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• Studies of ocular reflex adaptations support the cerebellar learning hypothesis. • Purkinje cell synapse plasticity driven by climbing fiber inputs induces adaptations. • The memory of adaptation is initially formed in cerebellar flocculus Purkinje cells. • Repetition of adaptations consolidate the memory of adaptations in vestibular nuclei. • The hypothesis includes integrative functions operated by the cerebrocerebellar loop. Masao Ito proposed a cerebellar learning hypothesis with Marr and Albus in the early 1970s. He suggested that cerebellar flocculus (FL) Purkinje cells (PCs), which directly inhibit the vestibular nuclear neurons driving extraocular muscle motor neurons, adaptively control the horizontal vestibulo-ocular reflex (HVOR) through the modification of mossy and parallel fiber-mediated vestibular responsiveness by visual climbing fiber (CF) inputs. Later, it was suggested that the same FL PCs adaptively control the horizontal optokinetic response (HOKR) in the same manner through the modification of optokinetic responsiveness in rodents and rabbits. In 1982, Ito and his colleagues discovered the plasticity of long-term depression (LTD) at parallel fiber (PF)–PC synapses after conjunctive stimulation of mossy or parallel fibers with CFs. Long-term potentiation (LTP) at PF–PC synapses by weak PF stimulation alone was found later. Many lines of experimental evidence have supported their hypothesis using various experimental methods and materials for the past 50 years by many research groups. Although several controversial findings were presented regarding their hypothesis, the reasons underlying many of them were clarified. Today, their hypothesis is considered as a fundamental mechanism of cerebellar learning. Furthermore, it was found that the memory of adaptation is transferred from the FL to vestibular nuclei for consolidation by repetition of adaptation through the plasticity of vestibular nuclear neurons. In this article, after overviewing their cerebellar learning hypothesis, I discuss possible roles of LTD and LTP in gain-up and gain-down HVOR/HOKR adaptations and refer to the expansion of their hypothesis to cognitive functions. [ABSTRACT FROM AUTHOR]

Masao Ito - A Visionary Neuroscientist with a Passion for the Cerebellum. [Extracted from the article]

Cerebellar Purkinje cells (PCs) project their axon collaterals to underneath of the PC layer and make GABAergic synaptic contacts with globular cells, a subgroup of Lugaro cells. GABAergic transmission derived from the PC axon collaterals is so powerful that it could inhibit globular cells and regulate their firing patterns. However, the physiological properties and implications of the GABAergic synapses on globular cells remain unknown. Using whole-cell patch-clamp recordings from globular cells in the mouse cerebellum, we examined the monoaminergic modulation of GABAergic inputs to these cells. Application of either serotonin (5-HT) or noradrenaline (NA) excited globular cells, thereby leading to their firing. The 5-HT- and NA-induced firing was temporally confined and attenuated by GABAergic transmission, although 5-HT and NA exerted an inhibitory effect on the release of GABA from presynaptic terminals of PC axon collaterals. Agonists for 5-HT 1B receptors and α 2 -adrenoceptors mimicked the 5-HT- and NA-induced suppression of GABAergic activity. Through their differential modulatory actions on the cerebellar inhibitory neural circuits, 5-HT facilitated PC firing, whereas NA suppressed it. These results indicate that 5-HT and NA regulate the membrane excitability of globular cells and PCs through their differential modulation of not only the membrane potential but also GABAergic synaptic circuits. Monoaminergic modulation of the neural connections between globular cells and PCs could play a role in cerebellar motor coordination. [ABSTRACT FROM AUTHOR]

Stimulation of type I metabotropic glutamate receptors (mGluR1/5) in several neuronal types induces slow excitatory responses through activation of transient receptor potential canonical (TRPC) channels. GABAergic cerebellar molecular layer interneurons (MLIs) modulate firing patterns of Purkinje cells (PCs), which play a key role in cerebellar information processing. MLIs express mGluR1, and activation of mGluR1 induces an inward current, but its precise intracellular signaling pathways are unknown. We found that mGluR1 activation facilitated spontaneous firing of mouse cerebellar MLIs through an inward current mediated by TRPC1 channels. This mGluR1-mediated inward current depends on both G protein-dependent and -independent pathways. The nonselective protein tyrosine kinase inhibitors genistein and AG490 as well as the selective extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors PD98059 and SL327 suppressed the mGluR1-mediated current responses. Following G protein blockade, the residual mGluR1-mediated inward current was significantly reduced by the selective Src tyrosine kinase inhibitor PP2. In contrast to cerebellar PCs, GABAB receptor activation in MLIs did not alter the mGluR1-mediated inward current, suggesting that there is no cross-talk between mGluR1 and GABAB receptors in MLIs. Thus, activation of mGluR1 facilitates firing of MLIs through the TRPC1-mediated inward current, which depends on not only G protein-dependent but also Src–ERK1/2-dependent signaling pathways, and consequently depresses the excitability of cerebellar PCs. [ABSTRACT FROM AUTHOR]

