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The central nervous system predictively controls posture against external disturbances; however, the detailed mechanisms remain unclear. We tested the hypothesis that the cerebellar vermis plays a substantial role in acquiring predictive postural control by using a standing task with floor disturbances in rats. The intact, lesioned, and sham groups of rats sequentially underwent 70 conditioned floor-tilting trials, and kinematics were recorded. Six days before these recordings, only the lesion group underwent focal suction surgery targeting vermal lobules IV-VIII. In the naïve stage of the sequential trials, the upright postures and fluctuations due to the disturbance were mostly consistent among the groups. Although the pattern of decrease in postural fluctuation due to learning corresponded among the groups, the learning rate estimated from the lumbar displacement was significantly lower in the lesion group than in the intact and sham groups. These results suggest that the cerebellar vermis contributes to predictive postural controls., (© 2024. The Author(s).)

Patients and rodents with cerebellar damage display ataxic gaits characterized by impaired coordination of limb movements. Here, gait ataxia in mice with a null mutation of the gene for the cerebellin 1 precursor protein (cbln1-null mice) was investigated by kinematic analysis of hindlimb movements during locomotion. The Cbln1 protein is predominately produced and secreted from cerebellar granule cells. The cerebellum of cbln1-null mice is characterized by an 80% reduction in the number of parallel fiber-Purkinje cell synapses compared with wild-type mice. Our analyses identified prominent differences in the temporal parameters of locomotion between cbln1-null and wild-type mice. The cbln1-null mice displayed abnormal hindlimb movements that were characterized by excessive toe elevation during the swing phase, and by severe hyperflexion of the ankles and knees. When recombinant Cbln1 protein was injected into the cerebellum of cbln1-null mice, the step cycle and stance phase durations increased toward those of wild-type mice, and the angular excursions of the knee during a cycle period showed a much closer agreement with those of wild-type mice. These findings suggest that dysfunction of the parallel fiber-Purkinje cell synapses might underlie the impairment of hindlimb movements during locomotion in cbln1-null mice.

Key Points: Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia. It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1. In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca 2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice. We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future., Abstract: Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca 2+ signals, and short- and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca 2+ signals linearly correlated with a reduction of PC capacitance (cell surface area) in disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABA B receptor agonist, led to an improvement of motor performance in SCA1 mice and the improvement lasted ∼1 week after a single application of baclofen. Moreover, the restoration of motor performance in baclofen-treated SCA1 mice matched the functional recovery of mGluR-mediated slow synaptic currents and mGluR-dependent short- and long-term synaptic plasticity. These results suggest that impairment of synaptic mGluR cascades is one of the important contributing factors to cerebellar ataxia in early and middle stages of SCA1 pathology, and that modulation of mGluR signalling by baclofen or other clinical interventions may be therapeutic targets to treat SCA1., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Monocarboxylate transporter 2 (MCT2) is an important component of the lactate transport system in neurons of the adult brain. Purkinje cells in the cerebellum have been shown to have high levels of MCT2, suggesting that this protein has a key function in energy metabolism and neuronal activities in these cells. However, it is not known whether inhibition of lactate transport via MCT2 in the cerebellum affects motor performance. To address this question, we examined motor performance in mice following the inhibition of lactate transport via MCT2 in the cerebellum using α-cyano-4-hydroxycinnamate (4-CIN). 4-CIN or saline was injected into the subarachnoidal space of the cerebellum of mice and motor performance was analyzed by a rotarod test both before and after injection. 4-CIN injection reduced retention time in the rotarod test by approximately 80% at 1h post-injection compared with pre-injection. No effect was observed at 2h post-injection or in mice treated with the vehicle control. Because we observed that MCT2 plays an important role in motor performance, we next investigated the effects of acute exercise on MCT2 transcription and protein levels in mice sampled pre-exercise and at 0 and 5h after 2h of treadmill running. We found a significant increase in MCT2 mRNA levels, but not of protein levels, in the cerebellum at 5h after exercise. Our results indicate that lactate transport via MCT2 in the cerebellum may play an important role in motor performance and that exercise can increase MCT2 expression at the transcriptional level., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The importance of the cerebellum in control of locomotion is demonstrated by the ataxic gait of cerebellar patients. The intermediate cerebellum contains somatotopical representations for forelimbs and hindlimbs in both anterior and posterior lobes. However, it is not known whether these separate regions have discrete roles in control of limb movements during locomotion. Here we compared the effect of muscimol-induced inactivation of the anterior or posterior intermediate cerebellum on limb movements in walking rats. Inactivation of the anterior intermediate cerebellum had clear effects on limb movements during overground locomotion, resulting in excessive toe elevation and hyperflexion of joints in the swing phase. Inactivation of the posterior region resulted in similar but less pronounced deficits. Postural defects were not present in either group of rats. These findings suggest that the intermediate cerebellum of the anterior lobe has a greater influence on the ability to control limb movements during overground locomotion than the posterior lobe., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

