal half of the MCN where it rests on the roof of the fourth ventricle. More rostrally and laterally, its borders with the anterior interposed and lateral cerebellar nuclei, respectively, are not always clear, especially in transverse sections. The rostromedial extension of the PIN continues as the interstitial cell groups (Buisseret-Delmas et al. 1993, 1998). In cat, the PIN carries a medial and lateral dorsal-ward protrusion. The human equivalent of the PIN is designated globose nucleus (Voogd and Ruigrok 2012).

The anterior interposed nucleus (AIN) of rat and cat has a mediolaterally elongated shape, whereas the macaque AIN is elongated mostly in the anteroposterior direction. The human equivalent, the emboliform nucleus, has a caudodorsal extension that reaches toward the dorsomedial part of the dentate nucleus (Fig. 1). In rat, the AIN displays a clear somatotopic pattern with representation of the hind limb located mediorostrally and the head region in its caudolateral aspect (e.g., see Lu et al. 2007; Pijpers et al. 2005). In the rat, a conspicuous bulge is noted at the border region between the AIN and the LCN. This dorsolateral hump (DLH) has been associated with either the AIN or the LCN (Voogd 2004; Korneliussen 1968). It has been shown to receive cortical afferents from a strip of Purkinje cells located between the D1 and D2 zones, which has been termed D0, and to receive climbing fiber collaterals that are derived from the dorsomedial group that is associated with the principal olive (Pijpers et al. 2005; Sugihara and Shinoda 2004, 2007). It is remarkable that the DLH provides a prominent ipsilateral descending projection to the lateral medullary reticular formation and adjacent spinal trigeminal nucleus (Fig. 2f; Bentivoglio and Kuypers 1982; Teune et al. 2000). Although, in the cat, the existence of an ipsilaterally descending tract originating from the cerebellar nuclei has been described by Ramon y Cajal (1903) and was also reported in monkey by Chan-Palay (1977), it has not been verified by others. Also, as far as we know, in man using diffusion tensor imaging, an ipsilateral descending tract originating from the cerebellar nuclei has not been reported (Ye et al. 2013).
Fig. 2

Serial plots (bg) of microscopical sections depicting patterns of labeled varicosities (i.e., terminal arborizations) in the caudal brainstem after various injections (shown in a) with an anterograde tracer in the cerebellar nuclei of the rat. The boundaries of several nuclei and fiber tracts are indicated. Note the generally widespread distribution of projections in every case. For abbreviations, see “List of Abbreviations.” (Adapted from Teune et al. 2000)

The LCN, also referred to as dentate nucleus in cat and primates, is rostrally separated from the AIN by traversing fibers from the inferior cerebellar peduncle. In the rat, the LCN consists of the dorsolateral magnocellular part and a ventromedial parvicellular part. In the rhesus monkey, these areas actually form a dentated area, with the medial sheath consisting of mostly small neurons, whereas the lateral sheath is made up of mostly large cells. Only in the human, a multiple dentated nucleus is present, which is considerably larger than the other cerebellar nuclei. Within its dentated form, a dorsal microgyric part and a ventral macrogyric part are recognized (Voogd and Ruigrok 2012). Throughout the neuropil of all cerebellar nuclei, small cells are located that have been demonstrated to supply GABAergic input to the inferior olive (De Zeeuw et al. 1989; Fredette and Mugnaini 1991; Teune et al. 1995). In primates, including man, a loosely packed group of neurons, the basal interstitial nucleus (BIN), is found ventral to the LCN that is continuous in a rostrolateral direction toward the floccular peduncle and which maintains reciprocal connections with the vestibulocerebellum (Langer 1985; Ding et al. 2016). In the cat and rat, neurons in a similar position are found but form an even less homogeneous nuclear contour (Ruigrok 2003). The BIN has not been indicated in the reconstructions of Fig. 1.

Medial and Lateral Descending Motor Systems from the Brainstem

Hans Kuypers divided the pathways descending to the spinal cord into three groups (Kuypers 1981, 1985). The first group consists of the corticospinal tract, which is subdivided into the crossed lateral and uncrossed medial descending tracts. A second group of descending tracts originates from the brainstem and is also divided into a medial and a lateral descending system based on the funicular course of the fibers and the termination pattern of the participating fibers within either the medial or lateral part of the intermediate region (i.e., layers V–VIII) of the spinal cord. A third group originates from the locus coeruleus and subcoeruleus as well as from the raphe nuclei and terminates diffusely throughout the gray matter of the spinal cord. This review will focus on the cerebellar influence of the second group of descending connections, i.e., the reticulospinal, vestibulospinal, tectospinal, rubrospinal, and interstitiospinal tracts.

Reticulospinal Tracts

The medial and medioventral pontomedullary reticular formation are the origin of several long descending tract systems (Torvik and Brodal 1957). Delineation and identification of various subregions has proven to be difficult and may be different in different species. For example, in the rat, over 25 reticular regions have been shown to contain neurons with descending fibers (Newman 1985a, b). Many of these areas have recently been shown to contain neurons that are presynaptic to motoneurons or to spinal interneurons (Arber 2017; Esposito et al. 2014). Here, we will describe the cerebellar influence on the reticulospinal tracts in a general sense.

It is well established that reticulospinal connections may follow several routes to the spinal cord (Nyberg-Hansen 1965; Peterson et al. 1975). Reticulospinal neurons located in the pontine and rostral medullary reticular formation mostly, but certainly not exclusively, follow a course by way of the ventral funiculus where they are found adjacent to the fibers of the medial longitudinal fascicle (mlf). They terminate throughout the length of the spinal cord predominantly in the medial and central parts of the intermediate zone (i.e., in laminae VII–VIII). Additional reticulospinal tracts are found in the ipsilateral and contralateral ventrolateral funiculus. Both tracts are followed by the axons of reticulospinal neurons from more caudal regions. Projections from these tracts are found throughout all laminae of the spinal cord. Individual reticulospinal axons can collateralize over considerable distances, thereby affecting different regions of the body (Peterson et al. 1975). To further exemplify the heterogeneous nature of the reticulospinal tracts, it has been shown that the individual fibers may be excitatory (glutamatergic), inhibitory (containing GABA, glycine, or both), or modulatory (e.g., serotonin) (Holstege and Kuypers 1987). At least part of the reticulospinal axons can have monosynaptic excitatory effects on motoneurons located throughout the length of the spinal cord (Shapovalov and Gurevitch 1970; Shapovalov 1972) as was also recently elegantly verified in mice using selective, monosynaptic, and conditional viral tracing techniques (Capelli et al. 2017; Esposito et al. 2014).

From the above, it follows that the actions of the reticulospinal system are extremely diverse (for review, see Arshavsky et al. 1986). Indeed, reticulospinal systems have been suggested to be involved in maintaining and controlling ongoing motor activity such as locomotion, in the gating of somatosensory information to segmental as well as supraspinal levels and in the control of autonomic activity including pain modulatory systems (Fields 2004; Saper 2004; Arber 2017).

The cerebellar nuclei are known to project prominently to the reticular formation (see Fig. 2), thereby involving the regions that give rise to the reticulospinal tracts. In fact the only nuclear region that does not seem to contribute significantly to pontomedullary reticular projections is the posterior interposed nucleus (PIN; Fig. 2, Table 1). Major inputs have been described to arise from specific areas of the MCN and LCN. In addition, in the rat, the nuclear region intercalated between the MCN and the interposed nuclei, i.e., the ICG, and the transition area between the interposed nuclei and the LCN, i.e., the DLH, also display projections to the pontomedullary reticular formation. Several of these cerebellar nuclear areas were recently shown to provide excitatory monosynaptic contacts to premotor neurons in the ventral part of the medullary reticular formation (Esposito et al. 2014). The organization of cerebellar nuclear projections to areas with reticulospinal input is further reviewed below.
Table 1

Overview of brainstem and diencephalic regions of the rat where labeled varicosities were found after injection with an anterograde tracer in the part of the cerebellar nuclei indicated and, at least partly, depicted in Figs. 2 and 3. Large dots denote dense labeling, intermediate dots indicate fair labeling, and small dots indicate sparse labeling. Question mark indicates that the area was not available for analysis; i indicates that the labeling was found ipsilateral to the injection side. (Based on Teune et al. 2000)

Medial Cerebellar Nucleus

Projections from especially the caudal aspect of the MCN have been shown to terminate in the dorsal aspect of the contralateral medial pontomedullary reticular formation by way of the uncinate tract in rat (Fig. 2d), cat, and monkey (Asanuma et al. 1983; Batton et al. 1977; Teune et al. 2000; Voogd 1964). In the monkey, the caudal region of the fastigial nucleus has been implicated in oculomotor functions subserving saccades (Noda 1991; Gonzalo-Ruiz et al. 1988). This area not only projects to the contralateral medial pontine reticular formation, known to be involved in saccade control (Enderle 2002), but also to the contralateral dorsomedial medullary reticular formation (Noda et al. 1990). This latter area would overlap the region from where neck muscles can be directly activated or inhibited (Peterson et al. 1975). Ipsilateral reticular projections that originate from the MCN are conspicuously less dense. They enter the brainstem by way of the direct fastigiobulbar tract located directly medial to the superior cerebellar peduncle (Teune et al. 2000; Voogd 1964; Ruigrok et al. 1990). The dorsolateral protuberance (DLP) of the MCN, which is prominent in rodents, has been shown to more specifically reach intermediate and lateral (i.e., parvicellular) parts of the contralateral reticular formation (Fig. 2c; Rubertone et al. 1990; Teune et al. 2000). The rostral MCN seems to preferentially target the vestibular nuclei (see below) and only sends moderate projections to the intermediate (mediolateral) levels of the reticular formation and to the lateral paragigantocellular nucleus (Fig. 2b). Bagnall et al. (2009) provided evidence that the ipsilateral connections of the MCN are glycinergic whereas glutamatergic MCN neurons project contralaterally. Glutamatergic but not glycinergic projections from the medial cerebellar nucleus control reticulospinal neurons involved in controlling manipulatory actions of the forelimbs (Esposito et al. 2014).

By definition, the Purkinje cells that innervate the MCN belong to the A zone (Voogd 1964; Voogd and Glickstein 1998), which has been subdivided into a number of subzones, each of which relate to a specific region of the MCN (Apps and Hawkes 2009; Voogd and Ruigrok 2004). Sugihara and Shinoda (2007) have suggested that three regions may be recognized in the MCN dealing with spinal (DLP and rostral MCN), eye movement (centrodorsocaudal MCN), and head orientation (centrocaudal MCN) aspects of motor control. The A zone has also been implicated in the control of emotional behavior, such as fear learning, affective state, cardiovascular control, and freezing behavior (Apps and Strata 2015; Bradley et al. 1991; Koutsikou et al. 2014), but it is not known to what extent this involvement is mediated by way of MCN projections to the reticular formation.

The Posterior Interposed Nucleus and the Interstitial Cell Groups

The ICG of the rat, which are intercalated between the MCN and both interposed nuclei, are the target of the Purkinje cells of the X and CX zone (Buisseret-Delmas et al. 1993, 1998; Voogd and Ruigrok 2004). They have been shown to have projections to the contralateral pontomedullary reticular formation, where they mostly terminate in the gigantocellular reticular nucleus (Fig. 2e; Teune et al. 2000). In the rat, apart from the nucleo-olivary projections, virtually no pontomedullary projections have been described that originate from the main body of the PIN.

