Cerebellothalamic Projections Research Articles

Purkinje cell ablation and Purkinje cell-specific deletion of Tsc1 in the developing cerebellum strengthen cerebellothalamic synapses.

Cerebellar damage early in life often causes long-lasting motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviours. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is a major direct target of the cerebellar nuclei, conveying cerebellar signals to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The ablation of Purkinje cells in the developing cerebellum strengthened cerebellothalamic synapses and enhanced thalamic suprathreshold activities. Purkinje-cell specific deletion of tuberous sclerosis complex subunit 1 (Tsc1), an autism-associated gene for which the protein product negatively regulates the mammalian target of rapamycin, also strengthened cerebellothalamic synapses. However, this strengthening occurred only in homozygous deletion, whereas both homozygous and hemizygous deletion are known to cause autism-like behaviours. These results suggest that, although the cerebellothalamic projection is vulnerable to disturbances in the developing cerebellar cortex, other changes may also drive the behavioural consequences of early cerebellar perturbation. KEY POINTS: Cerebellar damage early in life often causes motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. Recent studies focus on how the developing cerebellum affects the formation and function of the cerebral cortex, the higher-order centre for all behaviours. However, the cerebellum does not directly connect to the cerebral cortex. Here, we studied the consequences of early cerebellar perturbation on the thalamus because it is a direct postsynaptic target of the cerebellum, sending cerebellar signals to the cerebral cortex. Loss of cerebellar Purkinje cells, which are commonly associated with various neurological disorders, strengthened cerebellothalamic synapses, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum. Purkinje cell-specific loss of tuberous sclerosis complex-1, a negative regulator of mammalian target of rapamycin, is an established mouse model of autism. This mouse model also showed strengthened cerebellothalamic synapses.

Does Vestibular Motion Perception Correlate with Axonal Pathways Stimulated by Subthalamic Deep Brain Stimulation in Parkinson's Disease?

Perception of our linear motion - heading - is critical for postural control, gait, and locomotion, and it is impaired in Parkinson's disease (PD). Deep brain stimulation (DBS) has variable effects on vestibular heading perception, depending on the location of the electrodes within the subthalamic nucleus (STN). Here, we aimed to find the anatomical correlates of heading perception in PD. Fourteen PD participants with bilateral STN DBS performed a two-alternative forced-choice discrimination task where a motion platform delivered translational forward movements with a heading angle varying between 0 and 30° to the left or to the right with respect to the straight-ahead direction. Using psychometric curves, we derived the heading discrimination threshold angle of each patient from the response data. We created patient-specific DBS models and calculated the percentages of stimulated axonal pathways that are anatomically adjacent to the STN and known to play a major role in vestibular information processing. We performed correlation analyses to investigate the extent of these white matter tracts' involvement in heading perception. Significant positive correlations were identified between improved heading discrimination for rightward heading and the percentage of activated streamlines of the contralateral hyperdirect, pallido-subthalamic, and subthalamo-pallidal pathways. The hyperdirect pathways are thought to provide top-down control over STN connections to the cerebellum. In addition, STN may also antidromically activate collaterals of hyperdirect pathway that projects to the precerebellar pontine nuclei. In select cases, there was strong activation of the cerebello-thalamic projections, but it was not consistently present in all participants. Large volumetric overlap between the volume of tissue activation and the STN in the left hemisphere positively impacted rightward heading perception. Altogether, the results suggest heavy involvement of basal ganglia cerebellar network in STN-induced modulation of vestibular heading perception in PD.

Cerebellar control of thalamocortical circuits for cognitive function: A review of pathways and a proposed mechanism.

There is general agreement that cerebrocerebellar interactions via cerebellothalamocortical pathways are essential for a cerebellar cognitive and motor functions. Cerebellothalamic projections were long believed target mainly the ventral lateral (VL) and part of the ventral anterior (VA) nuclei, which project to cortical motor and premotor areas. Here we review new insights from detailed tracing studies, which show that projections from the cerebellum to the thalamus are widespread and reach almost every thalamic subnucleus, including nuclei involved in cognitive functions. These new insights into cerebellothalamic pathways beyond the motor thalamus are consistent with the increasing evidence of cerebellar cognitive function. However, the function of cerebellothalamic pathways and how they are involved in the various motor and cognitive functions of the cerebellum is still unknown. We briefly review literature on the role of the thalamus in coordinating the coherence of neuronal oscillations in the neocortex. The coherence of oscillations, which measures the stability of the phase relationship between two oscillations of the same frequency, is considered an indicator of increased functional connectivity between two structures showing coherent oscillations. Through thalamocortical interactions coherence patterns dynamically create and dissolve functional cerebral cortical networks in a task dependent manner. Finally, we review evidence for an involvement of the cerebellum in coordinating coherence of oscillations between cerebral cortical structures. We conclude that cerebellothalamic pathways provide the necessary anatomical substrate for a proposed role of the cerebellum in coordinating neuronal communication between cerebral cortical areas by coordinating the coherence of oscillations.