During locomotion, stepping over an obstacle under visual guidance is crucial to continuous safe walking. Studies of the role of the central nervous system in stepping movements have focused on cerebral cortical areas such as the primary motor cortex and posterior parietal cortex. There is speculation that the lateral cerebellum, which has strong anatomical connections with the cerebral cortex, also plays a key role in stepping movements over an obstacle, although this function of the lateral cerebellum has not yet been elucidated. Here we investigated the role of the lateral cerebellum during obstacle avoidance locomotion in rats with a lateral cerebellar lesion. A unilateral lesion in the lateral cerebellum did not affect limb movements during overground locomotion. Importantly, however, the lesioned animals showed overshooting of the toe trajectory specific to the leading forelimb ipsilateral to the lesion when stepping over an obstacle, and the peak toe position, in which the toe is maximally raised during stepping, shifted away from the upper edge of the obstacle. Recordings of EMG activity from elbow flexor and extensor muscles suggested that the overshooting toe trajectory in the ipsilateral leading forelimb possibly resulted from sustained elbow flexion and delayed elbow extension following prolonged activity of the biceps brachii. These results suggest that the lateral cerebellum specifically contributes to generating appropriate toe trajectories in the ipsilateral leading forelimb and to controlling related muscle activities in stepping over an obstacle, especially when accurate control of the distal extremity is achieved under visual guidance.

Animals as well as humans adapt their locomotor patterns to suit different situations. To perform smooth and stable locomotion, they coordinate not only parts of a limb but also different limbs. The cerebellum is important for sensorimotor control and plays a crucial role in intra- and inter-limb coordination. Cerebellar gait ataxia is characterized by postural deficiencies and decomposition of movements. During locomotion, the vermis and the intermediate region of the cerebellum receive information through the spinocerebellar pathways about the ongoing activities in the spinal stepping generator and the somatosensory receptors. The information is conveyed by mossy fiber afferents to Purkinje neurons via granule cells and their axons, i.e., parallel fibers. Purkinje neurons transform the mossy fiber input signals to output signals that in turn modulate activities in the brainstem descending tract neurons of the brainstem that are involved in locomotion. Further, Purkinje neurons receive enhanced climbing fiber signals during perturbed locomotion. These climbing fiber signals may induce synaptic plasticity at the parallel fiber-Purkinje neuron synapses. Long-term depression (LTD) occurs in parallel fiber-Purkinje neuron synapses and is regarded as the cellular basis for the learning mechanism of the cerebellar neuronal circuit. The activation of parallel fibers releases glutamate and nitric oxide, and the released glutamate activates the glutamate receptors in the Purkinje neurons. mGluR1, a subtype of the metabotropic glutamate receptors, is highly expressed in Purkinje neurons. In addition, delta 2 glutamate receptor is expressed in only Purkinje neurons throughout the brain. Genetically targeted mice for these glutamate receptors and/or pharmacological blocking studies have been promoted to determine the functional linkage between the molecules at the cellular level and the adaptability of locomotion at the behavioral level. This article highlights some recent advances in the understanding of the role played by the cerebellum in the adaptive control of locomotion.