The Anterior Interposed Nucleus and the Dorsolateral Hump

The dorsolateral hump (DLH) is sometimes also incorporated as part of the LCN (Angaut and Cicirata 1990), because it maintains reciprocal connections with the dorsomedial group of the principal olive (Ruigrok and Voogd 2000; Ruigrok et al. 2015). Nevertheless, it was originally described as part of the AIN (Goodman et al. 1963; Korneliussen 1968), and the DLH and lateral part of the AIN are the origin of the ipsilateral descending tract of the cerebellum (Bentivoglio and Kuypers 1982; Bentivoglio and Molinari 1985; Mehler 1967). They terminate mostly in the parvicellular regions of the ipsilateral pontomedullary reticular formation but also invade the deeper layers of the spinal trigeminal nucleus (Fig. 2f; Teune et al. 2000). Stimulation of the DLH induces movement of the lips, neck, and forelimbs (Cicirata et al. 1992; Angaut and Cicirata 1990). As such it has been suggested to be specifically involved in food manipulation. Indeed, the lateral and intermediate medullary reticular formation of the rat have been demonstrated to contain pre-oromotor neurons (Travers et al. 2000) and are involved with mastication and swallowing (Luo et al. 2001). More rostral regions of the lateral reticular region have been shown to be involved in vocalization in the squirrel monkey (Hannig and Jurgens 2006). The ventral part of the medullary reticular formation, on the other hand, has been shown to be critically involved in grasping (Esposito et al. 2014). Transneuronal transport of viral tracers suggests that the DLH may also be involved with eye blink as well as hind limb muscles (Morcuende et al. 2002; Ruigrok et al. 2008). The DLH receives its Purkinje fiber input from the D0 zone, which is intercalated between the D1 and D2 zones of lobules V–VII (Pijpers et al. 2005; Sugihara and Shinoda 2004).

The Lateral Cerebellar Nucleus

The connections of the LCN with the pontomedullary reticular formation are well documented for rat, cat, and monkey (Chan-Palay 1977; Teune et al. 2000; Tolbert et al. 1980). Particularly dense projections are noted in the contralateral gigantocellular reticular nuclei (Fig. 2g). The projection originates mostly from the magnocellular dorsal aspects of the nucleus suggesting that region receives its Purkinje cell projections mostly from the D2 zone. Projections also reach the ipsilateral reticular formation and have been shown to activate monosynaptically reticulospinal neurons to the lumbar cord in cat (Bantli and Bloedel 1975; Tolbert et al. 1980) and to the cervical cord in mice (Esposito et al. 2014). Especially, the recent work in mice suggests that the disynaptic dentate-reticulo-spinal may be used to control skilled motor behavior.

Vestibulospinal Tracts

Classically, the vestibular nuclear complex is divided into a medial (MV), spinal (SpV), lateral (LV), and superior vestibular nucleus (SuV). In addition, several subgroups have been recognized in various animals (i.e., groups F, L, X, Y, and Z) (Brodal 1974; Highstein and Holstein 2006). Vestibulospinal tracts are divided into a medial vestibulospinal tract, which descends by way of the mlf, originates mainly from the MV, and reaches to cervical levels where its fibers terminate bilaterally, and into a lateral vestibulospinal tract, which runs lateral to the mlf, originates from the LV, and descends and terminates mostly ipsilaterally throughout the length of the spinal cord (Brodal 1974; Holstege and Kuypers 1982; Nyberg-Hansen 1964b; Highstein and Holstein 2006; Kasumacic et al. 2015; Lambert et al. 2016; Voogd 2016). Apart from their termination in the ventromedial part of the intermediate zone of the spinal cord, projections to the dorsal horn have been described (Bankoul and Neuhuber 1992). Moreover, the medial vestibulospinal tract may carry both inhibitory and excitatory fibers, whereas the LV neurons that contribute to the lateral vestibulospinal tract are excitatory. In addition to the vestibulospinal tracts, projections from especially the MV and SV are directed to the oculomotor centers where they can have excitatory or inhibitory influences. Some neurons, mostly located in the rostral, magnocellular part of the MV, collateralize to both the oculomotor centers as well as the cervical cord (Highstein and Holstein 2006; Ruigrok et al. 1995; Voogd and Barmack 2006). Finally, vestibular connections to autonomic brainstem systems are known that may regulate cardiovascular responses (Balaban and Porter 1998; Highstein and Holstein 2006).

The vestibular nuclei are intimately connected with the cerebellum (Voogd 2016; Voogd et al. 1996). Not only is a large part of its output directed to the cerebellar cortex and nuclei, but it also receives a main input from the cerebellum (e.g., see Fig. 2b). The cerebellar input to the vestibular complex is special because it is the only brainstem system that receives afferents from the cerebellar nuclei as well as directly from the cerebellar cortex.

Cerebellar Corticovestibular Projections

Direct projections from the cerebellar cortex to the vestibular nuclei arise from the vermis (lateral A and B zones), from the caudal vermis (ventral uvula and nodulus), and from the flocculus and adjacent ventral paraflocculus (Voogd et al. 1996). The projections from the Purkinje cells of the B zone, which is mostly located in lobules I–VIa but also has a small component in lobule VIII (Ruigrok et al. 2008; Sugihara and Shinoda 2004), to the neurons of the LV constitute the most direct influence of the cerebellar cortex on a descending pathway (Ito and Yoshida 1966; Voogd 2016). The B-zone-lateral vestibulospinal connection is mostly involved in the control of extensor or anti-gravity musculature (Arshavsky et al. 1986). Purkinje cell projections from the nodulus and ventral uvula can be found throughout most of the vestibular complex with the exception of the LV (Bernard 1987; Wylie et al. 1994). This region is implicated in the control of head movement. Floccular projections to the vestibular nuclei seem to terminate in a more orderly fashion. Purkinje cells that show modulation in their firing frequency upon visual stimulation around a vertical axis project predominantly to the magnocellular part of the MV, whereas Purkinje cells modulated by visual stimulation around a horizontal axis project to SV and the Y-group (De Zeeuw et al. 1994; Schonewille et al. 2006; Tan et al. 1995; Balaban et al. 2000). Floccular function is predominantly attributed to the control of the vestibulo-ocular reflex and its coordination with pursuit movements (Ilg and Thier 2008; Voogd and Barmack 2006). The Purkinje cells of the flocculus target a specific population of the MV, termed floccular target neurons, which have physiological characteristics resembling cerebellar projections neurons (Sekirnjak et al. 2003).

Cerebellar Nucleo-Vestibular Connections

More indirect control of vestibular function is also induced by the Purkinje cells of the A zone by way of the MCN. Apart from the reticular connections mentioned above, prominent, usually bilateral, projections to virtually all components of the vestibular nuclei are found (Teune et al. 2000), which mostly, but not exclusively, originate from the rostral part of the MCN (Fig. 2, Table 1). In the mouse ipsilateral MCN projections, like the projections to the reticular formation, have been shown to be glycinergic, whereas contralateral vestibular projections are glutamatergic (Bagnall et al. 2009). It is not known if cortical and MCN projections converge upon the same vestibular regions or neurons. Sparse vestibular projections from the other cerebellar nuclei arise from ICG, AIN, DLH, and LCN and are mostly ipsilateral (Delfini et al. 2000; Teune et al. 2000). They suggest that cerebellar processes are widely integrated with vestibular functions.

Rubrospinal Tract

In most mammals the red nucleus (RN) can be recognized as a prominent round structure located centrally in the rostral part of the mesencephalic tegmentum. Usually, a distinction is made between a caudal magnocellular part (RNm) and a rostral parvicellular part (RNp). It should be recognized that this distinction to some extent relates to the difference in projections of both regions. The magnocellular part is the origin of the crossed rubrospinal tract. This part can be identified in the mesencephalon of most limb-carrying terrestrial vertebrates (ten Donkelaar 1988). In primates and carnivores, the parvicellular part is mostly associated with the uncrossed projection to the inferior olive by way of the central tegmental tract. Miller and Gibson (2009) have proposed the additional term of parvicellular contralateral red nucleus (RNpc) to identify small- and medium-sized neurons that also project to the contralateral spinal cord or the contralateral brainstem (Pong et al. 2008; Esposito et al. 2014). Thus, the axons of RNm and RNpc neurons cross at the level of the red nucleus, project mostly contralaterally, and basically only differ from each other with respect to the distance they have to travel to their respective main projection region, i.e., caudal cord versus rostral cord or brainstem. On the other hand, RNp neurons, by definition, project to the ipsilateral olive by way of the central tegmental tract. As such, the rodent red nucleus, as defined by the atlas of Paxinos and Watson (1998), essentially only consists of RNm and RNpc neurons (Ruigrok 2004; Rutherford et al. 1984). In many other species, such as cat, macaque, and human, a “real” RNp has been identified (for review see Onodera and Hicks 2009). In addition, in these animals, as well as in the rodent, immediately rostral, medial, and dorsal to the RN, several areas are located that basically surround the retroflex fascicle and carry names such as the nucleus of Bechterew, nucleus of Darkschewitsch, interstitial and rostral interstitial nucleus of the medial longitudinal fascicle, subparafascicular nucleus, and prerubral field. Homologies between various names that are presently in use are difficult to establish (e.g., see Onodera and Hicks 2009; Ruigrok 2004), but these nuclei mostly have in common the fact that they contain small neurons, which project massively to the inferior olive. For this reason they have been collectively named as nucleus parafascicularis prerubralis in the rat (Carlton et al. 1982; Ruigrok 2004). Onodera and Hicks (2009) have provided evidence that the projection from this mesodiencephalic area to the inferior olive is topographically organized and that some species differences may exist in whether these projections course by way of either the medial or central tegmental tracts.

Rubrospinal fibers terminate mostly within the intermediate zone of the spinal cord; however terminals are also found at cervical levels in lamina IX of monkey, cat, and rat (Miller and Gibson 2009) where they may sparsely terminate on motoneurons that innervate distal muscles (Al-Izki et al. 2008; Kuchler et al. 2002). Rubrospinal fibers also collateralize to the lateral reticular nucleus and to the anterior interposed nucleus (Beitzel et al. 2017; Huisman et al. 1983; Rajakumar et al. 1992; Shokunbi et al. 1986).

The function of the rubrospinal tract is still under debate. Selective lesion of this system produces only mild deficits in motor control. In cat and monkey, this affects grasping behavior and causes dragging of the dorsum of the paw during locomotion (Horn et al. 2002; Miller and Gibson 2009). In rat, mild changes in locomotion pattern have been described (Muir and Whishaw 2000; Whishaw et al. 1998). RNm stimulation mostly seems to affect distal extensor muscles in cat (Horn et al. 2002), whereas most RNm units display up-modulation during the swing phase in stepping decerebrate cats (Arshavsky et al. 1986, 1988).

Many authors have mentioned that the rubrospinal tract diminishes with the expansion of the corticospinal tract. In man, it is questioned if the rubrospinal tract, which may consist of only several hundreds of fibers, descends beyond the cervical level (for review see Onodera and Hicks 2009). The decrease in size of the rubrospinal tract is countered by an increase in the importance of the RNp and adjacent regions to the inferior olive. It has been speculated that the relative increase in the projection from the mesodiencephalic junction nuclei to the inferior olive or to specific parts thereof mimics the increased control of cerebellar and cortical structures over specific motor functions and, in man, may have enabled the advent of bipedalism and speech (Onodera and Hicks 1999, 2009; Hicks and Onodera 2012).