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience.

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience.

Deep Brain Stimulation of the Caudal Zona Incerta: Tremor Control in Relation to the Location of Stimulation Fields

Background: The caudal zona incerta (cZi) and posterior subthalamic area (PSA) are an emerging deep brain stimulation (DBS) target for essential tremor (ET). Objectives: To evaluate the efficacy of tremor control in relation to the anatomical locations of stimulation fields in 50 patients with ET and DBS of the cZi. Methods: A total of 240 contacts were evaluated separately with monopolar stimulation, and amplitudes were optimized for improvement of tremor and hand function. Stimulation fields, i.e., volumes of neural activation, were simulated for each optimized setting and assembled into probabilistic stimulation maps (PSMs). Results: There were differences in the anatomical distribution of PSMs associated with good versus poor tremor control. The location of PSMs which achieved good and excellent tremor control corresponded well with the PSM for the clinically used settings, and they were located within the superior part of the PSA. Conclusions: PSMs may serve as a useful tool for defining the most efficacious anatomical location of stimulation. The best tremor control in this series of cZi DBS was achieved with stimulation of the superior part of the PSA, which corresponds to the final part of the cerebellothalamic projections before they reach the ventral lateral thalamus.

Retrograde analysis of the cerebellar projections to the posteroventral part of the ventral lateral thalamic nucleus in the macaque monkey

The organization of cerebellothalamic projections was investigated in macaque monkeys using injections of retrograde tracers (cholera toxin B and fluorescent dextrans) in the posteroventral part of the ventrolateral thalamic nucleus (VLpv), the main source of thalamic inputs to the primary motor cortex. Injections that filled all of VLpv labeled abundant neurons that were inhomogeneously distributed among many unlabeled cells in the deep cerebellar nuclei (DCbN). Single large pressure injections made in face-, forelimb-, or hindlimb-related portions of VLpv using physiological guidance labeled numerous neurons that were broadly dispersed within a coarse somatotopographic anteroposterior (foot to face) gradient in the dentate and interposed nuclei. Small iontophoretic injections labeled fewer neurons with the same somatotopographic gradient, but strikingly, the labeled neurons in these cases were as broadly dispersed as in cases with large injections. Simultaneous injections of multiple tracers in VLpv (one tracer per somatic region with no overlap between injections) confirmed the general somatotopography but also demonstrated clearly the overlapping distributions and the close intermingling of neurons labeled with different tracers. Significantly, very few neurons (<2%) were double-labeled. This organizational pattern contrasts with the concept of a segregated "point-to-point" somatotopy and instead resembles the complex patterns that have been observed throughout the motor pathway. These data support the idea that muscle synergies are represented anatomically in the DCbN by a general somatotopography in which intermingled neurons and dispersed but selective connections provide the basis for plastic, adaptable movement coordination of different parts of the body. Indexing terms:

Deep brain stimulation in the subthalamic area is more effective than nucleus ventralis intermedius stimulation for bilateral intention tremor

