Nucleus reticularis tegmenti pontis: a bridge between the basal ganglia and cerebellum for movement control.

Neural processing in the basal ganglia is critical for normal movement. Diseases of the basal ganglia, such as Parkinson's disease, produce a variety of movement disorders including akinesia and bradykinesia. Many believe that the basal ganglia influence movement via thalamic projections to motor areas of the cerebral cortex and through projections to the cerebellum, which also projects to the motor cortex via the thalamus. However, lesions that interrupt these thalamic pathways to the cortex have little effect on many movements, including limb movements. Yet, limb movements are severely impaired by basal ganglia disease or damage to the cerebellum. We can explain this impairment as well as the mild effects of thalamic lesions if basal ganglia and cerebellar output reach brainstem motor regions without passing through the thalamus. In this report, we describe several brainstem pathways that connect basal ganglia output to the cerebellum via nucleus reticularis tegmenti pontis (NRTP). Additionally, we propose that widespread afferent and efferent connections of NRTP with the cerebellum could integrate processing across cerebellar regions. The basal ganglia could then alter movements via descending projections of the cerebellum. Pathways through NRTP are important for the control of normal movement and may underlie deficits associated with basal ganglia disease.

Consensus paper: current views on the role of cerebellar interpositus nucleus in movement control and emotion.

In the present paper, we examine the role of the cerebellar interpositus nucleus (IN) in motor and non-motor domains. Recent findings are considered, and we share the following conclusions: IN as part of the olivo-cortico-nuclear microcircuit is involved in providing powerful timing signals important in coordinating limb movements; IN could participate in the timing and performance of ongoing conditioned responses rather than the generation and/or initiation of such responses; IN is involved in the control of reflexive and voluntary movements in a task- and effector system-dependent fashion, including hand movements and associated upper limb adjustments, for quick effective actions; IN develops internal models for dynamic interactions of the motor system with the external environment for anticipatory control of movement; and IN plays a significant role in the modulation of autonomic and emotional functions.

Functional relations of cerebellar modules of the cat.

The cerebellum consists of parasagittal zones that define fundamental modules of neural processing. Each zone receives input from a distinct subdivision of the inferior olive (IO)-activity in one olivary subdivision will affect activity in one cerebellar module. To define functions of the cerebellar modules, we inactivated specific olivary subdivisions in six male cats with a glutamate receptor blocker. Olivary inactivation eliminates Purkinje cell complex spikes, which results in a high rate of Purkinje cell simple spike discharge. The increased simple spike discharge inhibits output from connected regions of the cerebellar nuclei. After inactivation, behavior was evaluated during a reach-to-grasp task and during locomotion. Inactivation of each subdivision produced unique behavioral deficits. Performance of the reach-to-grasp task was affected by inactivation of the rostral dorsal accessory olive (rDAO) and the rostral medial accessory olive (rMAO) and, possibly, the principal olive. rDAO inactivation produced paw drag during locomotion and a deficit in grasping the handle during the reach-to-grasp task. rMAO inactivation caused the cats to reach under the handle and produced severe limb drag during locomotion. Inactivation of the dorsal medial cell column, cell group beta, or caudal medial accessory olive produced little deficit in the reach-to-grasp task, but each produced a different deficit during locomotion. In all cases, the cats appeared to have intact sensation, good spatial awareness, and no change of affect. Normal cerebellar function requires low rates of IO discharge, and each cerebellar module has a specific and unique function in sensory-motor integration.

Activated autologous macrophage implantation in a large-animal model of spinal cord injury.