Cerebellar Projections to the Red Nucleus

Rubrospinal neurons are heavily targeted by the AIN (Fig. 3a, f–h, Table 1), fibers of which terminate in a somatotopic fashion (Daniel et al. 1987; Ruigrok 2004; Teune et al. 2000) on their somata and proximal dendrites (Ralston 1994). Although small changes may exist between different mammalian species, it appears that the medial or mediorostral part of the AIN projects to the RN part that sends projections to the lumbar cord whereas the (caudo-)lateral-most part of the AIN targets RN regions that terminate within the contralateral brainstem and upper cervical cord (Conde 1988; Daniel et al. 1987; Stanton 1980).
Fig. 3

Serial plots (bk) of coronal sections depicting patterns of labeled varicosities (i.e., terminal arborizations) in the rostral brainstem and mesodiencephalic junction after various injections (shown in a) with an anterograde tracer in the cerebellar nuclei of the rat. (Adapted from Teune et al. 2000)

The medial aspect of the PIN projects to the medial margin of the RNm in rat (Fig. 3a, e; Daniel et al. 1987) and cat (Robinson et al. 1987). This projection is less dense compared to the input derived from the AIN. RNm projections originating from the MCN and LCN are sparse or non-existent, the latter mostly targeting regions immediately lateral and rostral to the RNm (Fig. 3). The PIN and LCN projections to the primate and cat RNp and the rodent area of the nucleus parafascicularis prerubralis function in a cerebellar nucleo-midbrain-olivary loop (De Zeeuw and Ruigrok 1994; Onodera and Hicks 2009; Ruigrok and Voogd 1995; Guillain et al. 1933).

Tectospinal Tract

The superior colliculus is mostly associated with visual input and is involved in directing gaze to objects of interest. This is performed by saccades, head movements, or a combination of both. The control of the superior colliculus over the paramedian pontine reticular formation from where saccades are initiated is well established in most mammals (Enderle 2002). However, in addition, arm or even whole body movements may be evoked by stimulation of the superior colliculus. These body movements are triggered by tectoreticular and tectospinal pathways (Harting 1977; Nyberg-Hansen 1964a; Rose and Abrahams 1978). The tectospinal component seems to be small in most mammals with the largest component to be found in carnivores (Meredith et al. 2001; Murray and Coulter 1982; Nudo and Masterton 1989). Most tectospinal neurons do not project beyond the cervical segments from where the neck muscles are innervated (Nudo and Masterton 1989). Most axons arise from the caudolateral quadrant and, after decussating in the dorsal tegmental decussation, descend contralaterally close to the mlf where they form the predorsal bundle. In cat, a small ipsilateral projecting group of tectospinal fibers has been described (Olivier et al. 1994). Although tectospinal cells may terminate directly on cervical motoneurons (Olivier et al. 1995), conclusive anatomical proof has not yet been obtained (Muto et al. 1996; Shinoda et al. 2006). Therefore, the most direct impact of superior colliculus on cervical neck motoneurons seems to involve at least a segmental or reticular relay (Kakei et al. 1994; Shinoda et al. 2006).

Cerebellar Nucleo-Tectal Connections

The cerebellar nuclei have a profound and often neglected impact on the mesencephalic tectum. Cerebellar projections to this region mostly terminate in the intermediate and deep layers of the contralateral superior colliculus (Fig. 3, Table 1). In various animals they have consistently been shown to originate predominantly from two areas of the cerebellar nuclei. The lateral aspect of the PIN and adjacent area of the LCN supply the bulk of cerebellotectal projections (Hirai et al. 1982; Kurimoto et al. 1995; May and Hall 1986; May et al. 1990; Uchida et al. 1983). Both regions mediate information from the paraflocculus, which is known to receive mostly extrastriate visual information by way of the dorsolateral basal pons in rat, cat, and monkey (Gayer and Faull 1988; Glickstein et al. 1994; Robinson et al. 1984; Kralj-Hans et al. 2007). In the macaque, neurons in the lateral PIN and LCN have been shown to connect disynaptically to visually related regions in the posterior parietal cortex (Prevosto et al. 2010).

Projections to the superior colliculus also arise from the caudal, oculomotor, half of the MCN (Fig. 3a, b). This part mostly receives cortical input from the oculomotor vermis (caudal lobule VI and lobule VII) and has been suggested to be specifically involved with the control and adaptation of saccades (Thier et al. 2002; Noda and Fujikado 1987; Fujikado and Noda 1987; Takagi et al. 1998). Interestingly, the MCN of the rabbit, and hardly that of the gray squirrel, do not project to the superior colliculus (Uchida et al. 1983; May and Hall 1986), a finding that seems to correlate well with the observation that the rabbit superior colliculus does not seem to be essential for generating either saccades or optokinetic nystagmus (Collewijn 1975). The lateral aspect of the AIN has also been reported to provide input to the superior colliculus in the rat and rabbit (Kurimoto et al. 1995; Uchida et al. 1983). In the cat and monkey, the MCN has been shown to terminate bilaterally, generally located somewhat more superficial compared to the PIN projections which terminate strictly contralateral and deeper in the intermediate layer (Kawamura et al. 1982; May et al. 1990). Both types of projections seem to make use of a different type of synapse as judged from their respective degeneration characteristics (Warton et al. 1983) and have been suggested to play different roles in the control of saccades. A clear topographic pattern, however, has not been described in a variety of mammals (Hirai et al. 1982; Kawamura et al. 1982; Kurimoto et al. 1995; May and Hall 1986; May et al. 1990; Noda et al. 1990; Uchida et al. 1983; Teune et al. 2000). The ventrolateral aspect of the caudal superior colliculus reportedly receives the densest cerebellar input (Fig. 3). However, cerebellar terminals are also found in tectal areas that contain large tectospinal neurons. Presently, no specific anatomical information seems to be available that positively identifies the collicular targets of the cerebellar output (Warton et al. 1983). Although GABAergic projections to the pretectum have been reported to arise from the lateral PIN and ventral LCN in the cat (Nakamura et al. 2006), no evidence for cerebellar inhibitory synapses in the superior colliculus has been found (Warton et al. 1983).

Interstitiospinal Tract

The interstitiospinal tract originates from scattered large neurons located dorsomedially to the red nucleus and lateral to the oculomotor nuclei and periaqueductal gray within and surrounding the mlf. This poorly defined region is known as the interstitial nucleus of Cajal (INC). Fibers descend ipsilaterally by way of the mlf to the spinal cord where they terminate in laminae VII and VIII of the spinal gray. The interstitiospinal tract has excitatory monosynaptic contacts with neck musculature but also provides di- and polysynaptic mostly excitatory activation of back, forelimb, and hind limb muscles (Fukushima et al. 1978; Holstege and Cowie 1989). The INC, apart from acting as origin of the interstitiospinal tract, is also involved in the control of eye movements. Neurons participating in this function appear to form a different population from the cells that give rise to the interstitiospinal tract (Bianchi and Gioia 1995; Zuk et al. 1983). Projections from the INC also reach the oculomotor nuclei, the pontine reticular formation, and the vestibular nuclei. As such it plays an important role in coordinating eye and head movements. The area directly rostral the INC, known as the rostral interstitial nucleus of the mlf and containing many parvalbumin-containing neurons, provides input to the INC and is specifically involved in the control of vertical eye movements (Buttner-Ennever 2006; Fukushima-Kudo et al. 1987; Fukushima 1991; Horn and Buttner-Ennever 1998; Tolbert et al. 1978b).

Cerebellar Projections to the Interstitial Nucleus of Cajal

Most prominent cerebellar projections to the INC arise from the oculomotor part of the MCN in rat (Fig. 3b), cat, and monkey (Noda et al. 1990; Teune et al. 2000; Sugimoto et al. 1982). However, it also receives an afferent contribution from other parts of the cerebellar nuclei (Table 1) (Chan-Palay 1977; Teune et al. 2000).

Cerebellar Projections to Other Areas

Apart from the cerebellar projections to the five classic descending premotor tracts, all cerebellar nuclei also provide input to various regions of thalamus (Aumann et al. 1994; Chan-Palay 1977; Teune et al. 2000), which will not be reviewed here (but see Table 1). Also, many cerebellar nuclear neurons have been shown to provide input to the cerebellar cortex (Provini et al. 1998; Batini et al. 1992; Buisseret-Delmas and Angaut 1988; Tolbert et al. 1978b; Gao et al. 2016; Houck and Person 2015; Ankri et al. 2015), some of which may be inhibitory (Uusisaari and Knopfel 2010; Batini et al. 1989; Ankri et al. 2015).

In addition, the cerebellar nuclei provide input to a number of precerebellar nuclei in the brainstem. Cerebellar nuclear inputs to the reticulotegmental nucleus of the pons and the basal pontine nuclei are well-known and have been shown to participate in potential functionally important reverberating circuitry involving cerebello-bulbo-cerebellar loops (Mock et al. 2006; Tsukahara et al. 1983). However, projections to nuclei that give rise to the descending motor tracts may also provide feedback to the cerebellum, i.e., the vestibular nuclei and reticular formation form an important source of mossy fiber input to the cerebellum. In addition, many rubrospinal fibers have been demonstrated to collateralize specifically to the AIN (Huisman et al. 1983; Beitzel et al. 2017). A more prominent connection to a precerebellar nucleus, be it of a very different category, is formed by the cerebellar nuclear projections to the inferior olive. This connection has been shown to precisely match the collateral projection of the cerebellar climbing fibers to the cerebellar nuclei (Ruigrok and Voogd 1990, 2000) and to consist exclusively of GABAergic fibers (De Zeeuw et al. 1989; Fredette and Mugnaini 1991) that originate from a population of small neurons intermingled with the larger and generally excitatory projection neurons and to possess their own physiological characteristics (Fredette and Mugnaini 1991; Uusisaari et al. 2007; Najac and Raman 2015). The population of small GABAergic neurons in the cerebellar nuclei most likely exclusively targets the inferior olive (Teune et al. 1995; De Zeeuw and Ruigrok 1994).

Another major target of cerebellar nuclear projections is formed by nuclei that themselves supply a major input to the inferior olive. Especially the nuclei in the mesodiencephalic junction participate in this cerebellar nucleo-mesodiencephalo-olivo-cerebellar loop (De Zeeuw and Ruigrok 1994; Ruigrok and Voogd 1995). In man, the main circuit is formed by the projections from the dentate nucleus to the parvicellular RN, which, by way of the central tegmental tract, targets the principal olive. Although the function of this circuit is far from clear (Ruigrok 1997; Ruigrok and Voogd 1995; Hoebeek et al. 2010; Kennedy 1990), this so-called triangle of Guillain-Mollaret (Guillain et al. 1933) has received attention as lesions of this circuit may be instrumental to inducing myoclonus, or rhythmic tremor, of the palatal muscles (sometimes also involving pharyngeal, laryngeal, diaphragm, or extraocular muscles) but also of conspicuous enlargement of particular parts of the inferior olive (Gautier and Blackwood 1961; Boesten and Voogd 1985; Ruigrok et al. 1990; Shaikh et al. 2010).