The ventro-lateral thalamus is the stereotactic target of choice for severe intention tremor. Nevertheless, the optimal target area has remained controversial, and targeting of the subthalamic area has been suggested to be superior. Eleven patients with disabling intention tremor of different etiology (essential tremor (n = 8), multiple sclerosis (n = 2) and one with, spinocerebellar ataxia) were implanted bilaterally with DBS electrodes targeted to the ventro-lateral thalamus using micro-recording and micro-stimulation. Among five tracks explored in parallel optimal tracks were chosen for permanent electrode implantation. Postoperative tremor suppression elicited by individual electrode contacts was quantified using a lateralised tremor rating scale at least 3 months (in most patients >1 year) after implantation. The position of electrode contacts was determined retrospectively from stereotactic X-ray exams and by correlation of pre- and postoperative MRI. In all patients, DBS suppressed intention tremor markedly. On average, tremor on the left and right side of the body was improved by 68% (+/-19; standard deviation) and 73% (+/-21), respectively. In most patients, distal electrode contacts located in the subthalamic area proved to be more effective than proximal contacts in the ventro-lateral thalamus. In stereotactic coordinates, the optimal site was located 12.7 mm (+/-1.4; mean +/- standard deviation) lateral, 7.0 (+/-1.6) mm posterior, and 1.5 (+/-2.0) mm ventral to the mid-commissural point. In general, the best contacts could be selected for permanent stimulation. Nevertheless, in some instances, more proximal contacts had to be chosen because of adverse effects (paraesthesiae, dysarthria, gait ataxia) which were more pronounced with bilateral stimulation resulting in slightly less tremor suppression on the left and right side of body (63 +/- 18 and 68 +/- 19%, respectively). Direct comparison of different stimulation sites in individual patients revealed that DBS in the subthalamic area is more effective in suppressing pharmacoresistant intention tremor than the ventro-lateral thalamus proper. Anatomical structures possibly involved in tremor suppression include cerebello-thalamic projections, the prelemniscal radiation, and the zona incerta.

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

Neurochemical characterization of the cerebellar‐recipient motor thalamic territory in the macaque monkey

Abstract The immunoarchitectonics of the macaque motor thalamus was analysed to look for a possible neurochemical characterization of thalamic territories, which were not definable cytoarchitectonically, associated with different functional pathways. Thalamic sections from 15 macaque monkeys were processed for visualization of calbindin (CB), parvalbumin (PV), calretinin (CR) and SMI-32 immunoreactivity (ir). PV-, CR- and SMI-32ir distributions did not show any clear correlation with known functional subdivisions. In contrast, CBir distribution reliably defined two markedly distinct motor thalamic territories, one characterized by high cell and neuropil CBir (CB-positive territory), the other by very low cell and neuropil CBir (CB-negative territory). These two neurochemically distinct compartments, the CB-negative and the CB-positive territories, appear to correspond to the cerebellar- and basal ganglia-recipient territories, respectively. To verify the possible correspondence of the CB-negative territory with the cerebellar-recipient sector of the motor thalamus, we compared the distribution of cerebello-thalamic projections with the distribution of CBir in two monkeys. The distribution of cerebellar afferent terminals was similar to that reported from previous reports and in line with the notion that in the motor thalamus the cerebellar-recipient territory does not respect cytoarchitectonic boundaries. Comparison with CB immunoarchitecture showed very close correspondence in the motor thalamus between the distribution of the anterograde labeling and the CB-negative territory, suggesting that the CB-negative territory represents the architectonic counterpart of the cerebellar-recipient territory. CB immunostaining may therefore represent a helpful tool for describing the association between thalamocortical projections and the basal ganglia or the cerebellar loops and for establishing possible homologies between the motor thalamus of non-human primates and humans.

Ascending inputs to the pre-supplementary motor area in the macaque monkey: cerebello- and pallido-thalamocortical projections

The goal of the present study was to determine the ascending sources to the pre-supplementary motor area (pre-SMA) in macaque monkeys using multiple labeling techniques. We labeled the pallidothalamic projections using biotinylated dextran amine (BDA) and the cerebellothalamic projections using wheatgerm agglutinin conjugated to horseradish peroxidase. The pre-SMA thalamocortical projections neurons were also labeled using cholera toxin subunit b following identification of the pre-SMA by location, and by movements evoked by intracortical microstimulation. The extent of pre-SMA was later confirmed by identifying characteristics from Nissl cytoarchitecture and SMI-32 immunoreactivity. Thalamic nuclear boundaries were based on Nissl cytoarchitecture, acetylcholinesterase chemoarchitecture and Cat-301 immunoreactivity. Cerebellothalamic afferents were distributed predominantly to ventral lateral posterior nucleus (VLp), including medial and dorsal VLp, while the pallidothalamic afferents projected more rostrally to ventral lateral anterior nucleus (VLa) and ventral anterior nucleus (VA). The pre-SMA thalamocortical projection neurons were primarily found in VA and medial VLp. However, scattered cells were also found in VLa, dorsal VLp, central lateral nucleus (CL) and mediodorsal nucleus (MD). Scattered pre-SMA projecting cells overlapped foci of cerebellar label in medial VLp. Additionally, limited overlap of pre-SMA cells and pallidothalamic labeling was found in caudal VA. These findings suggest that the pre-SMA is uniquely positioned to integrate ascending basal ganglia and cerebellar information after a relay from VA and medial VLp. These anatomical findings are consistent with the recent hypothesis that the pre-SMA acts as the coordinator of visual and motor loops in motor learning [J. Cogn. Neurosci. 13 (2001) 626].