OBJECT: Axonal regeneration may be hindered following spinal cord injury (SCI) by a limited immune response and insufficient macrophage recruitment. This limitation has been partially surmounted in small-mammal models of SCI by implanting activated autologous macrophages (AAMs). The authors sought to replicate these results in a canine model of partial SCI. METHODS: Six dogs underwent left T-13 spinal cord hemisection. The AAMs were implanted at both ends of the lesion in 4 dogs, and 2 other dogs received sham implantations of cell media. Cortical motor evoked potentials (MEPs) were used to assess electrophysiological recovery. Functional motor recovery was assessed with a modified Tarlov Scale. After 9 months, animals were injected with wheat germ agglutinin-horseradish peroxidase at L-2 and killed for histological assessment. RESULTS: Three of the 4 dogs that received AAM implants and 1 of the 2 negative control dogs showed clear recovery of MEP response. Behavioral assessment showed no difference in motor function between the AAM-treated and control groups. Histological investigation with an axonal retrograde tracer showed neither local fiber crossing nor significant uptake in the contralateral red nucleus in both implanted and negative control groups. CONCLUSIONS: In a large-animal model of partial SCI treated with implanted AAMs, the authors saw no morphological or histological evidence of axonal regeneration. Although they observed partial electrophysiological and functional motor recovery in all dogs, this recovery was not enhanced in animals treated with implanted AAMs. Furthermore, there was no morphological or histological evidence of axonal regeneration in animals with implants that accounted for the observed recovery. The explanation for this finding is probably multifactorial, but the authors believe that the AAM implantation does not produce axonal regeneration, and therefore is a technology that requires further investigation before it can be clinically relied on to ameliorate SCI.

Pathways for control of face and neck musculature by the basal ganglia and cerebellum.

The basal ganglia are believed to influence movement via thalamo-cortical projections. However, the basal ganglia may also affect brainstem areas involved in movement control such as the red nucleus. The red nucleus receives input from the cerebellum and projects to motor neurons and premotor neurons in the contralateral brainstem and spinal cord. Are there pathways that allow output from the basal ganglia to influence processing in the red nucleus? This study uses the bidirectional tracer, WGA-HRP, to demonstrate that regions of the cat red nucleus receive input from the basal ganglia as well as from the cerebellum. Output from the entopeduncular nucleus, the feline equivalent of the internal segment of the globus pallidus, provides a modest direct input to the red nucleus as well as a more substantial indirect input via projections to the zona incerta and the fields of Forel. Regions of the red nucleus with input from the basal ganglia also receive input from the cerebellar dentate nucleus and lateral regions of interpositus. The regions of the red nucleus receiving basal gangliar input project to the contralateral facial nucleus and upper segments of the cervical spinal cord. Therefore, the red nucleus provides a junction where output from the basal ganglia can interact with output of the cerebellum for movement control of the head and face. The pathway may provide a substrate for a variety of movement disorders that are seen with diseases of the basal ganglia such as cervical dystonia and Parkinson's facies.

Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury.

OBJECT: Therapies that use bioactive materials as replacement extracellular matrices may hold the potential to mitigate the inhibition of regeneration observed after central nervous system trauma. Hyaluronic acid (HA), a nonsulfated glycosaminoglycan ubiquitous in all tissues, was investigated as a potential neural tissue engineering matrix. METHODS: Chick dorsal root ganglia were cultured in 3D hydrogel matrices composed of cross-linked thiol-modified HA or fibrin. Samples were cultured and images were acquired at 48-, 60-, and 192-hour time points. Images of all samples were analyzed at 48 hours of incubation to quantify the extent of neurite growth. Cultures in crosslinked thiolated HA exhibited more than a 50% increase in neurite length compared with fibrin samples. Furthermore, cross-linked thiolated HA supported neurites for the entire duration of the culture period, whereas fibrin cultures exhibited collapsed and degenerating extensions beyond 60 hours. Two concentrations of the thiolated HA (0.5 and 1%) were then placed at the site of a complete thoracic spinal cord transection in rats. The ability of the polymer to promote regeneration was tested using motor evoked potentials, retrograde axonal labeling, and behavioral assessments. There were no differences in any of the parameters between rats treated with the polymer and controls. CONCLUSIONS: The use of a cross-linked HA scaffold promoted robust neurite outgrowth. Although there was no benefit from the polymer in a rodent spinal cord injury model, the findings in this study represent an early step in the development of semisynthetic extracellular matrice scaffolds for the treatment of neuronal injury.

Discharge of inferior olive cells during reaching errors and perturbations.