Finally, cerebellar nuclear connections have been described that do not fall within any of the categories mentioned above (Table 1). Examples include the cerebellar projections to hypothalamic areas, zona incerta, parvicellular reticular formation, parabrachial nuclei, and periaqueductal gray (Teune et al. 2000; Zhu and Wang 2008; Haines et al. 1997). These connections suggest a wide impact of cerebellar processing involving various autonomic as well as pain functions.

Divergence of Cerebellar Projections

The wide array of cerebellar targets described with anterograde techniques, even after small injections, suggests that individual nucleo-bulbar fibers may collateralize to multiple brainstem and diencephalic areas (Chan-Palay 1977; Teune et al. 2000). A survey of cerebellar nuclear targets based on a study with anterograde tracers in the rat is provided in Table 1 and was, partly, shown in Fig. 3 (both based on Teune et al. 2000). A systematic survey of collateralization based on reconstructions of individual fibers has not yet been performed, but two examples of completely reconstructed axons originating from the posterior interposed nuclei are shown in Fig. 4 (Ruigrok, unpublished data). Information on the wide collateralization of cerebellar nuclear axons is further based on available partial reconstructions (Shinoda et al. 1988), double retrograde tracing (Bentivoglio and Kuypers 1982; Lee et al. 1989; Gonzalo-Ruiz and Leichnetz 1987; Ruigrok and Teune 2014), and electrophysiological data (Tolbert et al. 1978a; Bharos et al. 1981). From these studies it is evident that, as a rule, individual nucleo-bulbar neurons, with the exception of the nucleo-olivary neurons, influence multiple areas simultaneously. Indeed, from Table 1 (also see Figs. 2 and 3), it can be seen that relatively small injections result in labeled varicosities within at least ten different areas (and usually considerably more). From the available anterograde and retrograde tracing data, it can be deduced that individual projection neurons in the cerebellar nuclei are likely to be involved in the control of several motor pathways. For example, a neuron in the AIN projecting to the magnocellular red nucleus may also influence, by way of ongoing projections to the ventrolateral and ventro-anterior region of the thalamus, motor output by way of the corticospinal tract. Simultaneously, activity may be fed back to the cerebellar cortex directly by way of nucleocortical collaterals (Gao et al. 2016; Houck and Person 2015; Tolbert et al. 1978b), by way of direct nuclear projections to the basal pontine nuclei (Tsukahara et al. 1983), by way of rubrocerebellar collaterals of the rubrospinal tract (Beitzel et al. 2017), or by way of longer circuits such as the cortico-ponto-cerebellar route. It is evident that a more elaborate knowledge on the circuitry involving individual neurons will be necessary in order to be able to evaluate the functional processing within these multiple circuits.
Fig. 4

(a, b) Reconstructions of bulbar course and terminations of two axons originating in the interposed nuclei. Axons were labeled from a small injection with biotinylated dextran amine in the interposed nucleus. Individual axons were isolated and followed in consecutive coronal sections (80 μ) using Neurolucida (MicroBrightfield, Inc., Williston, VT, USA). Axonal varicosities are indicated with red dots; contours of CN, BPN, RN, and VTh are indicated in green; ventricular system is indicated in gray. Left-hand panels depict lateral view; right-hand panels depict dorsal view. Axon shown in (a) has main branches in deep layers of SC, BPN, ZI, and intralaminar and ventrolateral thalamic nuclei. Axon in (b) has main branches in parabrachial nuclei, PAG, ZI, and ventrolateral thalamus. For abbreviations see “List of Abbreviations.” (Based on Ruigrok, unpublished data)

Convergence of Cerebellar Projections

In contrast to the apparent divergence of cerebellar nuclear connections, a considerable convergence of cerebellar output to specific muscles has also been noted. Injections with the retrogradely and transneuronally transported rabies virus into several muscles have resulted in viral labeling of several locations within the cerebellar nuclei and cerebellar cortex (Graf et al. 2002; Morcuende et al. 2002; Ruigrok et al. 2008; Tang et al. 1999). Ruigrok et al. (2008) showed that viral injections in antagonistic muscles of hind limb and forelimb result in infection of several longitudinal strips of Purkinje cells which were partly overlapping (Fig. 5). Initial strips were observed only in the vermis, but, with only slightly longer survival times, additional strips were found in paravermal and hemispheral parts of the cerebellum (Fig. 5). This suggests that multiple cerebellar modules, by way of their individual nuclear output, ultimately can converge to control the activity of the same muscle. Simultaneously however, the overlap of labeled strips suggests that a single module, by way of its nuclear output, can influence the activity of several, and even antagonistic, muscles or muscle groups. It is clear that the latter characteristic, at least partly, is also based on the distributed nature of the termination of individual fibers of the, e.g., reticulospinal and rubrospinal tracts (Shinoda et al. 1977, 2006).
Fig. 5

Demonstration of involvement of multiple cerebellar modules in the control of single muscles using transneuronal retrograde transport of rabies virus in rat. (a1) Pattern of Purkinje cell labeling in the lateral vermis 5 days after rabies injection in the ipsilateral gastrocnemius muscle. (a2) 3-D reconstruction of the anterior lobe of this case indicating rabies-labeled Purkinje cells (red) together with zebrin II-labeled Purkinje cells (yellow). Note that the zebrin II-labeled bands identified as p1–p6 can all be recognized. The position of the rabies-labeled Purkinje cells between p2 and p3 (left-hand white arrowhead) is identical to that of the B zone. In addition, a contralateral strip of labeled Purkinje cells is noted just medial to the p2 zebrin II band (right-hand white arrowhead), which corresponds to the location of the lateral A1 zone. (b1, 2) Similar to (a1, 2) after injection of rabies virus in the ipsilateral anterior tibial muscle. This time both the B and lateral A1 zone (arrowhead) are noted ipsilateral to the injection. (c) Pattern of infection 6 days after injection of the gastrocnemius muscle. Note that the original zones can still be recognized but also have a mirror representation in the other cerebellar hemisphere. However, several additional zones are also recognized (arrowhead) in paravermis and hemisphere (not shown). (d) Similar to (c) for injection of the anterior tibial muscle. (Modified from Ruigrok et al. 2008 and Ruigrok 2011)

Functional Implications

The modular characteristics of the cerebellar circuitry, where strips of Purkinje cells converge upon an entity of the cerebellar nuclei and that is matched by the organization of the olivocerebellar climbing fiber system, have been suggested to lie at the basis of the functional working blocks of the cerebellum (Apps and Garwicz 2005; Ruigrok 2011). However, from the account sketched above, it will be obvious that as yet it is by no means clear how individual cerebellar modules interact with brainstem structures to result in functionally meaningful signals. For example, individual modules, by way of their collateralizing output, are capable of influencing numerous brainstem structures simultaneously, which may include several nuclei that have descending connections to the spinal cord. On the other hand, as shown with viral tracing techniques, multiple modules may participate in the control of the same muscle. This particular organization suggests that each cerebellar module may serve a specific function in the control of muscles. The interaction of multiple strips of Purkinje cells with several targets areas has most clearly been demonstrated in the relatively simple system of floccular control on reflexive eye movements (van der Steen et al. 1994; Voogd and Wylie 2004; Ruigrok et al. 1992; Sugihara et al. 2004; Wylie et al. 2017). However, studies that attempted to study the contribution of individual modules to skeletomotor function also suggest that a single module may affect a particular type of muscle control (Horn et al. 2010; Cerminara and Apps 2010; Pijpers et al. 2008). For example, impairment of the C1 hind limb module has been shown to affect the phase-locked modulation of reflexes during locomotion (Pijpers et al. 2008). Inactivation or lesion of various olivary regions, resulting in inactivation or severe functional impairment of related cerebellar nuclear areas, also results in highly specific deficits in motor control (Horn et al. 2010; Cerminara and Apps 2010). Hence, different cerebellar modules seem to be able to participate in the control of potentially the same muscles that are being used in different functional contexts.

Clinical Implications

From this account it will be obvious that the impacts of cerebellar malfunctioning are diverse and not infrequently difficult to fully understand. Due to the distributed connectivity, specific damage of the vestibulocerebellar, vermal, paravermal, and hemispheral components of the cerebellum results in various combinations of specific cerebellar disorders (Thach and Bastian 2004). Conversely, due to the nature of ongoing spinocerebellar degenerative disease, this may differentially influence a multitude of cerebellar modules. Likewise, cerebellar tumors or lesions will almost invariably involve several adjacent modules in an incomplete way (i.e., the modules are organized in longitudinal cortical arrays which can be discontinuous and may be found in both the anterior and posterior lobes (Pijpers et al. 2006; Ruigrok 2011). The resulting clinical syndrome, therefore, is hard to predict or explain.

Nevertheless, and despite the recent recognition that the cerebellum may be involved in a large array of non-motor brain functions, cerebellar disorders can lead to very clear motor deficits. Obviously, due to the double decussation of most cerebellofugal projections (i.e., the decussation of the superior cerebellar peduncle in the caudal mesencephalon, followed by the decussation of corticospinal and rubrospinal tracts), unilateral cerebellar deficits usually involve affected movements of the ipsilateral side of the body.

Cerebellar-based handicaps in motor control commonly involve three symptoms: muscle weakness (hypotonia), ataxia, and tremor (Thach and Bastian 2004).


Sudden removal of cerebellar nuclear output in cases of, e.g., trauma, will diminish the tonic excitatory drive to premotor regions. This is likely to result in a general reduction of activation of the related motoneuron pools, which will be reflected in reduced muscle tone (hypotonia). Similarly, however, cerebellar lesions that do not involve the nuclei are likely to diminish the inhibitory drive of the cortical Purkinje cells on the cerebellar nuclei, thereby increasing nuclear output resulting in hypertonic responses. Hypotonia and hypertonia may (partly) disappear after a period of weeks or months, probably by adjustment of the tonic drive to premotor regions by other, unaffected, cerebellar or extracerebellar brain regions.


Although ataxia is typical for cerebellar disorders, it is not easily characterized. It usually reflects the inability of a patient to execute voluntary movements in a “normal” way. Movements, or parts thereof, are not initiated at the correct moment, are not terminated at the appropriate time, and are not corrected adequately. This results in improperly conducted and dysmetric movements. To some extent hypo- and hypertonia of muscles or muscle groups form the foundation of these motor deficits. Because antagonistic and correcting activity is inadequately timed, oscillations will easily occur around the intended target or result in pendular reflexes. Due to dysmetria and failure to time movements, cerebellar patients also encounter problems with the execution of fast rhythmic movements (dysdiadochokinesis). When these disorders concern the mouth, pharynx, or larynx musculature, it results in cerebellar dysarthria that typically involves changes in rhythm and amplitude in combination with a careless or “slurred” pronunciation.

Intention Tremor

This form of tremor is also very characteristic in cerebellar disorders and may be related to dysfunction of properly timed components of movements, resulting in a disturbance in the beat and rhythm of movements with tremor as a consequence. Increased pendular reflexes are clearly related to this phenomenon. Cerebellar nystagmus may be seen as a form of intention tremor reflecting dysfunction of the vestibulocerebellum.