Ascending inputs to the pre-supplementary motor area in the macaque monkey: cerebello- and pallido-thalamocortical projections

The goal of the present study was to determine the ascending sources to the pre-supplementary motor area (pre-SMA) in macaque monkeys using multiple labeling techniques. We labeled the pallidothalamic projections using biotinylated dextran amine (BDA) and the cerebellothalamic projections using wheatgerm agglutinin conjugated to horseradish peroxidase. The pre-SMA thalamocortical projections neurons were also labeled using cholera toxin subunit b following identification of the pre-SMA by location, and by movements evoked by intracortical microstimulation. The extent of pre-SMA was later confirmed by identifying characteristics from Nissl cytoarchitecture and SMI-32 immunoreactivity. Thalamic nuclear boundaries were based on Nissl cytoarchitecture, acetylcholinesterase chemoarchitecture and Cat-301 immunoreactivity. Cerebellothalamic afferents were distributed predominantly to ventral lateral posterior nucleus (VLp), including medial and dorsal VLp, while the pallidothalamic afferents projected more rostrally to ventral lateral anterior nucleus (VLa) and ventral anterior nucleus (VA). The pre-SMA thalamocortical projection neurons were primarily found in VA and medial VLp. However, scattered cells were also found in VLa, dorsal VLp, central lateral nucleus (CL) and mediodorsal nucleus (MD). Scattered pre-SMA projecting cells overlapped foci of cerebellar label in medial VLp. Additionally, limited overlap of pre-SMA cells and pallidothalamic labeling was found in caudal VA. These findings suggest that the pre-SMA is uniquely positioned to integrate ascending basal ganglia and cerebellar information after a relay from VA and medial VLp. These anatomical findings are consistent with the recent hypothesis that the pre-SMA acts as the coordinator of visual and motor loops in motor learning [J. Cogn. Neurosci. 13 (2001) 626].

Pallidal and cerebellar afferents to pre-supplementary motor area thalamocortical neurons in the owl monkey: A multiple labeling study

In the present study, we determined where thalamic neurons projecting to the pre-supplementary motor area (pre-SMA) are located relative to pallidothalamic and cerebellothalamic inputs and nuclear boundaries. We employed a triple-labeling technique in the same owl monkey (Aotus trivirgatus). The cerebellothalamic projections were labeled with injections of wheat germ agglutinin conjugated to horseradish peroxidase, and the pallidothalamic projections were labeled with biotinylated dextran amine. The pre-SMA was identified by location and movement patterns evoked by intracortical microstimulation and injected with the retrograde tracer cholera toxin subunit B. Brain sections were processed sequentially using different chromogens to visualize all three tracers in the same section. Alternate sections were processed for Nissl cytoarchitecture or acetylcholinesterase chemoarchitecture for nuclear boundaries. The cerebellar nuclei primarily projected to posterior (VLp), medial (VLx), and dorsal (VLd) divisions of the ventral lateral nucleus; the pallidum largely projected to the anterior division (VLa) of the ventral lateral nucleus and the parvocellular part of the ventral anterior nucleus (VApc). However, we also found zones of overlapping projections, as well as interdigitating foci of pallidal and cerebellar label, particularly in border regions of the VLa and VApc. Thalamic neurons labeled by pre-SMA injections occupied a wide band and were especially concentrated in the VLx and VApc, cerebellar and pallidal territories, respectively. Labeled thalamocortical neurons overlapped cerebellar inputs in the VLd and VApc and overlapped pallidal inputs in the VLa and the ventral medial nucleus. The results demonstrate that inputs from both the cerebellum and globus pallidus are relayed to the pre-SMA.