Previous gene knockout studies have shown that the orphan glutamate receptor delta2 (GluRdelta2) is critically involved in synaptogenesis between parallel fibers and Purkinje cells during development. However, the precise function of GluRdelta2 and whether it is functional in the mature cerebellum remain unclear. To address these issues, we developed an antibody specific for the putative ligand-binding region of GluRdelta2, and application of this antibody to cultured Purkinje cells induced AMPA receptor endocytosis, attenuated synaptic transmission and abrogated long-term depression. Moreover, injection of this antibody into the subarachnoidal supracerebellar space of adult mice caused transient cerebellar dysfunction, such as ataxic gait and poor performance in the rotorod test. These results indicate that GluRdelta2 is involved in AMPA receptor trafficking and cerebellar function in adult mice.

Diverse roles in cellular functions have been ascribed to nitric oxide (NO), and its involvement in induction of long-term depression in cerebellar Purkinje cells has been demonstrated. Manipulations of NO concentration or its synthesis in cerebellar tissues therefore provide a means for investigating roles of NO in cerebellar functions at both cellular and behavioral levels. We tested adaptive control of locomotion to perturbation in cats, and found that this form of motor learning was abolished by application of either an inhibitor of NO synthase or a scavenger of NO to the cerebellar cortical locomotion area. This finding supports the view that NO in the cerebellum plays a key role in motor learning.

We recorded spike potentials from Purkinje cells in the lateral vermis of lobule V in cat cerebellum, and found significant enhancement in climbing fiber discharges during perturbed locomotion. Five adult cats were decerebrated at a precollicular level, and 4-5 days thereafter, they were mounted on a treadmill. During stable locomotion at 36 cm/s belt velocity, climbing fiber responses were slightly modulated with a weak increment at the swing phase of the ipsilateral forelimb. When the left contralateral forelimb alone was suddenly imposed with a faster belt velocity of 61 cm/s, the occurrence of the climbing fiber discharges was significantly enhanced during the late swing phase of the ipsilateral forelimb. This observation is in accordance with the general notion that climbing fiber responses represent error signals in control of movements.

Most fish swim freely in three dimensions. The vestibular organs of fish are well developed and play an important role in maintaining postural equilibrium. Postural equilibrium in teleost fish also depend on visual information. Dorsal light response (DLR) of fish has been well-known as representative visually guided behavioral response since von Holst's description in 1935. The DLR, an innate behavior of teleost fish, whereby the back is oriented toward a given light source, represents a simple interaction between the visual and vestibular sensory inputs. In order to identify the neural center of the DLR in goldfish, lesion studies of the goldfish brain were conducted in our laboratory. The DLR was not affected by the extirpation of the corpus cerebelli, but was entirely abolished after bilateral lesions of the valvula cerebelli. The valvula cerebelli in goldfish was separated into the medial and lateral lobes by a longitudinal fissure. As to the afferent connections of the corpus cerebelli, many findings have been reported. However, the function and the fiber connections of the valvula cerebelli, especially its lateral lobe, are still unknown. Therefore, we examined the afferent connections of the lateral lobe of the valvula cerebelli by means of tracing technique with horseradish peroxidase. Furthermore, we investigated the effects of selective lesions of the medial and lateral valvula cerebelli on the DLR.

The dorsal light response (DLR) to the continuously rotating light source was investigated in goldfish that had lesioned the valvula cerebelli. The body inclination was observed and analyzed for every 10 degrees of light rotation. The effects of selective lesions of the medial and lateral valvula cerebelli on the DLR were compared. After the lesion of the medial valvula cerebelli, the fish responded to the rotating light in the similar pattern to that seen preoperatively. However, after the unilateral lesion of the lateral valvula cerebelli, the fish did not respond to light from the side contralateral to the lesion, as if the fish had been unilaterally blindfolded. The lesion induced by kainic acid of the rostral and caudal part of the lateral valvula cerebelli differently influenced on the DLR. The DLR was impaired only after the caudal part of the lateral valvula cerebelli was lesioned by kainic acid. These findings suggest that the lateral valvula cerebelli in goldfish mediate the induction of the visually guided aspects of the DLR.