Conclusions and Future Directions

The cerebellum is usually appreciated as a structure with a uniform internal structure that will perform a particular type of information processing. Within this internal structure, based on the organization of corticonuclear and olivocerebellar connections, a number of parallel, longitudinally organized, modules can be recognized which form functional entities. The organization of the input to these modules and in particular the organization of their output channels, therefore, will determine the type of information processed within a module and which structures will be informed of its result. The above account shows that the output of a particular module is directed to many regions in brainstem and diencephalon and may affect multiple centers with descending connections to the spinal cord. In addition, several modules may ultimately affect activity patterns of the same muscle or muscle group. In order to fully understand the cerebellar involvement in motor control and learning (and in other functions), it will be imperative to understand to what extent individual modules or micromodules control different aspects of controlling muscles. In addition, a precise description of the often di- and polysynaptic pathways involved will be necessary. The advent of new neuroanatomical and physiological techniques such as selective (modular) lesioning, conditional transneuronal tracing, single-axon reconstructions, and optogenetics is expected to greatly aid in fulfilling these requirements for further understanding cerebellar function and dysfunction.




This work was supported by the Dutch Ministry of Health, Welfare and Sports (T.R.).


  1. Al-Izki S, Kirkwood PA, Lemon RN, Enriquez Denton M (2008) Electrophysiological actions of the rubrospinal tract in the anaesthetised rat. Exp Neurol 212(1):118–131PubMedGoogle Scholar
  2. Allen GI, Tsukahara N (1974) Cerebrocerebellar communication systems. Physiol Rev 54(4): 957–1006PubMedGoogle Scholar
  3. Angaut P, Cicirata F (1990) Dentate control pathways of cortical motor activity. Anatomical and physiological studies in rat: comparative considerations. Arch Ital Biol 128(2–4):315–330PubMedGoogle Scholar
  4. Ankri L, Husson Z, Pietrajtis K, Proville R, Lena C, Yarom Y, Dieudonne S, Uusisaari MY (2015) A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity. Elife 4.
  5. Apps R, Garwicz M (2005) Anatomical and physiological foundations of cerebellar information processing. Nat Rev 6(4):297–311Google Scholar
  6. Apps R, Hawkes R (2009) Cerebellar cortical organization: a one-map hypothesis. Nat Rev 10(9):670–681Google Scholar
  7. Apps R, Strata P (2015) Neuronal circuits for fear and anxiety – the missing link. Nat Rev 16(10):642. Scholar
  8. Arber S (2017) Organization and function of neuronal circuits controlling movement. EMBO Mol Med 9(3):281–284. Scholar
  9. Arshavsky YI, Gelfand IM, Orlovsky GN (1986) Cerebellum and rhythmical movements. Studies of brain function, vol 13. Springer, Berlin/HeidelbergGoogle Scholar
  10. Arshavsky YI, Orlovsky GN, Perret C (1988) Activity of rubrospinal neurons during locomotion and scratching in the cat. Behav Brain Res 28(1–2):193–199PubMedGoogle Scholar
  11. Asanuma C, Thach WT, Jones EG (1983) Brainstem and spinal projections of the deep cerebellar nuclei in the monkey, with observations on the brainstem projections of the dorsal column nuclei. Brain Res 286(3):299–322PubMedGoogle Scholar
  12. Aumann TD, Rawson JA, Finkelstein DI, Horne MK (1994) Projections from the lateral and interposed cerebellar nuclei to the thalamus of the rat: a light and electron microscopic study using single and double anterograde labelling. J Comp Neurol 349(2):165–181. Scholar
  13. Bagnall MW, Zingg B, Sakatos A, Moghadam SH, Zeilhofer HU, du Lac S (2009) Glycinergic projection neurons of the cerebellum. J Neurosci 29(32):10104–10110Google Scholar
  14. Balaban CD, Porter JD (1998) Neuroanatomic substrates for vestibulo-autonomic interactions. J Vestib Res 8(1):7–16PubMedGoogle Scholar
  15. Balaban CD, Schuerger RJ, Porter JD (2000) Zonal organization of flocculo-vestibular connections in rats. Neuroscience 99(4):669–682PubMedGoogle Scholar
  16. Bankoul S, Neuhuber WL (1992) A direct projection from the medial vestibular nucleus to the cervical spinal dorsal horn of the rat, as demonstrated by anterograde and retrograde tracing. Anat Embryol 185(1):77–85PubMedGoogle Scholar
  17. Bantli H, Bloedel JR (1975) Monosynaptic activation of a direct reticulo-spinal pathway by the dentate nucleus. Pflugers Arch 357(3–4):237–242PubMedGoogle Scholar
  18. Batini C, Buisseret-Delmas C, Compoint C, Daniel H (1989) The GABAergic neurones of the cerebellar nuclei in the rat: projections to the cerebellar cortex. Neurosci Lett 99:251–256PubMedGoogle Scholar
  19. Batini C, Compoint C, Buisseret-Delmas C, Daniel H, Guegan M (1992) Cerebellar nuclei and the nucleocortical projections in the rat: retrograde tracing coupled to GABA and glutamate immunohistochemistry. J Comp Neurol 315:74–84PubMedGoogle Scholar
  20. Batton RR, Jayaraman D, Ruggiero D, Carpenter MB (1977) Fastigial afferent projections in the monkey: an autoradiographic study. J Comp Neurol 174:281–306Google Scholar
  21. Beitzel CS, Houck BD, Lewis SM, Person AL (2017) Rubrocerebellar feedback loop isolates the interposed nucleus as an independent processor of corollary discharge information in mice. J Neurosci 37(42):10085–10096. Scholar
  22. Bentivoglio M, Kuypers HGJM (1982) Divergent axon collaterals from rat cerebellar nuclei to diencephalon, mesencephalon, medulla oblongata and cervical cord. Exp Brain Res 46:339–356PubMedGoogle Scholar
  23. Bentivoglio M, Molinari M (1985) Crossed divergent axon collaterals from cerebellar nuclei to thalamus and lateral medulla oblongata in the rat. Brain Res 362:180–184Google Scholar
  24. Bernard JF (1987) Topographical organization of olivocerebellar and corticonuclear connections in the rat – an WGA-HRP study: I. Lobules IX, X, and the flocculus. J Comp Neurol 263(2): 241–258PubMedGoogle Scholar
  25. Bharos TB, Kuypers HGJM, Lemon RN, Muir RB (1981) Divergent collaterals from deep cerebellar neurons to thalamus and tectum, and to the medulla oblongata and spinal cord: retrograde fluorescent and electrophysiological studies. Exp Brain Res 42:399–410PubMedGoogle Scholar
  26. Bianchi R, Gioia M (1995) Fine structure of the interstitial nucleus of Cajal of the cat. J Anat 187(Pt 1):141–150PubMedPubMedCentralGoogle Scholar
  27. Boesten AJP, Voogd J (1985) Hypertrophy of neurons in the inferior olive after cerebellar ablations in the cat. Neurosci Lett 61:49–54PubMedGoogle Scholar
  28. Bradley DJ, Ghelarducci B, Spyer KM (1991) The role of the posterior cerebellar vermis in cardiovascular control. Neurosci Res 12(1):45–56. Scholar
  29. Brodal A (1974) Anatomy of the vestibular nuclei and their connections. In: Kornhuber HH (ed) Handbook of sensory physiology, vol VI, I: Vestibular system. Springer, New York, pp 239–352Google Scholar
  30. Buisseret-Delmas C, Angaut P (1988) The cerebellar nucleo-cortical projections in the rat. A retrograde labeling study using horseradish peroxidase combined to a lectin. Neurosci Lett 84:255–260PubMedGoogle Scholar
  31. Buisseret-Delmas C, Yatim N, Buisseret P, Angaut P (1993) The X zone and CX subzone of the cerebellum in the rat. Neurosci Res 16:195–207PubMedGoogle Scholar
  32. Buisseret-Delmas C, Angaut P, Compoint C, Diagne M, Buisseret P (1998) Brainstem efferents from the interface between the nucleus medialis and the nucleus interpositus in the rat. J Comp Neurol 402:264–275PubMedGoogle Scholar
  33. Buttner-Ennever JA (2006) The extraocular motor nuclei: organization and functional neuroanatomy. Prog Brain Res 151:95–125PubMedGoogle Scholar
  34. Capelli P, Pivetta C, Soledad Esposito M, Arber S (2017) Locomotor speed control circuits in the caudal brainstem. Nature 551(7680):373–377. Scholar
  35. Carlton SM, Leichnetz GR, Mayer DJ (1982) Projections from the nucleus parafascicularis prerubralis to medullary raphe nuclei and inferior olive in the rat: a horseradish peroxidase and autoradiography study. Neurosci Lett 30:191–197PubMedGoogle Scholar
  36. Cerminara NL, Apps R (2010) Behavioural significance of cerebellar modules. Cerebellum.
  37. Cerminara NL, Aoki H, Loft M, Sugihara I, Apps R (2013) Structural basis of cerebellar microcircuits in the rat. J Neurosci 33(42):16427–16442. Scholar
  38. Chan-Palay V (1977) Cerebellar dentate nucleus: organization, cytology and transmitters. Springer, BerlinGoogle Scholar
  39. Cicirata F, Angaut P, Serapide MF, Panto MR, Nicotra G (1992) Multiple representation in the nucleus lateralis of the cerebellum: an electrophysiologic study in the rat. Exp Brain Res 89(2):352–362PubMedGoogle Scholar
  40. Collewijn H (1975) Oculomotor areas in the rabbits midbrain and pretectum. J Neurobiol 6(1):3–22PubMedGoogle Scholar
  41. Conde F (1988) Cerebellar projections to the red nucleus of the cat. Behav Brain Res 28(1–2):65–68PubMedGoogle Scholar
  42. Daniel H, Billard JM, Angaut P, Batini C (1987) The interposito-rubrospinal system. Anatomical tracing of a motor control pathway in the rat. Neurosci Res 5(2):87–112PubMedGoogle Scholar
  43. De Zeeuw CI, Ruigrok TJH (1994) Olivary projecting neurons in the nucleus of Darkschewitsch in the cat receive excitatory monosynaptic input from the cerebellar nuclei. Brain Res 653: 345–350PubMedGoogle Scholar
  44. De Zeeuw CI, Holstege JC, Ruigrok TJH, Voogd J (1989) Ultrastructural study of the GABAergic, cerebellar and mesodiencephalic innervation of the cat medial accessory olive: anterograde tracing combined with immunocytochemistry. J Comp Neurol 284:12–35PubMedGoogle Scholar
  45. De Zeeuw CI, Wylie DR, DiGiorgi PL, Simpson JI (1994) Projections of individual Purkinje cells of identified zones in the flocculus to the vestibular and cerebellar nuclei in the rabbit. J Comp Neurol 349(3):428–447PubMedGoogle Scholar