Thalamic territories innervated by cerebellar nuclear afferents in the hedgehog tenrec,Echinops telfairi

To gain more insight into the evolution and functional significance of cerebrocerebellar circuits, the cerebellothalamic projections were studied with anterograde tracer substances in the Madagascan lesser hedgehog, tenrec. This insectivore shows one of the lowest size indices among mammals for both the cerebellar nuclei and the neocortex. Almost all cerebellodiencephalic target areas found in the tenrec have been described in other mammals. The intensity and extent of particular projections, however, vary considerably in the tenrec compared with the other mammals investigated so far. The most remarkable finding may be the tenrec's cerebellar projection to the nucleus ventralis medialis. This projection is the most prominent cerebellothalamic projection and originates in predominantly the lateral portion of the cerebellar nuclear complex. The projection to the caudolateral portion of the ventralis anterior complex (VAC) is located immediately rostral to the area receiving ascending somatosensory afferents and appears to originate, in particular, from the intermediate cerebellar nuclear complex. Another cerebellothalamic focus of terminations lies in the paralamellar region of the VAC, whereas the proper intralaminar nuclei, at best, receive a sparse cerebellar input. A faint-to-moderate projection, on the other hand, has been traced consistently to the ventral portion of the lateralis posterior-pulvinar complex and the adjacent dorsal geniculate nucleus. In addition, there are prominent cerebellosubthalamic projections to the zona incerta and the ventral geniculate nucleus. The latter projection is confined mainly to the ventralmost subdivision, which has been shown previously to receive ascending somatosensory, but not retinal, afferents. With the exception of the nucleus ventralis medialis, the projections were essentially confined to the contralateral side.

Thalamic territories innervated by cerebellar nuclear afferents in the hedgehog tenrec, Echinops telfairi.

To gain more insight into the evolution and functional significance of cerebrocerebellar circuits, the cerebellothalamic projections were studied with anterograde tracer substances in the Madagascan lesser hedgehog, tenrec. This insectivore shows one of the lowest size indices among mammals for both the cerebellar nuclei and the neocortex. Almost all cerebellodiencephalic target areas found in the tenrec have been described in other mammals. The intensity and extent of particular projections, however, vary considerably in the tenrec compared with the other mammals investigated so far. The most remarkable finding may be the tenrec's cerebellar projection to the nucleus ventralis medialis. This projection is the most prominent cerebellothalamic projection and originates in predominantly the lateral portion of the cerebellar nuclear complex. The projection to the caudolateral portion of the ventralis anterior complex (VAC) is located immediately rostral to the area receiving ascending somatosensory afferents and appears to originate, in particular, from the intermediate cerebellar nuclear complex. Another cerebellothalamic focus of terminations lies in the paralamellar region of the VAC, whereas the proper intralaminar nuclei, at best, receive a sparse cerebellar input. A faint-to-moderate projection, on the other hand, has been traced consistently to the ventral portion of the lateralis posterior-pulvinar complex and the adjacent dorsal geniculate nucleus. In addition, there are prominent cerebellosubthalamic projections to the zona incerta and the ventral geniculate nucleus. The latter projection is confined mainly to the ventralmost subdivision, which has been shown previously to receive ascending somatosensory, but not retinal, afferents. With the exception of the nucleus ventralis medialis, the projections were essentially confined to the contralateral side.

Projections of the central cerebellar nuclei to the intralaminar thalamic nuclei in cats

Projections of the central cerebellar nuclei to the intralaminar thalamic nuclei were studied in cats with the use of light and electron microscopy. Almost all intralaminar nuclei were shown to obtain cerebello-thalamic projections. The entire complex of the central cerebellar nuclei serves as a source of such projections; yet, involvement of different nuclei is dissimilar. Destruction of the central and, especially, caudal regions of the fastigial nucleus evoked in the intralaminar thalamic nuclei degenerative changes in the nerve fibers (from swelling and development of varicosities up to total fragmentation). Pathological phenomena could be noticed in the most caudal regions of the above thalamic nuclear group, including the medial dorsal nucleus. Projections of the cerebellar interpositus nucleus were directed toward nearly the same regions of the intralaminar nuclei; degeneration was more intensive (covered thecentrum medianum) when posterior regions of the interpositus nucleus were destroyed. Destruction of the lateral cerebellar nucleus evoked a similar pattern of pathological changes, but degeneration was also observed in some structures of the ventral and anterior nuclear groups of the thalamus. Electron microscopic examination showed that degeneration of dark and light types developed in the fiber preterminals and terminals. It can be concluded that the central cerebellar nuclei project not only to the ventral complex of the thalamic nuclei, but also to the anterior, medial, and intralaminar nuclear groups (rostral and caudal portions).