The afferent connections of the lateral lobe of the valvula cerebelli in goldfish were investigated by retrograde labeling with horseradish peroxidase (HRP). Retrogradely labeled neurons were observed ipsilaterally in the lateral nucleus of the valvula and contralaterally in the inferior olivary nucleus after HRP injection into all parts of the lateral valvula. The valvulopetal projections from these nuclei were topographically arranged. After HRP injection confined to the rostral half of the lateral valvula, labeled neurons were also found ipsilaterally in the octavolateral and trigeminal cell groups: the eminentia granularis, the medial nucleus of the octavolateralis column, and the isthmic primary sensory trigeminal nucleus. HRP injection confined to the caudal half of the lateral valvula resulted in retrograde labeling of the following vision-related cell groups; the central pretectal nucleus, nucleus paracommissuralis, and the nucleus isthmi. However, the octavolateral and trigeminal cell groups did not project to the caudal half of the lateral valvula. These data provide insight into central nervous integration of visual and vestibular information, and help reveal the mechanism of the dorsal light response (DLR). Bilateral lesions of either the valvula cerebelli or pretectal area completely abolish this visually-guided response, but lesions of the optic tectum have no such effect. The pretectal nuclei (central pretectal nucleus, nucleus paracommissuralis) project to the lateral valvula directly, not via the optic tectum. These direct projections from the pretectal accessory optic nuclei to the lateral valvula may control the DLR. On the other hand, the lateral valvula receives vestibular and lateral line inputs indirectly, via the eminentia granularis and the medial nucleus of the octavolateralis column, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Motor skills and powerful movements seen in a variety of sports are acquired through repetitive practice and experience. Motor learning is the process of acquiring motor skills and involves the establishment of appropriate motor programs within the neuronal circuits of the brain. The cerebellum has been implicated as an important area of plasticity for motor learning. Purkinje cells(PCs) have great ability to express a characteristic type of activity dependent synaptic plasticity. Following the simultaneous activation of two major excitatory inputs to a PC, parallel fibers(PFs) and a climbing fiber, long-term depression(LTD) occurs in PF-PC synapses and is regarded as the cellular basis for the memory mechanism of the cerebellar neuronal circuit. LTD represents a persistent reduction in the efficacy of PF induced excitatory postsynaptic potentials(EPSPs). PF activation releases glutamate, which activates glutamate receptors in the dendritic spine of the PCs. mGluR1, a subtype of the metabotropic glutamate receptors, is highly expressed in the PCs. In addition, delta 2 ionotropic glutamate receptor(GluR δ 2) is expressed in only PCs throughout the brain. Our recent studies demonstrate that these glutamate receptors play a key role in the induction of LTD and motor learning. The present review will be expressed in terms of the involvement of these types of glutamate receptors in LTD and motor coordination during locomotion. Mice null mutant for mGluR1 exhibit characteristic cerebellar symptoms such as ataxia and motor discoordination, and also lack the LTD. Although the mGluR1 is abundantly expressed in PCs. mGluR1 is also expressed by many types of neurons in the nervous system. Hence, we returned the missing mGluR1 only into PCs with a PC-specific L7 promotor. The cell-selective rescue of mGluR1 in PCs off mGluR1 null mutant mice restored both LTD and motor coordination. GluR δ 2 is classified as an ionotropic glutamate receptor. In GluR δ 2(-/-) mice, LTD is deficient and motor coordination is also impaired. In addition, GluR δ 2(-/-) mice show abnormal synaptogenesis between PFs and PCs during development. Therefore, it is unclear whether GluR δ 2 is functional in the adult cerebellum because impairment of motor behavior may be attributed to abnormal development. Application of a blocking antibody is useful to resolve the developmental side-effects, which are inherent in conventional knockout mice. Using an antibody specific for the putative ligand-binding region of GluR δ 2, we demonstrated that GluR δ 2 is involved in LTD and motor learning in adult mice. [ABSTRACT FROM AUTHOR]

Highlights: [•] We studied a conditional transgenic mouse of spinocerebellar ataxia type 3 (SCA3Tg). [•] SCA3Tg mice exhibited striking hindlimb instability during quadrupedal standing. [•] We established the reaching task that required anticipatory postural adjustments (APAs). [•] Kinematic and electromyographic analyses in SCA3Tg mice showed APAs were impaired. [•] The cerebellum is critically involved in APAs to prevent any equilibrium disturbance. [ABSTRACT FROM AUTHOR]