  46. Delfini C, Diagne M, Angaut P, Buisseret P, Buisseret-Delmas C (2000) Dentatovestibular projections in the rat. Exp Brain Res 135(3):285–292PubMedGoogle Scholar
  47. Ding SL, Royall JJ, Sunkin SM, Ng L, Facer BA, Lesnar P, Guillozet-Bongaarts A, McMurray B, Szafer A, Dolbeare TA, Stevens A, Tirrell L, Benner T, Caldejon S, Dalley RA, Dee N, Lau C, Nyhus J, Reding M, Riley ZL, Sandman D, Shen E, van der Kouwe A, Varjabedian A, Write M, Zollei L, Dang C, Knowles JA, Koch C, Phillips JW, Sestan N, Wohnoutka P, Zielke HR, Hohmann JG, Jones AR, Bernard A, Hawrylycz MJ, Hof PR, Fischl B, Lein ES (2016) Comprehensive cellular-resolution atlas of the adult human brain. J Comp Neurol 524(16): 3127–3481. Scholar
  48. Enderle JD (2002) Neural control of saccades. Prog Brain Res 140:21–49PubMedGoogle Scholar
  49. Esposito MS, Capelli P, Arber S (2014) Brainstem nucleus MdV mediates skilled forelimb motor tasks. Nature 508(7496):351–356. Scholar
  50. Fields H (2004) State-dependent opioid control of pain. Nat Rev 5(7):565–575Google Scholar
  51. Fredette BJ, Mugnaini E (1991) The GABAergic cerebello-olivary projection in the rat. Anat Embryol 184:225–243PubMedGoogle Scholar
  52. Fujikado T, Noda H (1987) Saccadic eye movements evoked by microstimulation of lobule VII of the cerebellar vermis of macaque monkeys. J Physiol 394:573–594PubMedPubMedCentralGoogle Scholar
  53. Fukushima K (1991) The interstitial nucleus of Cajal in the midbrain reticular formation and vertical eye movement. Neurosci Res 10(3):159–187PubMedGoogle Scholar
  54. Fukushima K, van der Hoeff-van Halen R, Peterson BW (1978) Direct excitation of neck motoneurons by interstitiospinal fibers. Exp Brain Res 33(3–4):565–581Google Scholar
  55. Fukushima-Kudo J, Fukushima K, Tashiro K (1987) Rigidity and dorsiflexion of the neck in progressive supranuclear palsy and the interstitial nucleus of Cajal. J Neurol Neurosurg Psychiatry 50(9):1197–1203PubMedPubMedCentralGoogle Scholar
  56. Gao Z, Proietti-Onori M, Lin Z, Ten Brinke MM, Boele HJ, Potters JW, Ruigrok TJ, Hoebeek FE, De Zeeuw CI (2016) Excitatory cerebellar nucleocortical circuit provides internal amplification during associative conditioning. Neuron 89(3):645–657. S0896-6273(16)00009-XPubMedPubMedCentralGoogle Scholar
  57. Gautier JC, Blackwood W (1961) Enlargement of the inferior olivary nucleus in association with lesions of the central tegmental tract or dentate nucleus. Brain 84:341–363PubMedGoogle Scholar
  58. Gayer NS, Faull RL (1988) Connections of the paraflocculus of the cerebellum with the superior colliculus in the rat brain. Brain Res 449(1–2):253–270PubMedGoogle Scholar
  59. Glickstein M, Gerrits N, Kralj-Hans I, Mercier B, Stein J, Voogd J (1994) Visual pontocerebellar projections in the macaque. J Comp Neurol 349(1):51–72PubMedGoogle Scholar
  60. Gonzalo-Ruiz A, Leichnetz GR (1987) Collateralization of cerebellar efferent projections to the paraoculomotor region, superior colliculus, and medial pontine reticular formation in the rat: a fluorescent double labeling study. Exp Brain Res 68:365–378PubMedGoogle Scholar
  61. Gonzalo-Ruiz A, Leichnetz GR, Smith DJ (1988) Origin of cerebellar projections to the region of the oculomotor complex, medial pontine reticular formation, and superior colliculus in New World monkeys: a retrograde horseradish peroxidase study. J Comp Neurol 268(4):508–526PubMedGoogle Scholar
  62. Goodman DC, Hallett RE, Welch RB (1963) Patterns of localization in the cerebellar corticonuclear projections of albino rat. J Comp Neurol 121:51–67PubMedGoogle Scholar
  63. Graf W, Gerrits N, Yatim-Dhiba N, Ugolini G (2002) Mapping the oculomotor system: the power of transneuronal labelling with rabies virus. Eur J Neurosci 15(9):1557–1562Google Scholar
  64. Guillain GC, Mollaret P, Bertrand IG (1933) Sur la lesion responsable du syndrome myoclonique de tronc cerebral. Rev Neurol (Paris) 3:666–673Google Scholar
  65. Haines DE, Dietrichs E, Mihailoff GA, McDonald EF (1997) The cerebellar-hypothalamic axis: basic circuits and clinical observations. Int Rev Neurobiol 41:83–107PubMedGoogle Scholar
  66. Hannig S, Jurgens U (2006) Projections of the ventrolateral pontine vocalization area in the squirrel monkey. Exp Brain Res 169(1):92–105PubMedGoogle Scholar
  67. Harting JK (1977) Descending pathways from the superior collicullus: an autoradiographic analysis in the rhesus monkey (Macaca mulatta). J Comp Neurol 173(3):583–612PubMedPubMedCentralGoogle Scholar
  68. Hicks TP, Onodera S (2012) The mammalian red nucleus and its role in motor systems, including the emergence of bipedalism and language. Prog Neurobiol 96(2):165–175. Scholar
  69. Highstein SM, Holstein GR (2006) The anatomy of the vestibular nuclei. Prog Brain Res 151: 157–203PubMedGoogle Scholar
  70. Hirai T, Onodera S, Kawamura K (1982) Cerebellotectal projections studied in cats with horseradish peroxidase or tritiated amino acids axonal transport. Exp Brain Res 48(1):1–12PubMedGoogle Scholar
  71. Hoebeek FE, Witter L, Ruigrok TJ, De Zeeuw CI (2010) Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei. Proc Natl Acad Sci USA 107:8410PubMedGoogle Scholar
  72. Holstege G, Cowie RJ (1989) Projections from the rostral mesencephalic reticular formation to the spinal cord. An HRP and autoradiographical tracing study in the cat. Exp Brain Res 75(2):265–279PubMedPubMedCentralGoogle Scholar
  73. Holstege G, Kuypers HG (1982) The anatomy of brain stem pathways to the spinal cord in cat. A labeled amino acid tracing study. Prog Brain Res 57:145–175Google Scholar
  74. Holstege JC, Kuypers HG (1987) Brainstem projections to spinal motoneurons: an update. Neuroscience 23(3):809–821PubMedGoogle Scholar
  75. Horn AK, Buttner-Ennever JA (1998) Premotor neurons for vertical eye movements in the rostral mesencephalon of monkey and human: histologic identification by parvalbumin immunostaining. J Comp Neurol 392(4):413–427Google Scholar
  76. Horn KM, Pong M, Batni SR, Levy SM, Gibson AR (2002) Functional specialization within the cat red nucleus. J Neurophysiol 87(1):469–477PubMedGoogle Scholar
  77. Horn KM, Pong M, Gibson AR (2010) Functional relations of cerebellar modules of the cat. J Neurosci 30(28):9411–9423. Scholar
  78. Houck BD, Person AL (2015) Cerebellar premotor output neurons collateralize to innervate the cerebellar cortex. J Comp Neurol 523(15):2254–2271. Scholar
  79. Huisman AM, Kuypers HG, Conde F, Keizer K (1983) Collaterals of rubrospinal neurons to the cerebellum in rat. A retrograde fluorescent double labeling study. Brain Res 264(2):181–196PubMedGoogle Scholar
  80. Ilg UJ, Thier P (2008) The neural basis of smooth pursuit eye movements in the rhesus monkey brain. Brain Cogn 68(3):229–240PubMedGoogle Scholar
  81. Ito M, Yoshida M (1966) The origin of cerebellar-induced inhibition of Deiters’ neurones. I. Monosynaptic initiation of the inhibitory postsynaptic potentials. Exp Brain Res 2:330–349PubMedGoogle Scholar
  82. Kakei S, Muto N, Shinoda Y (1994) Innervation of multiple neck motor nuclei by single reticulospinal tract axons receiving tectal input in the upper cervical spinal cord. Neurosci Lett 172(1–2):85–88PubMedGoogle Scholar
  83. Kasumacic N, Lambert FM, Coulon P, Bras H, Vinay L, Perreault MC, Glover JC (2015) Segmental organization of vestibulospinal inputs to spinal interneurons mediating crossed activation of thoracolumbar motoneurons in the neonatal mouse. J Neurosci 35(21):8158–8169. Scholar
  84. Kawamura S, Hattori S, Higo S, Matsuyama T (1982) The cerebellar projections to the superior colliculus and pretectum in the cat: an autoradiographic and horseradish peroxidase study. Neuroscience 7(7):1673–1689PubMedGoogle Scholar
  85. Kennedy PR (1990) Corticospinal, rubrospinal and rubro-olivary projections: a unifying hypothesis. Trends Neurosci 13:474–479PubMedGoogle Scholar
  86. Korneliussen HK (1968) On the morphology and subdivision of the cerebellar nuclei of the rat. J Hirnforsch 10:109–122PubMedGoogle Scholar
  87. Koutsikou S, Crook JJ, Earl EV, Leith JL, Watson TC, Lumb BM, Apps R (2014) Neural substrates underlying fear-evoked freezing: the periaqueductal grey-cerebellar link. J Physiol 592(10): 2197–2213. Scholar
  88. Kralj-Hans I, Baizer JS, Swales C, Glickstein M (2007) Independent roles for the dorsal paraflocculus and vermal lobule VII of the cerebellum in visuomotor coordination. Exp Brain Res 177(2):209–222PubMedGoogle Scholar
  89. Kuchler M, Fouad K, Weinmann O, Schwab ME, Raineteau O (2002) Red nucleus projections to distinct motor neuron pools in the rat spinal cord. J Comp Neurol 448(4):349–359PubMedGoogle Scholar
  90. Kurimoto Y, Kawaguchi S, Murata M (1995) Cerebellotectal projection in the rat: anterograde and retrograde WGA-HRP study of individual cerebellar nuclei. Neurosci Res 22(1):57–71PubMedGoogle Scholar
  91. Kuypers HGJM (1981) Anatomy of the descending pathways. In: Brookhart JM, Mountcastle VB, VBrooks VB, Geiger SR (eds) Handbook of physiology. Volume II, Motor control Part 1. American Physiological Society, Bethesda, pp 597–666Google Scholar
  92. Kuypers HGJM (1985) The anatomical and functional organization of the output of the motor system. In: Swash E (ed) Science basis of clinical neurology. Churchill Livingstone, Edinburgh, pp 1–17Google Scholar
  93. Lambert FM, Bras H, Cardoit L, Vinay L, Coulon P, Glover JC (2016) Early postnatal maturation in vestibulospinal pathways involved in neck and forelimb motor control. Dev Neurobiol 76(10):1061–1077. Scholar
  94. Langer TP (1985) Basal interstitial nucleus of the cerebellum: cerebellar nucleus related to the flocculus. J Comp Neurol 235:38–47Google Scholar
  95. Lee HS, Kosinski RJ, Mihailoff GA (1989) Collateral branches of cerebellopontine axons reach the thalamus, superior colliculus or inferior olive: a double-fluorescence and combined fluorescence-horseradish peroxidase study in the rat. Neuroscience 28:725–735PubMedGoogle Scholar