1612 Cerebello-thalamic projections in monkeys with special reference to the rostral regions of motor thalamic nuclei

The efferent projections of the deep cerebellar nuclei were studied and their fiber trajectories and thalamic termination zones described. The thalamic termination zones for the dentate, interposed and fastigial nuclei are identical and coincide with the cytoarchitectonically unique cell-sparse region of the ventral lateral complex. This region includes nuclei VPLo, VLc, VLps, X64 and extensions of these between the cell clusters of nucleus VLo. The inputs from dentate and interpositus are contralateral dense, and their termination patterns extend continuously throughout all nuclear components of the cell-sparse zone. Interdigitation of these two inputs within the cell-sparse region is directly demonstrated The fastigial input is more restricted but bilateral. Each of the deep cerebellar nuclei also projects to the central lateral nucleus of the intralaminar complex.The strong interconnection of the cell-sparse zone with cortical area 4 is confirmed. The patterns of retrogradely labeled thalamocortical cells and of anterogradely labeled corticothalamic terminations following cortical injections of horseradish peroxidase and of tritiated amino acids, extend continuously through the VPLo-VLc region and its extensions but do not invade the posteriorly situated VPLc nucleus.Thalamic inputs from the dorsal column nuclei terminate independently within the morphologically distinct VPLc nucleus adjacent to the cell-sparse cerebellar terminal zone. The dorsal column-lemniscal terminations do not overlap the cerebellar terminations The clear segregation of the two sets of terminations is demonstrated directly using an anterograde double labeling method.Spinothalamic terminations end in VPLc but extend into the cerebellar terminal zone. Another ascending input, from the vestibular nuclei, is also shown to terminate within the cell-sparse zone.Comparison with other studies implies that cerebellar pallidal and substantia nigral inputs do not converge in the monkey thalamus and that the nuclei in which they terminate project to different cortical areas. The relation of these and of sensory influences ascending to motor cortex from the periphery are discussed.

Distribution of cerebellothalamic and nigrothalamic projections in the dog: a double anterograde tracing study.

The distribution of nigrothalamic and cerebellothalamic projections was investigated in the dog by a double labeling strategy combining the anterograde transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) and tritiated amino acids. Following tritiated amino acid injections into the substantia nigra pars reticulata (SNr) and WGA-HRP injections into the contralateral cerebellar nuclei, we found that the nigrothalamic and cerebellothalamic afferents distribute to three main targets: the central portion of the ventral anterior nucleus (VA) and the ventral lateral nucleus (VL), the internal medullary lamina (IML) region, which includes the paralaminar VA, the mediodorsal nucleus (MD) and the central lateral nucleus (CL), and finally the ventromedial nucleus (VM). We observed three distribution patterns of labeled fibers: a) Dense single label was observed in the central portion of VA following the SNr injections and in VL following the cerebellar nuclei injections. b) A complementary pattern consisting of alternating foci of nigral and cerebellar label was found in the IML region. This pattern was also observed in the caudal intralaminar nuclei where cerebellar label predominated in the centrum medianum (CM), while the parafascicular nucleus (Pf) primarily contained nigral label. c) An overlapping pattern of autoradiographic and WGA-HRP label was found in the lateral half of the VM. Overall, the distribution of nigrothalamic and cerebellothalamic projections was widespread throughout much of rostrocaudal thalamus. However, the pattern of projections varied along a continuum from lateral to medial thalamus. In lateral thalamus, nigral and cerebellar projections distributed to separate nuclei while in medial thalamus, the projection pattern changed to focal and complementary in the IML and overlapping in VM. Taken together, these thalamic projections may constitute crucial links in different functional channels involved in alerting and orienting mechanisms associated with motor behavior. Our findings also suggest that the organization of motor thalamic afferents in the dog shares similarities with the segregated and parallel circuitry characteristic of primates as well as with the overlapping and converging circuits of rodents and other carnivores.