Abstract: Accumulating experimental evidence suggests that the memory trace of ocular reflex adaptation is initially encoded in the cerebellar cortex, and later transferred to the cerebellar nuclei for consolidation through repetitions of training. However, the memory transfer is not well characterized in the learning of voluntary movement. Here, we implement our model of memory transfer to interpret the data of prism adaptation (Martin, Keating, Goodkin, Bastian, & Thach, 1996a, 1996b), assuming that the cerebellar nuclear memory formed by memory transfer is used for normal throwing. When the subject was trained to throw darts wearing prisms in 30–40 trials, the short-term memory for recalibrating the throwing direction by gaze would be formed in the cerebellar cortex, which was extinguished by throwing with normal vision in a similar number of trials. After weeks of repetitions of short-term prism adaptation, the long-term memory would be formed in the cerebellar nuclei through memory transfer, which enabled one to throw darts to the center wearing prisms without any training. These two long-term memories, one for throwing with normal vision and the other for throwing wearing prisms, are assumed to be utilized automatically under volitional control. Moreover, when the prisms were changed to new prisms, a new memory for adapting to the new prisms would be formed in the cerebellar cortex, just to counterbalance the nuclear memory of long-term adaptation to the original prisms in a similar number of trials. These results suggest that memory transfer may occur in the learning of voluntary movements. [Copyright &y& Elsevier]

Precise gain and timing control is the goal of cerebellar motor learning. Because the basic neural circuitry of the cerebellum is homogeneous throughout the cerebellar cortex, a single computational mechanism may be used for simultaneous gain and timing control. Although many computational models of the cerebellum have been proposed for either gain or timing control, few models have aimed to unify them. In this paper, we hypothesize that gain and timing control can be unified by learning of the complete waveform of the desired movement profile instructed by climbing fiber signals. To justify our hypothesis, we adopted a large-scale spiking network model of the cerebellum, which was originally developed for cerebellar timing mechanisms to explain the experimental data of Pavlovian delay eyeblink conditioning, to the gain adaptation of optokinetic response (OKR) eye movements. By conducting large-scale computer simulations, we could reproduce some features of OKR adaptation, such as the learning-related change of simple spike firing of model Purkinje cells and vestibular nuclear neurons, simulated gain increase, and frequency-dependent gain increase. These results suggest that the cerebellum may use a single computational mechanism to control gain and timing simultaneously. [ABSTRACT FROM AUTHOR]

Abstract: Recent lesion studies on monkeys suggest that the cerebellar lobulus petrosus of the paraflocculus (LP) and crura I and II of hemispheric lobule VII (H-7) are involved in smooth pursuit eye movement control. To reveal the relationship between the LP and H-7, we studied mossy and climbing fiber collateral inputs to these areas in four cynamolgus monkeys. After unilateral injections of retrograde tracers into the LP, labeled mossy fibers were seen ipsilaterally in the crura I and II of H-7. A very small number of labeled mossy fiber collaterals were also seen in the dorsal paraflocculus (DP). Labeled climbing fibers were seen exclusively in the ipsilateral crus I. No labeled mossy/climbing fibers were seen in the flocculus, ventral paraflocculus and other cortical areas. Combined injections of fast blue in the LP and cholera toxin subunit B in the posterior crus I and crus II of H-7 resulted in a small number of the double-labeled pontine and principal olivary neurons. Combined injections in the LP and DP induced only a few double-labeled neurons in the pontine nuclei, and no double-labeled neurons in the olivary nuclei. These results suggest that the LP and crura I and II of H-7 may share some of their mossy and climbing fiber inputs and mediate similar functional roles involving smooth pursuit eye movement control. [Copyright &y& Elsevier]

The pontine nuclei relay information derived from the cerebral cortex to the cerebellum. In addition to the motor command signals generated in the motor cortex, the cerebellum may generate motor command signals independent of the cerebral cortex using pontine nuclei-mediated signals. The cerebellar motor command signals generated in the vermis-medial cerebellar nuclear system may directly drive peripheral motoneurons in simple and autonomic movements. Those generated in the hemisphere-lateral cerebellar nuclear system, which are used in complicated movements, may not only drive the premotor or motor nuclei but may also be fed back to the cerebellum through the parvocellular red nucleus-inferior olive pathway, and may be compared with the motor command signals generated in the cerebral cortex. The long-term depression of parallel fiber-Purkinje cell synapses may be utilized in optimizing these cerebellar motor command signals. Voluntary movements may be executed through cooperation of the cerebellum- and cerebrum-generated motor command signals. [ABSTRACT FROM AUTHOR]