  96. Lu X, Miyachi S, Ito Y, Nambu A, Takada M (2007) Topographic distribution of output neurons in cerebellar nuclei and cortex to somatotopic map of primary motor cortex. Eur J Neurosci 25(8):2374–2382Google Scholar
  97. Luo P, Moritani M, Dessem D (2001) Jaw-muscle spindle afferent pathways to the trigeminal motor nucleus in the rat. J Comp Neurol 435(3):341–353PubMedGoogle Scholar
  98. May PJ, Hall WC (1986) The cerebellotectal pathway in the grey squirrel. Exp Brain Res 65(1):200–212PubMedGoogle Scholar
  99. May PJ, Hartwich-Young R, Nelson J, Sparks DL, Porter JD (1990) Cerebellotectal pathways in the macaque: implications for collicular generation of saccades. Neuroscience 36(2):305–324PubMedGoogle Scholar
  100. Mehler WR (1967) Double descending pathways originating from the superior cerebellar peduncle: an example of neural species differences. Anat Rec 157:374Google Scholar
  101. Meredith MA, Miller LK, Ramoa AS, Clemo HR, Behan M (2001) Organization of the neurons of origin of the descending pathways from the ferret superior colliculus. Neurosci Res 40(4):301–313PubMedGoogle Scholar
  102. Miller LE, Gibson AR (2009) Red nucleus. In: Squire LR (ed) Encyclopedia of neuroscience, vol 8. Elsevier, Amsterdam, pp 55–62Google Scholar
  103. Mock M, Butovas S, Schwarz C (2006) Functional unity of the ponto-cerebellum: evidence that intrapontine communication is mediated by a reciprocal loop with the cerebellar nuclei. J Neurophysiol 95(6):3414–3425. Scholar
  104. Morcuende S, Delgado-Garcia JM, Ugolini G (2002) Neuronal premotor networks involved in eyelid responses: retrograde transneuronal tracing with rabies virus from the orbicularis oculi muscle in the rat. J Neurosci 22(20):8808–8818PubMedPubMedCentralGoogle Scholar
  105. Muir GD, Whishaw IQ (2000) Red nucleus lesions impair overground locomotion in rats: a kinetic analysis. Eur J Neurosci 12(3):1113–1122PubMedGoogle Scholar
  106. Murray EA, Coulter JD (1982) Organization of tectospinal neurons in the cat and rat superior colliculus. Brain Res 243(2):201–214PubMedGoogle Scholar
  107. Muto N, Kakei S, Shinoda Y (1996) Morphology of single axons of tectospinal neurons in the upper cervical spinal cord. J Comp Neurol 372(1):9–26PubMedGoogle Scholar
  108. Najac M, Raman IM (2015) Integration of Purkinje cell inhibition by cerebellar nucleo-olivary neurons. J Neurosci 35(2):544–549. Scholar
  109. Nakamura H, Wu R, Watanabe K, Onozuka M, Itoh K (2006) Projections of glutamate decarboxylase positive and negative cerebellar neurons to the pretectum in the cat. Neurosci Lett 403(1–2):30–34PubMedGoogle Scholar
  110. Newman DB (1985a) Distinguishing rat brainstem reticulospinal nuclei by their neuronal morphology. I. Medullary nuclei. J Hirnforsch 26:187–226PubMedPubMedCentralGoogle Scholar
  111. Newman DB (1985b) Distinguishing rat brainstem reticulospinal nuclei by their neuronal morphology. II. Pontine and mesencephalic nuclei. J Hirnforsch 26:385–418PubMedPubMedCentralGoogle Scholar
  112. Noda H (1991) Cerebellar control of saccadic eye movements: its neural mechanisms and pathways. Jpn J Physiol 41(3):351–368PubMedGoogle Scholar
  113. Noda H, Fujikado T (1987) Topography of the oculomotor area of the cerebellar vermis in macaques as determined by microstimulation. J Neurophysiol 58(2):359–378PubMedGoogle Scholar
  114. Noda H, Sugita S, Ikeda Y (1990) Afferent and efferent connections of the oculomotor region of the fastigial nucleus in the macaque monkey. J Comp Neurol 302(2):330–348PubMedGoogle Scholar
  115. Nudo RJ, Masterton RB (1989) Descending pathways to the spinal cord: II. Quantitative study of the tectospinal tract in 23 mammals. J Comp Neurol 286(1):96–119PubMedGoogle Scholar
  116. Nyberg-Hansen R (1964a) The location and termination of tectospinal fibers in the cat. Exp Neurol 9:212–227PubMedGoogle Scholar
  117. Nyberg-Hansen R (1964b) Origin and termination of fibers from the vestibular nuclei descending in the medial longitudinal fasciculus. An experimental study with silver impregnation methods in the cat. J Comp Neurol 122:355–367PubMedGoogle Scholar
  118. Nyberg-Hansen R (1965) Sites and mode of termination of reticulo-spinal fibers in the cat. An experimental study with silver impregnation methods. J Comp Neurol 124:71–99PubMedGoogle Scholar
  119. Olivier E, Kitama T, Grantyn A (1994) Anatomical evidence for ipsilateral collicular projections to the spinal cord in the cat. Exp Brain Res 100(1):160–164PubMedGoogle Scholar
  120. Olivier E, Grantyn A, Kitama T, Berthoz A (1995) Post-spike facilitation of neck EMG by cat tectoreticulospinal neurones during orienting movements. J Physiol 482(Pt 2):455–466PubMedPubMedCentralGoogle Scholar
  121. Onodera S, Hicks TP (1999) Evolution of the motor system: why the elephant’s trunk works like a human’s hand. Neuroscientist 5(4):217–226Google Scholar
  122. Onodera S, Hicks TP (2009) A comparative neuroanatomical study of the red nucleus of the cat, macaque and human. PLoS One 4(8):e6623PubMedPubMedCentralGoogle Scholar
  123. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, San DiegoGoogle Scholar
  124. Paxinos G, Huang X-F, Toga AW (2000) The rhesus monkey in stereotaxic coordinates. Academic, San DiegoGoogle Scholar
  125. Peterson BW, Maunz RA, Pitts NG, Mackel RG (1975) Patterns of projection and branching of reticulospinal neurons. Exp Brain Res 23(4):333–351PubMedGoogle Scholar
  126. Pijpers A, Voogd J, Ruigrok TJ (2005) Topography of olivo-cortico-nuclear modules in the intermediate cerebellum of the rat. J Comp Neurol 492(2):193–213PubMedGoogle Scholar
  127. Pijpers A, Apps R, Pardoe J, Voogd J, Ruigrok TJ (2006) Precise spatial relationships between mossy fibers and climbing fibers in rat cerebellar cortical zones. J Neurosci 26(46): 12067–12080PubMedPubMedCentralGoogle Scholar
  128. Pijpers A, Winkelman BH, Bronsing R, Ruigrok TJ (2008) Selective impairment of the cerebellar C1 module involved in rat hind limb control reduces step-dependent modulation of cutaneous reflexes. J Neurosci 28(9):2179–2189PubMedPubMedCentralGoogle Scholar
  129. Pong M, Horn KM, Gibson AR (2008) Pathways for control of face and neck musculature by the basal ganglia and cerebellum. Brain Res Rev 58(2):249–264PubMedPubMedCentralGoogle Scholar
  130. Prevosto V, Graf W, Ugolini G (2010) Cerebellar inputs to intraparietal cortex areas LIP and MIP: functional frameworks for adaptive control of eye movements, reaching, and arm/eye/head movement coordination. Cereb Cortex 20(1):214–228Google Scholar
  131. Provini L, Marcotti W, Morara S, Rosina A (1998) Somatotopic nucleocortical projections to the multiple somatosensory cerebellar maps. Neuroscience 83:1085–1104PubMedGoogle Scholar
  132. Rajakumar N, Hrycyshyn AW, Flumerfelt BA (1992) Afferent organization of the lateral reticular nucleus in the rat: an anterograde tracing study. Anat Embryol 185(1):25–37PubMedGoogle Scholar
  133. Ralston DD (1994) Cerebellar terminations in the red nucleus of Macaca fascicularis: an electron-microscopic study utilizing the anterograde transport of WGA:HRP. Somatosens Mot Res 11(2):101–107PubMedGoogle Scholar
  134. Robinson FR, Cohen JL, May J, Sestokas AK, Glickstein M (1984) Cerebellar targets of visual pontine cells in the cat. J Comp Neurol 223(4):471–482PubMedGoogle Scholar
  135. Robinson FR, Houk JC, Gibson AR (1987) Limb specific connections of the cat magnocellular red nucleus. J Comp Neurol 257(4):553–577PubMedGoogle Scholar
  136. Rose PK, Abrahams VC (1978) Tectospinal and tectoreticular cells: their distribution and afferent connections. Can J Physiol Pharmacol 56(4):650–658PubMedGoogle Scholar
  137. Rubertone JA, Haroian AJ, Vincent SL, Mehler WR (1990) The rat parvocellular reticular formation: I. Afferents from the cerebellar nuclei. Neurosci Lett 119(1):79–82PubMedGoogle Scholar
  138. Ruigrok TJ (1997) Cerebellar nuclei: the olivary connection. Prog Brain Res 114:167–192PubMedGoogle Scholar
  139. Ruigrok TJ (2003) Collateralization of climbing and mossy fibers projecting to the nodulus and flocculus of the rat cerebellum. J Comp Neurol 466(2):278–298PubMedGoogle Scholar
  140. Ruigrok TJH (2004) Precerebellar nuclei and red nucleus. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier Academic, San Diego, pp 167–204Google Scholar
  141. Ruigrok TJ (2011) Ins and outs of cerebellar modules. Cerebellum 10(3):464–474. Scholar
  142. Ruigrok TJ, Teune TM (2014) Collateralization of cerebellar output to functionally distinct brainstem areas. A retrograde, non-fluorescent tracing study in the rat. Front Syst Neurosci 8:23. Scholar
  143. Ruigrok TJH, Voogd J (1990) Cerebellar nucleo-olivary projections in rat. An anterograde tracing study with Phaseolus vulgaris-leucoagglutinin (PHA-L). J Comp Neurol 298:315–333PubMedGoogle Scholar
  144. Ruigrok TJH, Voogd J (1995) Cerebellar influence on olivary excitability in the cat. Eur J Neurosci 7:679–693PubMedGoogle Scholar
  145. Ruigrok TJ, Voogd J (2000) Organization of projections from the inferior olive to the cerebellar nuclei in the rat. J Comp Neurol 426(2):209–228Google Scholar
  146. Ruigrok TJH, de Zeeuw CI, Voogd J (1990) Hypertrophy of inferior olivary neurons: a degenerative, regenerative or plasticity phenomenon. Eur J Morphol 28:224–239Google Scholar
  147. Ruigrok TJH, Osse R-J, Voogd J (1992) Organization of inferior olivary projections to the flocculus and ventral paraflocculus of the rat cerebellum. J Comp Neurol 316:129–150PubMedGoogle Scholar
  148. Ruigrok TJH, Teune TM, van der Burg J, Sabel-Goedknegt H (1995) A retrograde double labeling technique for light microscopy. A combination of axonal transport of cholera toxin B-subunit and a gold-lectin conjugate. J Neurosci Methods 61:127–138PubMedGoogle Scholar
  149. Ruigrok TJ, Pijpers A, Goedknegt-Sabel E, Coulon P (2008) Multiple cerebellar zones are involved in the control of individual muscles: a retrograde transneuronal tracing study with rabies virus in the rat. Eur J Neurosci 28(1):181–200. Scholar