Projection from the deep cerebellar nuclei to the pedunculopontine nucleus in the squirrel monkey

Large injections of the anterograde tracer biocytin in the deep nuclei of the cerebellum of squirrel monkeys ( Saimiri sciureus) led to a massive labeling of the superior cerebellar peduncle fibers which could be followed up to their major termination site in the thalamus. Along their course through the brainstem, biocytin-labeled fibers emitted fine collaterals that arborized profusely within the entire rostrocaudal extent of the pedunculopontine nucleus (PPN). These fibers were long, slightly varicose, and broke off into numerous shorter and thinner fibers whose terminal portions consisted of a few large varicosities that were often closely apposed to dendrites and cell bodies of PPN neurons. Some PPN cells that were contacted displayed immunoreactivity for choline acetyltransferase. Ultrastructural analysis revealed that synapses formed by cerebellar fibers in PPN were of the asymmetric type and occured predominantly on dendrites of PPN neurons. Thus, beside the well established cerebellothalamic projection, our findings reveal the existence of a cerebellotegmental projection, whereby the cerebellum may influence the basal ganglia and/or the thalamus via a relay in PPN.

Choline acetyltransferase immunoreactivity in the cat cerebellum

Choline acetyltransferase immunoreactivity was demonstrated in particular projection systems in cat cerebellum by combining immunohistochemistry, retrograde tracing and lesioning paradigms. The monoclonal antibody used in this study recognized a 68,000 mol. wt protein on immunoblots of cat cerebellum and striatum. Choline acetyltransferase immunoreactivity was localized to some neurons and varicose fibers in the cerebellar nuclei, and also to some mossy fibers and endings (rosettes), fiber plexuses around Purkinje cells, granule cells and parallel fibers in the cerebellar cortex. In addition, the presence of choline acetyltransferase-immunoreactive large cells, presumptive Golgi cells, in the granular layer was confirmed. In each cerebellar nucleus, choline acetyltransferase-immunoreactive neurons contained either large, medium-sized or small cell bodies and were distributed evenly in the entire nuclear domain. Large and medium-sized ones were frequently encountered. Choline acetyltransferase-immunoreactive mossy fibers and rosettes were most abundant in the vermal lobules I–III, VIII, IX and the simple lobule, moderately accumulated in the vermal lobules IV–VII, X, crus I and crus II, and less abundant in the paramedian lobule, paraflocculus and flocculus. Some granule cells with prominent dendritic claws and bifurcating parallel axons were immunolabeled in the entire vermis with infrequent occurrence in the remaining cortices. Following unilateral lesioning of the cerebellar nuclei with electrocoagulation or kainate injections, a reduction in number of choline acetyltransferase-immunoreactive fibers occurred ipsilaterally in the cerebellar cortex and contralaterally in the red nucleus, ventrolateral thalamic nucleus and ventroanterior thalamic nucleus. In addition, perikarya of some cerebellothalamic neurons were shown to contain choline acetyltransferase immunoreactivity. The results indicate that some nucleocortical, cerebellorubral and cerebellothalamic projections are cholinergic and that a subpopulation of cholinergic granule cell-parallel fibers exists.

Converging cerebellofugal inputs to the thalamus. I. Mapping of monosynaptic field potentials in the ventrolateral nucleus of the thalamus.

The extent of thalamic projections from punctate sites in the cerebellar nuclei was examined in 22 acutely prepared cats by mapping monosynaptic field potentials evoked in the ventrolateral (VL) nucleus by stimulation of the interpositus and dentate nuclei (IN and DN). The monosynaptic field potentials were evoked in the VL by low current stimulating pulses applied at high frequency to these cerebellar nuclei. Quantification of the projections was possible since the conditions of stimulation and recording were strictly controlled. The incoming volley recorded in the brachium conjunctivum caudally to the VL was also analysed. It was composed of two amplitude peaks with different latencies, corresponding to two groups of fibres conducting at 60-90 m/s and 20-25 m/s respectively. The negative field potentials in VL also showed two amplitude peaks and different latencies. The differences in latency between the first and second peaks in the presynaptic and postsynaptic field potentials are compatible with the possibility that both groups of afferent fibres may be monosynaptically connected to VL relay cells. The cerebello-thalamic projections were mapped and their density gradient was established. Two or three small thalamic strips of dense projections surrounded by a large zone of weaker projections were observed to emerge from each punctate cerebellar site. In the discussion of the functional significance of these findings, it is suggested that this organization might constitute a modulatable morphological support for a mechanism focalizing the cerebello-cortical inputs.