Protocadherin 9 (Pcdh9) is a member of the cadherin superfamily and is uniquely expressed in the vestibular and limbic systems; however, its physiological role remains unclear. Here, we studied the expression of Pcdh9 in the limbic system and phenotypes of Pcdh9-knock-out mice (Pcdh9 KO mice). Pcdh9 mRNA was expressed in the fear extinction neurons that express protein phosphatase 1 regulatory subunit 1 B (Ppp1r1b) in the posterior part of the basolateral amygdala (pBLA), as well as in the Cornu Ammonis (CA) and Dentate Gyrus (DG) neurons of the hippocampus. We show that the Pcdh9 protein was often localised at synapses. Phenotypic analysis of Pcdh9 KO mice revealed no apparent morphological abnormalities in the pBLA but a decrease in the spine number of CA neurons. Further, the Pcdh9 KO mice were related to features such as the abnormal optokinetic response, less approach to novel objects, and reduced fear extinction during recovery from the fear. These results suggest that Pcdh9 is involved in eliciting positive emotional behaviours, possibly via fear extinction neurons in the pBLA and/or synaptic activity in the hippocampal neurons, and normal optokinetic eye movement in brainstem optokinetic system-related neurons. [ABSTRACT FROM AUTHOR]

Abstract: The adaptation of the horizontal vestibulo-ocular reflex (HVOR) provides an experimental model for motor learning. Two studies, using cats and mice, respectively, have recently suggested pharmacologically that the memory of adaptation is located multiply in the cerebellum and brainstem. Here, we examined the effects of acute cerebellar flocculus shutdown on the adaptation in four monkeys. Two hours of 0.11Hz-10° turntable oscillation while viewing a stationary checked-patterned screen through the left–right reversing prism decreased the HVOR gains by 0.16, and 3 days of prism wearing combined with 2h of daily turntable oscillation decreased the HVOR gains by 0.27. Injections of lidocaine into bilateral flocculi did not affect the nonadapted HVOR gains, but depressed the visual suppression of the HVOR. They recovered the HVOR gains decreased by 2h of training, but very little affected the HVOR gains decreased by previous 2 days of training. Injections of control Ringer''s solution did not affect the gains adapted by 2h or 3 days of training. These results are consistent with the previous studies, and suggest that the memory trace of adaptation of the HVOR initially resides in the flocculus but later resides, presumably, in the vestibular nuclei in the monkey. [Copyright &y& Elsevier]

The relationship between axons derived from the prearcuate region and pontine neurons projecting to contralateral cerebellar hemispheric lobule VII, lobulus petrosus (LP) of the paraflocculus or the dorsal paraflocculus (DPFl) was investigated in the monkey. The frontopontine axons were labeled with biotinylated dextran and pontocerebellar neurons with cholera toxin subunit B or fast blue. Labeled frontopontine axons and terminals were seen in the dorsal, medial, paramedian and dorsolateral parts of the pontine nuclei. The distribution of the labeled frontopontine axons overlapped that of labeled neurons projecting to hemispheric lobule VII but did not overlap that of labeled neurons projecting to LP or DPFl. The pathway from the prearcuate region to hemispheric lobule VII may provide an anatomical substrate for the involvement of hemispheric lobule VII in voluntary eye movements. [Copyright &y& Elsevier]

Highlights • GPRC5B KO mice in Purkinje cells (PCs) have morphological swellings at the distal axons of PCs in the DCN and VN. • Misshapen mitochondria accumulate in the distal axonal swellings of Gprc5b −/− PCs. • GPRC5B loss impairs both synaptic plasticity of synapses in deep cerebellar nuclei and long-term motor learning. Abstract GPRC5B is a membrane glycoprotein robustly expressed in mouse cerebellar Purkinje cells (PCs). Its function is unknown. In Gprc5b −/− mice that lack GPRC5B, PCs develop distal axonal swellings in deep cerebellar nuclei (DCN). Numerous misshapen mitochondria, which generated excessive amounts of reactive oxygen species (ROS), accumulated in these distal axonal swellings. In primary cell cultures of Gprc5b −/− PCs, pharmacological reduction of ROS prevented the appearance of such swellings. To examine the physiological role of GPRC5B in PCs, we analyzed cerebellar synaptic transmission and cerebellum-dependent motor learning in Gprc5b −/− mice. Patch-clamp recordings in cerebellum slices in vitro revealed that the induction of long-term depression (LTD) at parallel fiber-PC synapses was normal in adult Gprc5b −/− mice, whereas the induction of long-term potentiation (LTP) at mossy fiber-DCN neuron synapses was attenuated in juvenile Gprc5b −/− mice. In Gprc5b−/− mice, long-term motor learning was impaired in both the rotarod test and the horizontal optokinetic response eye movement (HOKR) test. These observations suggest that GPRC5B plays not only an important role in the development of distal axons of PCs and formation of synapses with DCN neurons, but also in the synaptic plasticity that underlies long-term motor learning. [ABSTRACT FROM AUTHOR]

Abstract: Ataxia and impaired motor learning are both fundamental features in diseases affecting the cerebellum. However, it remains unclarified whether motor learning is impaired only when ataxia clearly manifests, nor it is known whether the progression of ataxia, the speed of which often varies among patients with the same disease, can be monitored by examining motor learning. We evaluated motor learning and ataxia at intervals of several months in 40 patients with degenerative conditions [i.e., multiple system atrophy (MSA), Machado–Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), SCA6, and SCA31]. Motor learning was quantified as the adaptability index (AI) in the prism adaptation task and ataxia was scored using the Scale for the Assessment and Rating of Ataxia (SARA). We found that AI decreased most markedly in both MSA-C and MSA-P, moderately in MJD, and mildly in SCA6 and SCA31. Overall, the AI decrease occurred more rapidly than the SARA score increase. Interestingly, AIs remained normal in purely parkinsonian MSA-P patients (n = 4), but they dropped into the ataxia range when these patients started to show ataxia. The decrease in AI during follow-up (dAI/dt) was significant in patients with SARA scores < 10.5 compared with patients with SARA scores ≥ 10.5, indicating that AI is particularly useful for diagnosing the earlier phase of cerebellar degeneration. We conclude that AI is a useful marker for progressions of cerebellar diseases, and that evaluating the motor learning of patients can be particularly valuable for detecting cerebellar impairment, which is often masked by parkinsonisms and other signs. [ABSTRACT FROM AUTHOR]

Adaptations of vestibulo-ocular and optokinetic response eye movements have been studied as an experimental model of cerebellum-dependent motor learning. Several previous physiological and pharmacological studies have consistently suggested that the cerebellar flocculus (FL) Purkinje cells (P-cells) and the medial vestibular nucleus (MVN) neurons targeted by FL (FL-targeted MVN neurons) may respectively maintain the memory traces of short- and long-term adaptation. To study the basic structures of the FL-MVN synapses by light microscopy (LM) and electron microscopy (EM), we injected green florescence protein (GFP)-expressing lentivirus into FL to anterogradely label the FL P-cell axons in C57BL/6J mice. The FL P-cell axonal boutons were distributed in the magnocellular MVN and in the border region of parvocellular MVN and prepositus hypoglossi (PrH). In the magnocellular MVN, the FL-P cell axons mainly terminated on somata and proximal dendrites. On the other hand, in the parvocellular MVN/PrH, the FL P-cell axonal synaptic boutons mainly terminated on the relatively small-diameter (< 1 μm) distal dendrites of MVN neurons, forming symmetrical synapses. The majority of such parvocellular MVN/PrH neurons were determined to be glutamatergic by immunocytochemistry and in-situ hybridization of GFP expressing transgenic mice. To further examine the spatial relationship between the synapses of FL P-cells and those of vestibular nerve on the neurons of the parvocellular MVN/PrH, we added injections of biotinylated dextran amine into the semicircular canal and anterogradely labeled vestibular nerve axons in some mice. The MVN dendrites receiving the FL P-cell axonal synaptic boutons often closely apposed vestibular nerve synaptic boutons in both LM and EM studies. Such a partial overlap of synaptic boutons of FL P-cell axons with those of vestibular nerve axons in the distal dendrites of MVN neurons suggests that inhibitory synapses of FL P-cells may influence the function of neighboring excitatory synapses of vestibular nerve in the parvocellular MVN/PrH neurons. [ABSTRACT FROM AUTHOR]

The cerebellum plays important roles in motor coordination and learning. However, motor learning has not been quantitatively evaluated clinically. It thus remains unclear how motor learning is influenced by cerebellar diseases or aging, and is related with incoordination. Here, we present a new application for testing human cerebellum-dependent motor learning using prism adaptation. In our paradigm, the participant wearing prism-equipped goggles touches their index finger to the target presented on a touchscreen in every trial. The whole test consisted of three consecutive sessions: (1) 50 trials with normal vision (BASELINE), (2) 100 trials wearing the prism that shifts the visual field 25° rightward (PRISM), and (3) 50 trials without the prism (REMOVAL). In healthy subjects, the prism-induced finger-touch error, i.e., the distance between touch and target positions, was decreased gradually by motor learning through repetition of trials. We found that such motor learning could be quantified using the “adaptability index (AI)”, which was calculated by multiplying each probability of [acquisition in the last 10 trials of PRISM], [retention in the initial five trials of REMOVAL], and [extinction in the last 10 trials of REMOVAL]. The AI of cerebellar patients less than 70 years old (mean, 0.227; n = 62) was lower than that of age-matched healthy subjects (0.867, n = 21; p < 0.0001). While AI did not correlate with the magnitude of dysmetria in ataxic patients, it declined in parallel with disease progression, suggesting a close correlation between the impaired cerebellar motor leaning and the dysmetria. Furthermore, AI decreased with aging in the healthy subjects over 70 years old compared with that in the healthy subjects less than 70 years old. We suggest that our paradigm of prism adaptation may allow us to quantitatively assess cerebellar motor learning in both normal and diseased conditions. [ABSTRACT FROM AUTHOR]

Summary Neuronal networks are dynamically modified by selective synapse pruning during development and adulthood. However, how certain connections win the competition with others and are subsequently maintained is not fully understood. Here, we show that C1ql1, a member of the C1q family of proteins, is provided by climbing fibers (CFs) and serves as a crucial anterograde signal to determine and maintain the single-winner CF in the mouse cerebellum throughout development and adulthood. C1ql1 specifically binds to the brain-specific angiogenesis inhibitor 3 (Bai3), which is a member of the cell-adhesion G-protein-coupled receptor family and expressed on postsynaptic Purkinje cells. C1ql1-Bai3 signaling is required for motor learning but not for gross motor performance or coordination. Because related family members of C1ql1 and Bai3 are expressed in various brain regions, the mechanism described here likely applies to synapse formation, maintenance, and function in multiple neuronal circuits essential for important brain functions. [ABSTRACT FROM AUTHOR]

The structural maintenance of neural circuits is critical for higher brain functions in adulthood. Although several molecules have been identified as regulators for spine maintenance in hippocampal and cortical neurons, it is poorly understood how Purkinje cell (PC) spines are maintained in the mature cerebellum. Here we show that the calcium channel type 1 inositol trisphosphate receptor (IP3R1) in PCs plays a crucial role in controlling the maintenance of parallel fiber (PF)-PC synaptic circuits in the mature cerebellum in vivo. Significantly, adult mice lacking IP3R1 specifically in PCs (L7-Cre;Itpr1flox/flox) showed dramatic increase in spine density and spine length of PCs, despite having normal spines during development. In addition, the abnormally rearranged PF-PC synaptic circuits in mature cerebellum caused unexpectedly severe ataxia in adult L7-Cre;Itprlflox/flox mice. Our findings reveal a specific role for IP3R1 in PCs not only as an intracellular mediator of cerebellar synaptic plasticity induction, but also as a critical regulator of PF-PC synaptic circuit maintenance in the mature cerebellum in vivo; this mechanism may underlie motor coordination and learning in adults. [ABSTRACT FROM AUTHOR]

Some central nervous system neurons express receptors of gastrointestinal hormones, but their pharmacological actions are not well known. Previous anatomical and unit recording studies suggest that a group of cerebellar Purkinje cells express motilin receptors, and motilin depresses the spike discharges of vestibular nuclear neurons that receive direct cerebellar inhibition in rats or rabbits. Here, by the slice-patch recording method, we examined the pharmacological actions of motilin on the mouse medial vestibular nuclear neurons (MVNs), which play an important role in the control of ocular reflexes. A small number of MVNs, as well as cerebellar floccular Purkinje cells, were labeled with an anti-motilin receptor antibody. Bath application of motilin (0.1 μ m) decreased the discharge frequency of spontaneous action potentials in a group of MVNs in a dose-dependent manner ( Kd, 0.03 μ m). The motilin action on spontaneous action potentials was blocked by apamin (100 n m), a blocker of small-conductance Ca2+-activated K+ channels. Furthermore, motilin enhanced the amplitudes of inhibitory postsynaptic currents (IPSCs) and miniature IPSCs, but did not affect the frequencies of miniature IPSCs. Intracellular application of pertussis toxin (PTx) (0.5 μg/μL) or guanosine triphosphate-γ-S (1 m m) depressed the motilin actions on both action potentials and IPSCs. Only 30% of MVNs examined on slices obtained from wild-type mice, but none of the GABAergic MVNs that were studied on slices obtained from vesicular γ-aminobutyric acid transporter-Venus transgenic mice, showed such a motilin response on action potentials and IPSCs. These findings suggest that motilin could modulate small-conductance Ca2+-activated K+ channels and postsynaptic γ-aminobutyric acid receptors through heterotrimeric guanosine triphosphate-binding protein-coupled receptor in a group of glutamatergic MVNs. [ABSTRACT FROM AUTHOR]

Inhibitory interneurons in the cerebellar granular layer are more heterogeneous than traditionally depicted. In contrast to Golgi cells, which are ubiquitously distributed in the granular layer, small fusiform Lugaro cells and globular cells are located underneath the Purkinje cell layer and small in number. Globular cells have not been characterized physiologically. Here, using cerebellar slices obtained from a strain of gene-manipulated mice expressing GFP specifically in GABAergic neurons, we morphologically identified globular cells, and compared their synaptic activity and monoaminergic influence of their electrical activity with those of small Golgi cells and small fusiform Lugaro cells. Globular cells were characterized by prominent IPSCs together with monosynaptic inputs from the axon collaterals of Purkinje cells, whereas small Golgi cells or small fusiform Lugaro cells displayed fewer and smaller spontaneous IPSCs. Globular cells were silent at rest and fired spike discharges in response to application of either serotonin (5-HT) or noradrenaline. The two monoamines also facilitated small Golgi cell firing, but only 5-HT elicited firing in small fusiform Lugaro cells. Furthermore, globular cells likely received excitatory monosynaptic inputs through mossy fibers. Because globular cells project their axons long in the transversal direction, the neuronal circuit that includes interplay between Purkinje cells and globular cells could regulate Purkinje cell activity in different microzones under the influence of monoamines and mossy fiber inputs, suggesting that globular cells likely play a unique modulatory role in cerebellar motor control. [ABSTRACT FROM AUTHOR]

Abstract: Adaptation of mouse horizontal optokinetic response (HOKR) eye movement provides an experimental model for cerebellum-dependent motor learning. Our previous study revealed that the memory trace of HOKR adaptation is initially encoded in the cerebellar flocculus after hours of optokinetic training, and transferred to the vestibular nuclei to be consolidated to long-term motor memory after days of training . To reveal how the cerebellar cortex operates in the transfer of the memory trace of adaptation, we examined the effects of shutdown of the cerebellar cortex after daily training. Three groups of mice received 1h of optokinetic training daily for 4 days, and showed similar amounts of adaptation after the end of 1h of training throughout 4 days. However, in the mice which daily received bilateral floccular muscimol infusion under gas anesthesia in the post-training period, consolidation of memory of the adaptation was markedly impaired, compared with the control mice which daily received bilateral floccular Ringer''s solution infusions under gas anesthesia or those which daily received only gas anesthesia. These results are consistent with the studies of the effects of inactivation of cerebellar cortex on the consolidation of motor memory of rabbit eyeblink conditioning , and suggest that the post-training cerebellar cortex activity play an important for the consolidation of motor memory of HOKR adaptation. [Copyright &y& Elsevier]

Information processing of the cerebellar granular layer composed of granule and Golgi cells is regarded as an important first step toward the cerebellar computation. Our previous theoretical studies have shown that granule cells can exhibit random alternation between burst and silent modes, which provides a basis of population representation of the passage-of-time (POT) from the onset of external input stimuli. On the other hand, another computational study has reported that granule cells can exhibit synchronized oscillation of activity, as consistent with observed oscillation in local field potential recorded from the granular layer while animals keep still. Here we have a question of whether an identical network model can explain these distinct dynamics. In the present study, we carried out computer simulations based on a spiking network model of the granular layer varying two parameters: the strength of a current injected to granule cells and the concentration of Mg2+ which controls the conductance of NMDA channels assumed on the Golgi cell dendrites. The simulations showed that cells in the granular layer can switch activity states between synchronized oscillation and random burst-silent alternation depending on the two parameters. For higher Mg2+ concentration and a weaker injected current, granule and Golgi cells elicited spikes synchronously (synchronized oscillation state). In contrast, for lower Mg2+ concentration and a stronger injected current, those cells showed the randomburstsilent alternation (POT-representing state). It is suggested that NMDA channels on the Golgi cell dendrites play an important role for determining how the granular layer works in response to external input. [ABSTRACT FROM AUTHOR]

We developed a new protocol that induces long-term adaptation of horizontal optokinetic response (HOKR) eye movement by hours of spaced training and examined the role of protein synthesis in the cerebellar cortex in the formation of memory of adaptation. Mice were trained to view 800 cycles of screen oscillation either by1hof massed training or by 2.5 h to8dof training with 0.5 h to 1 d space intervals. The HOKR gains increased similarly by 20-30% at the end of training; however, the gains increased by 1 h of massed training recovered within 24 h, whereas the gains increased by spaced training were sustained over 24 h. Bilateral floccular lidocaine microinfusions immediately after the end of training recovered the gains increased by 1 h of massed training but did not affect the gains increased by 4 h of spaced training, suggesting that the memory trace of adaptation was transferred from the flocculus to the vestibular nuclei within 4 h of spaced training. Blockade of floccular protein synthesis, examined by bilateral floccular microinfusions of anisomycin or actinomycin D 1-4 h before the training, impaired the gains increased by 4 h of spaced training but did not affect the gains increased by 1 h of massed training. These findings suggest that the transfer of the memory trace of adaptation occurs within 4 h of spaced training, and proteins synthesized in the flocculus during training period may play an important role in memory transfer. [ABSTRACT FROM AUTHOR]

A recent study revealed that Slitrk6, a transmembrane protein containing a leucine-rich repeat domain, has a critical role in the development of the inner ear neural circuit. However, it is still unknown how the absence of Slitrk6 affects auditory and vestibular functions. In addition, the role of Slitrk6 in regions of the central nervous system, including the dorsal thalamus, has not been addressed. To understand the physiological role of Slitrk6, Slitrk6-knockout (KO) mice were subjected to systematic behavioral analyses including auditory and vestibular function tests. Compared to wild-type mice, the auditory brainstem response (ABR) of Slitrk6-KO mice indicated a mid-frequency range (8-16 kHz) hearing loss and reduction of the first ABR wave. The auditory startle response was also reduced. A vestibulo-ocular reflex (VOR) test showed decreased vertical (head movement-induced) VOR gains and normal horizontal VOR. In an open field test, locomotor activity was reduced; the tendency to be in the center region was increased, but only in the first 5 min of the test, indicating altered adaptive responses to a novel environment. Altered adaptive responses were also found in a hole-board test in which headdip behavior was increased and advanced. Aside from these abnormalities, no clear abnormalities were noted in the mood, anxiety, learning, spatial memory, or fear memory-related behavioral tests. These results indicate that the Slitrk6-KO mouse can serve as a model of hereditary sensorineural deafness. Furthermore, the altered responses of Slitrk6-KO mice to the novel environment suggest a role of Slitrk6 in some cognitive functions. [ABSTRACT FROM AUTHOR]

In this study, we show the crucial roles of lipid signaling in longterm depression (LTD), that is, synaptic plasticity prevailing in cerebellar Purkinje cells. In mouse brain slices,, we found that cPLA2a knockout blocked LTD induction, which was rescued by replenishing arachidonic acid (AA) or prostaglandin (PG) D2 or E2. Moreover, cyclooxygenase (COX)-2 inhibitors block LTD, which is rescued by supplementing PGD2/E2. The blockade or rescue occurs when these reagents are applied within a time window of 5-15 mm following the onset of LTD-inducing stimulation. Furthermore, PGD2/E2 facilitates the chemical induction of LTD by a PKC activator but is unable to rescue the LTD blocked by a PKC inhibitor. We conclude that PGD2/E2 mediates LTD jointly with PKC, and suggest possible pathways for their interaction. Finally, we demonstrate in awake mice that cPLA2α deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning. [ABSTRACT FROM AUTHOR]

Abstract: The cerebellar flocculus–paraflocculus complex, vermal lobule VII (V-7) and hemispheric lobule VII (H-7) are involved in learning-dependent smooth pursuit eye movement control. To locate the sources of climbing fiber inputs to the H-7 and V-7, we injected retrograde tracers and examined the locations of retrogradely labeled neurons in the inferior olive in 4 monkeys. After the injection of cholera toxin B (CTB) into the H-7, retrogradely labeled neurons were observed abundantly in cell group d, i.e., dorsal cap, of the caudal medial accessory olive (MAO) and ventral lamella of principal olive (PO). After injections of fast blue (FB) into the V-7, retrogradely labeled neurons were observed mainly in cell group b of MAO, but rarely in cell group d or PO. Cell group d is known to receive inputs from the nucleus optic tract (NOT) and project climbing fibers to the flocculus and ventral paraflocculus, and cell group b is known to receive inputs from the superior colliculus. These results suggest that the three oculomotor cerebellar areas may use different visual signals for the control of smooth pursuit: the flocculus–paraflocculus complex and H-7 receive visual climbing fiber inputs derived mainly from the NOT via cell group d, while the V-7 receive visual climbing fiber inputs derived mainly from the superior colliculus via cell group b. [Copyright &y& Elsevier]

In this study, we generated mice lacking the gene for G-substrate, a specific substrate for cGMP-dependent protein kinase uniquely located in cerebellar Purkinje cells, and explored their specific functional deficits. G-substrate-deficient Purkinje cells in slices obtained at postnatal weeks (PWs) 10-15 maintained electrophysiological properties essentially similar to those from WT littermates. Conjunction of parallel fiber stimulation and depolarizing pulses induced long-term depression (LTD) normally. At younger ages, however. LTD attenuated temporarily at PW6 and recovered thereafter. In parallel with LTD. short-term (1 h) adaptation of optokinetic eye movement response (OKR) temporarily diminished at PW6. Young adult G-substrate knockout mice tested at PW12 exhibited no significant differences from their WT littermates in terms of brain structure, general behavior, locomotor behavior on a rotor rod or treadmill, eyeblink conditioning, dynamic characteristics of OKR, or short-term OKR adaptation. One unique change detected was a modest but significant attenuation in the long-term (5 days) adaptation of OKR. The present results support the concept that LTD is causal to short-term adaptation and reveal the dual functional involvement of G-substrate in neuronal mechanisms of the cerebellum for both short-term and long-term adaptation. [ABSTRACT FROM AUTHOR]

Abstract: The primate lobulus petrosus (LP) of the cerebellar paraflocculus receives inputs from visual system-related pontine nuclei, and projects to eye movement-related cerebellar nuclei. To reveal a potential involvement of LP in oculomotor control, we lesioned LP unilaterally by local injections of ibotenic acid in three Macaca fuscata. We examined the effects of lesion on eye movements evoked by step (3°)–ramp (5–15°/s) moving target. To step–ramp moving target, the monkeys showed an initial slow eye movement and later a small catch-up saccade, which was followed by the post-saccadic pursuit nearly matching to the velocity of the ramp target motion. After LP lesioning, the velocity of post-saccadic pursuits in the ipsiversive and down-ward directions decreased by 20–40% in all three monkeys. These deficits lasted for at least 1 month, and some recovery was observed. In the amplitudes of catch-up saccades, no consistent changes were seen among the three monkeys after LP lesioning. These results suggest an involvement of LP in the primate smooth pursuit eye movement control. [Copyright &y& Elsevier]

Ca2+-dependent activator protein for secretion 2 (CAPS2/CADPS2) is a secretory granule-associated protein that is abundant at the parallel fiber terminals of granule cells in the mouse cerebellum and is involved in the release of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), both of which are required for cerebellar development. The human homolog gene on chromosome 7 is located within susceptibility locus 1 of autism, a disease characterized by several cerebellar morphological abnormalities. Here we report that CAPS2 knock-out mice are deficient in the release of NT-3 and BDNF, and they consequently exhibit suppressed phosphorylation of Trk receptors in the cerebellum; these mice exhibit pronounced impairments in cerebellar development and functions, including neuronal survival, differentiation and migration of postmitotic granule cells, dendritogenesis of Purkinje cells, lobulation between lobules VI and VII, structure and vesicular distribution of parallel fiber--Purkinje cell synapses, paired-pulse facilitation at parallel fiber--Purkinje cell synapses, rotarod motor coordination, and eye movement plasticity in optokinetic training. Increased granule cell death of the external granular layer was noted in lobules VI-VII and IX, in which high BDNF and NT-3 levels are specifically localized during cerebellar development. Therefore, the deficiency of CAPS2 indicates that CAPS2-mediated neurotrophin release is indispensable for normal cerebellar development and functions, including neuronal differentiation and survival, morphogenesis, synaptic function, and motor leaning/control. The possible involvement of the CAPS2 gene in the cerebellar deficits of autistic patients is discussed. [ABSTRACT FROM AUTHOR]

We examined the adult neural phenotypes of theBent tailmutant mouse. TheBent tailmutant mouse was recently shown to lack a submicroscopic part of the X chromosome containing theZic3gene, which encodes a zinc-finger protein controlling vertebrate neural development. While nearly one-fourth of hemizygousBent tail(Bn/Y,Zic3-deficient)mice developed neural tube defects in their midbrain and hindbrain region, the otherBn/Ymice showed apparently normal behaviour in a C57BL/6 genetic background. A battery of behavioural and eye movement tests revealed impaired spontaneous locomotor activity, reduction of muscle tone and impairments of vestibuloocular and optokinetic eye movements in these mice. Morphological examination of the mutant brain showed a significant reduction in the cell numbers in the cerebellar anterior lobe and paraflocculus–flocculus complex. Our results indicate that the cerebellar dysgenesis characterized by subregional hypoplasia affects the locomotor activity, muscle tone and eye movement control of the mice. These findings may have some clinical implications in relation to disorders characterized by cerebellar dysgenesis, such as Joubert syndrome. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor subtype 1 (mGluR1) plays an essential role in the cerebellar long-term depression (LTD). We examined the dynamic characteristics and adaptability of horizontal vestibulo-ocular reflex (HVOR) and optokinetic response (HOKR) eye movements in mGluR1 knockout mice. A mild difference was seen in the HOKR/HVOR dynamics between the wild-type and mGluR1(−/−) mice. Exposure to 1 h of sustained screen oscillation, which induced HOKR adaptation in wild-type mice, induced no change in mutant mice. These results suggest that the mGluR1 plays an essential role in the adaptation of HOKR, and LTD underlies the adaptation of ocular reflexes. [Copyright &y& Elsevier]

Cites a study which measured the characteristics of reflex eye movements, using an infrared television camera system. What the reflex eye movement in mice showed; Inforamtion on the evaluation of dynamic characteristics of eye movement in mice; In-depth look at the results of the study.

Abstract Among the subtypes of the Ca2+ -dependent protein kinase C (PKC), which play a crucial role in long-term depression (LTD), both α and γ are expressed in the cerebellar floccular Purkinje cells. To reveal the functional differences of PKC subtypes, we examined the adaptability of ocular reflexes of PKCγ mutant mice, which show mild ataxia and normal LTD. In mutant mice, gains of the horizontal optokinetic eye response (HOKR) were reduced. Adaptation of the HOKR was not affected but its retinal slip dependency was altered in mutant mice. Sustained 1-h sinusoidal screen oscillation, which induced a relatively large amount of retinal slips in both mutant and wild-type mice, increased the HOKR gain in wild-type mice but not in mutant mice. In contrast, exposure to 1 h of sustained slower screen oscillations, which induced relatively small retinal slips in mutant and wild-type mice, increased the HOKR gain in both mutant and wild-type mice. Adaptation of the HOKR of the mutant mice to slow screen oscillation and those of wild-type mice to fast and slow screen oscillations were all abolished by local applications of a PKC inhibitor (chelerythrine) within the flocculi. Electrophysiological and anatomical studies showed no appreciable changes in the sources and magnitudes of climbing fibre inputs, which mediate retinal slip signals to the flocculus in the mutant mice. These results suggest that PKCγ has a modulatory role in determining retinal slip dependency, and other PKC subtypes, e.g. PKCα, may play a crucial role in the adaptation of the HOKR. [ABSTRACT FROM AUTHOR]