It is widely believed that inferior olive (IO) neurons signal the occurrence of movement errors. The IO compares descending motor commands with information about movement and detects mismatches. Presumably, this error signal is used by the cerebellum to improve motor performance. To test this theory, we trained cats to reach out, grasp and retrieve a handle on cue. After training, the handle was displaced on selected trials so the cats would reach but miss the handle. Fifty-five IO cells with receptive fields on the forelimb were tested with the displaced handle condition. No cell fired at or near the time of "expected" contact, but some cells fired when the cats struck objects while attempting to grasp. A mismatch between a motor command and expected result is not sufficient to activate IO neurons; appropriate stimulation must occur. To define conditions for appropriate stimulation, the limb was stimulated at various times during the task. Sixty-six cells (including the 55 tested under the displaced handle condition) were tested with mechanical stimulation during quiet stance, and 98% responded to stimulation. A smaller percentage (68%) fired when stimulation was introduced during the reaching task, and the probability of these responses varied with the subdivision of the olive as well as the phase of the task. We conclude that it is unlikely that IO discharge provides information about movement or movement error. Olivary cells respond reliably to appropriate somatosensory stimulation but not to active movement or movement error.

Activation of climbing fibers.

Cells in the inferior olive are the sole source of climbing fibers to the cerebellum. In this article, we review some of the discharge properties of olivary cells that are important for understanding its functional role in cerebellar processing. It is generally believed that climbing fiber input supplies the cerebellum with information related to movement errors in order to improve motor performance. As a whole, olivary properties are not consistent with this function. The properties are consistent with the hypothesis that the olive is important for associating arbitrary sensory stimuli with somatosensory events. Although such associations would not be useful for improving the accuracy of motor commands, they may be useful for organizing appropriate behaviors to cope with the predicted event.

Spinal projections of the cat parvicellular red nucleus.

Traditionally, the red nucleus of the cat is divided into two parts: a large-celled, magnocellular, division (RNm) and a small-celled, parvicellular, division (RNp). The RNm projects to the spinal cord and receives input from the cerebellar interpositus nucleus. The RNp projects to the inferior olive and receives input from the cerebellar dentate nucleus. In this report, we reexamine the connections of the red nucleus using the bidirectional tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP). Our findings demonstrate that the cat RNp has a large caudal and lateral region that projects to contralateral spinal cord and not to the inferior olive. The spinally projecting region of RNp receives input from the dentate nucleus and a lateral segment of anterior interpositus. Cervical projections from the red nucleus show a topography with the rostral portion of RNp favoring upper segments and the caudal portion of RNm favoring lower segments. The results show that dentate output can influence spinal activity without passing through the cerebral cortex. For the control of movements such as reaching and grasping, we suggest that RNp and dentate focus on the control of proximal limb musculature, whereas RNm and the anterior interpositus focus on the control of distal limb musculature. We also suggest that other species are likely to have a small-celled area of red nucleus projecting to the spinal cord.

Inhibitory control of olivary discharge.

The inferior olivary nucleus is the sole source of an entire afferent system to the cerebellum, the climbing-fiber system. Inferior olivary neurons are very sensitive to the appropriate sensory stimuli, such as light contact to the paw. Yet, when animals move about, olivary cells show little change in discharge rate. Apparently some mechanism prevents the cells from discharging to stimuli generated by the animal's own movement. The inferior olive receives a massive inhibitory input from small cells in the cerebellar and vestibular nuclei. This article reviews the results from several experiments that suggest that the inferior olive is specifically targeted by inhibitory inputs that prevent responses to stimuli resulting from self-produced movement. Oscarsson proposed that the inferior olive provides the cerebellum with information about errors of motor performance and about spinal reflexes. We argue that it is unlikely that the inferior olive provides information about movement errors, although the olive may signal the occurrence of sensory events that are likely to elicit reflex movements. Another popular theory of climbing-fiber action argues that the climbing fibers play a role in altering the strength of the parallel fiber-Purkinje cell synapse. The cerebellum is important for the formation of classically conditioned responses, and input generated by the unconditioned stimulus does provide effective stimulation of olivary neurons. Although the olive does not generate the unconditioned response, it may provide the cerebellum with information necessary for the formation of conditioned responses.