  150. Ruigrok TJH, Sillitoe RV, Voogd J (2015) Cerebellum and cerebellar connections. In: Paxinos G (ed) The rat nervous system, 4th edn. Elsevier, Amsterdam, pp 133–205Google Scholar
  151. Rutherford JG, Anderson WA, Gwyn DG (1984) A reevaluation of midbrain and diencephalic projections to the inferior olive in rat with particular reference to the rubro-olivary pathway. J Comp Neurol 229:285–300PubMedGoogle Scholar
  152. Saper CB (2004) Central autonomic system. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier Academic, San Diego, pp 761–796Google Scholar
  153. Schonewille M, Luo C, Ruigrok TJ, Voogd J, Schmolesky MT, Rutteman M, Hoebeek FE, De Jeu MT, De Zeeuw CI (2006) Zonal organization of the mouse flocculus: physiology, input, and output. J Comp Neurol 497(4):670–682PubMedGoogle Scholar
  154. Sekirnjak C, Vissel B, Bollinger J, Faulstich M, du Lac S (2003) Purkinje cell synapses target physiologically unique brainstem neurons. J Neurosci 23(15):6392–6398PubMedPubMedCentralGoogle Scholar
  155. Shaikh AG, Hong S, Liao K, Tian J, Solomon D, Zee DS, Leigh RJ, Optican LM (2010) Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity. Brain 133(Pt 3):923–940PubMedPubMedCentralGoogle Scholar
  156. Shapovalov AI (1972) Extrapyramidal monosynaptic and disynaptic control of mammalian alpha-motoneurons. Brain Res 40(1):105–115PubMedGoogle Scholar
  157. Shapovalov AI, Gurevitch NR (1970) Monosynaptic and disynaptic reticulospinal actions on lumbar motoneurons of the rat. Brain Res 21(2):249–263PubMedGoogle Scholar
  158. Shinoda Y, Ghez C, Arnold A (1977) Spinal branching of rubrospinal axons in the cat. Exp Brain Res 30(2–3):203–218PubMedGoogle Scholar
  159. Shinoda Y, Futami T, Mitoma H, Yokota J (1988) Morphology of single neurones in the cerebello-rubrospinal system. Behav Brain Res 28:59–64PubMedGoogle Scholar
  160. Shinoda Y, Sugiuchi Y, Izawa Y, Hata Y (2006) Long descending motor tract axons and their control of neck and axial muscles. Prog Brain Res 151:527–563PubMedGoogle Scholar
  161. Shokunbi MT, Hrycyshyn AW, Flumerfelt BA (1986) A horseradish peroxidase study of the rubral and cortical afferents to the lateral reticular nucleus in the rat. J Comp Neurol 248(3):441–454. Scholar
  162. Stanton GB (1980) Topographical organization of ascending cerebellar projections from the dentate and interposed nuclei in Macaca mulatta: an anterograde degeneration study. J Comp Neurol 190(4):699–731PubMedGoogle Scholar
  163. Sugihara I, Shinoda Y (2004) Molecular, topographic, and functional organization of the cerebellar cortex: a study with combined aldolase C and olivocerebellar labeling. J Neurosci 24(40): 8771–8785PubMedPubMedCentralGoogle Scholar
  164. Sugihara I, Shinoda Y (2007) Molecular, topographic, and functional organization of the cerebellar nuclei: analysis by three-dimensional mapping of the olivonuclear projection and aldolase C labeling. J Neurosci 27(36):9696–9710PubMedPubMedCentralGoogle Scholar
  165. Sugihara I, Ebata S, Shinoda Y (2004) Functional compartmentalization in the flocculus and the ventral dentate and dorsal group y nuclei: an analysis of single olivocerebellar axonal morphology. J Comp Neurol 470(2):113–133PubMedGoogle Scholar
  166. Sugimoto T, Mizuno N, Uchida K (1982) Distribution of cerebellar fiber terminals in the midbrain visuomotor areas: an autoradiographic study in the cat. Brain Res 238(2):353–370PubMedGoogle Scholar
  167. Takagi M, Zee DS, Tamargo RJ (1998) Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. J Neurophysiol 80(4):1911–1931PubMedGoogle Scholar
  168. Tan J, Epema AH, Voogd J (1995) Zonal organization of the flocculovestibular nucleus projection in the rabbit: a combined axonal tracing and acetylcholinesterase histochemical study. J Comp Neurol 356(1):51–71PubMedGoogle Scholar
  169. Tang Y, Rampin O, Giuliano F, Ugolini G (1999) Spinal and brain circuits to motoneurons of the bulbospongiosus muscle: retrograde transneuronal tracing with rabies virus. J Comp Neurol 414(2):167–192PubMedGoogle Scholar
  170. ten Donkelaar HJ (1988) Evolution of the red nucleus and rubrospinal tract. Behav Brain Res 28(1–2):9–20PubMedGoogle Scholar
  171. Teune TM, Van der Burg J, Ruigrok TJH (1995) Cerebellar projections to the red nucleus and inferior olive originate from separate populations of neurons in the rat. A non-fluorescent double labeling study. Brain Res 673:313–319PubMedGoogle Scholar
  172. Teune TM, van der Burg J, van der Moer J, Voogd J, Ruigrok TJ (2000) Topography of cerebellar nuclear projections to the brain stem in the rat. Prog Brain Res 124:141–172PubMedGoogle Scholar
  173. Thach WT, Bastian AJ (2004) Role of the cerebellum in the control and adaptation of gait in health and disease. Prog Brain Res 143:353–366PubMedGoogle Scholar
  174. Thier P, Dicke PW, Haas R, Thielert CD, Catz N (2002) The role of the oculomotor vermis in the control of saccadic eye movements. Ann N Y Acad Sci 978:50–62PubMedGoogle Scholar
  175. Tolbert DL, Bantli H, Bloedel JR (1978a) Multiple branching of cerebellar efferent projections in cats. Exp Brain Res 31:305–316PubMedGoogle Scholar
  176. Tolbert DL, Bantli H, Bloedel JR (1978b) Organizational features of the cat and monkey cerebellar nucleocortical projection. J Comp Neurol 182:39–56PubMedGoogle Scholar
  177. Tolbert DL, Bantli H, Hames EG, Ebner TJ, McMullen TA, Bloedel JR (1980) A demonstration of the dentato-reticulospinal projection in the cat. Neuroscience 5(8):1479–1488PubMedGoogle Scholar
  178. Torvik A, Brodal A (1957) The origin of reticulospinal fibers in the cat; an experimental study. Anat Rec 128(1):113–137PubMedGoogle Scholar
  179. Travers JB, DiNardo LA, Karimnamazi H (2000) Medullary reticular formation activity during ingestion and rejection in the awake rat. Exp Brain Res 130(1):78–92PubMedGoogle Scholar
  180. Tsukahara N, Bando T, Murakami F, Oda Y (1983) Properties of cerebello-precerebellar reverberating circuits. Brain Res 274:249–259PubMedGoogle Scholar
  181. Uchida K, Mizuno N, Sugimoto T, Itoh K, Kudo M (1983) Direct projections from the cerebellar nuclei to the superior colliculus in the rabbit: an HRP study. J Comp Neurol 216(3):319–326PubMedGoogle Scholar
  182. Uusisaari M, Knopfel T (2010) GlyT2+ neurons in the lateral cerebellar nucleus. Cerebellum 9(1):42–55. Scholar
  183. Uusisaari M, Obata K, Knopfel T (2007) Morphological and electrophysiological properties of GABAergic and non-GABAergic cells in the deep cerebellar nuclei. J Neurophysiol 97(1): 901–911PubMedGoogle Scholar
  184. van der Steen J, Simpson JI, Tan J (1994) Functional and anatomic organization of three-dimensional eye movements in rabbit cerebellar flocculus. J Neurophysiol 72(31–46):31–46PubMedGoogle Scholar
  185. Voogd J (1964) The cerebellum of the cat: structure and fiber connections. Van Gorcum, AssenGoogle Scholar
  186. Voogd J (2004) Cerebellum. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier Academic, San Diego, pp 205–242Google Scholar
  187. Voogd J (2011) Cerebellar zones: a personal history. Cerebellum 10(3):334–350. Scholar
  188. Voogd J (2016) Deiters’ nucleus. Its role in cerebellar ideogenesis: the Ferdinando Rossi memorial lecture. Cerebellum 15(1):54–66. Scholar
  189. Voogd J, Barmack NH (2006) Oculomotor cerebellum. Prog Brain Res 151:231–268PubMedGoogle Scholar
  190. Voogd J, Glickstein M (1998) The anatomy of the cerebellum. Trends Neurosci 2:305–371Google Scholar
  191. Voogd J, Ruigrok TJ (2004) The organization of the corticonuclear and olivocerebellar climbing fiber projections to the rat cerebellar vermis: the congruence of projection zones and the zebrin pattern. J Neurocytol 33(1):5–21PubMedGoogle Scholar
  192. Voogd J, Ruigrok TJH (2012) Cerebellum and precerebellar nuclei. In: Mai JK, Paxinos G (eds) The human nervous system, 3rd edn. Elsevier, Amsterdam, pp 471–545Google Scholar
  193. Voogd J, Wylie DR (2004) Functional and anatomical organization of floccular zones: a preserved feature in vertebrates. J Comp Neurol 470(2):107–112. Scholar
  194. Voogd J, Gerrits NM, Ruigrok TJH (1996) Organization of the vestibulocerebellum. Ann N Y Acad Sci 781:553–579PubMedGoogle Scholar
  195. Warton S, Jones DG, Ilinsky IA, Kultas-Ilinsky K (1983) Nigral and cerebellar synaptic terminals in the intermediate and deep layers of the cat superior colliculus revealed by lesioning studies. Neuroscience 10(3):789–800PubMedGoogle Scholar
  196. Whishaw IQ, Gorny B, Sarna J (1998) Paw and limb use in skilled and spontaneous reaching after pyramidal tract, red nucleus and combined lesions in the rat: behavioral and anatomical dissociations. Behav Brain Res 93(1–2):167–183PubMedGoogle Scholar
  197. Wylie DR, De Zeeuw CI, DiGiorgi PL, Simpson JI (1994) Projections of individual Purkinje cells of identified zones in the ventral nodulus to the vestibular and cerebellar nuclei in the rabbit. J Comp Neurol 349(3):448–463PubMedGoogle Scholar
  198. Wylie DR, Gutierrez-Ibanez C, Corfield JR, Craciun I, Graham DJ, Hurd PL (2017) Inferior olivary projection to the zebrin II stripes in lobule IXcd of the pigeon flocculus: a retrograde tracing study. J Comp Neurol 525(14):3158–3173. Scholar
  199. Ye C, Bogovic JA, Ying SH, Prince JL (2013) Segmentation of the complete superior cerebellar peduncles using a multi-object geometric deformable model. Proc IEEE Int Symp Biomed Imaging 2013:49–52. Scholar
  200. Zhu JN, Wang JJ (2008) The cerebellum in feeding control: possible function and mechanism. Cell Mol Neurobiol 28(4):469–478. Scholar
  201. Zuk A, Rutherford JG, Gwyn DG (1983) Projections from the interstitial nucleus of Cajal to the inferior olive and to the spinal cord in cat: a retrograde fluorescent double-labeling study. Neurosci Lett 38(2):95–101PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of NeuroscienceErasmus Medical Center RotterdamRotterdamThe Netherlands

Section editors and affiliations

  • Jeremy D. Schmahmann
    • 1
  1. 1.Department of Neurology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations