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PP2B-Dependent Cerebellar Plasticity Sets the Amplitude of the Vestibulo-ocular Reflex during Juvenile Development [ABSTRACT FROM AUTHOR]

The sense of orientation of an animal is derived from the head direction (HD) system found in several limbic structures and depends on an intact vestibular labyrinth. However, how the vestibular system influences the generation and updating of the HD signal remains poorly understood. Anatomical and lesion studies point toward three key brainstem nuclei as key components for generating the HD signal--nucleus prepositus hypoglossi, supragenual nucleus, and dorsal paragigantocellularis reticular nuclei. Collectively, these nuclei are situated between the vestibular nuclei and the dorsal tegmental and lateral mammillary nuclei, which are thought to serve as the origin of the HD signal. To determine the types of information these brain areas convey to the HD network, we recorded neurons from these regions while female rats actively foraged in a cylindrical enclosure or were restrained and rotated passively. During foraging, a large subset of cells in all three nuclei exhibited activity that correlated with the angular head velocity (AHV) of the rat. Two fundamental types of AHV cells were observed; (1) symmetrical AHV cells increased or decreased their firing with increases in AHV regardless of the direction of rotation, and (2) asymmetrical AHV cells responded differentially to clockwise and counterclockwise head rotations. When rats were passively rotated, some AHV cells remained sensitive to AHV, whereas firing was attenuated in other cells. In addition, a large number of AHV cells were modulated by linear head velocity. These results indicate the types of information conveyed from the vestibular nuclei that are responsible for generating the HD signal. [ABSTRACT FROM AUTHOR]

Sensory stimuli can trigger an orienting reflex (response) by which animals move the head to position their sensors (e.g., eyes, pinna, whiskers). Orienting responses may be important to evaluate stimuli that call for action (e.g., approach, escape, ignore), but little is known about the dynamics of orienting responses in the context of goal-directed actions. Using mice of either sex, we found that, during a signaled avoidance action, the orienting response evoked by the conditioned stimulus (CS) consisted of a fast head movement containing rotational and translational components that varied substantially as a function of the behavioral and underlying brain states of the animal set by different task contingencies. Larger CS-evoked orienting responses were associated with high-intensity auditory stimuli, failures to produce the appropriate signaled action, and behavioral states resulting from uncertain or demanding situations and the animal's ability to cope with them. As a prototypical orienting neural circuit, we confirmed that the superior colliculus controls and codes the direction of spontaneous exploratory orienting movements. In addition, superior colliculus activity correlated with CS-evoked orienting responses, and either its optogenetic inhibition or excitation potentiated CS-evoked orienting responses, which are likely generated downstream in the medulla. CS-evoked orienting responses may be a useful probe to assess behavioral and related brain states, and state-dependent modulation of orienting responses may involve the superior colliculus. [ABSTRACT FROM AUTHOR]

Procedural memories formed in the cerebellum in response to motor errors depend on changes to Purkinje cell (PC) spiking patterns that correct movement when the erroneous context is repeated. Because molecular layer interneurons (MLIs) inhibit PCs, learning-induced changes to MLI output may participate in reshaping PC spiking patterns. However, it remains unclear whether error-driven learning alters MLI activity and whether such changes are necessary for the memory engram. We addressed this knowledge gap by measuring and manipulating MLI activity in the flocculus of both sexes of mice before and after vestibulo-ocular reflex (VOR) adaptation. We found that MLIs are activated during vestibular stimuli and that their population response exhibits a phase shift after the instantiation of gain-increase VOR adaptation, a type of error-driven learning thought to require climbing-fiber-mediated instructive signaling. Although acute optogenetic suppression of MLI activity did not affect baseline VOR performance, it negated the expression of gain-increase learning, demonstrating a specific role of MLI activity changes in motor memory expression. This effect was transitory; after a multiday consolidation period, the expression of VOR gain-increase learning was no longer sensitive to MLI activity suppression. Together, our results indicate that error-driven alteration of MLI activity is necessary for labile, climbing-fiber-induced motor memory expression. [ABSTRACT FROM AUTHOR]

The sense of balance relies on vestibular hair cells, which detect head motions. Mammals have two types of vestibular hair cell, I and II, with unique morphological, molecular, and physiological properties. Furthermore, each hair cell type signals to a unique form of afferent nerve terminal. Little is known about the mechanisms in mature animals that maintain the specific features of each hair cell type or its postsynaptic innervation. We found that deletion of the transcription factor Sox2 from Type II hair cells in adult mice of both sexes caused many cells in utricles to acquire features unique to Type I hair cells and to lose Type II-specific features. This cellular transdifferentiation, which included changes in nuclear size, chromatin condensation, soma and stereocilium morphology, and marker expression, resulted in a significantly higher proportion of Type I-like hair cells in all epithelial zones. Furthermore, Sox2 deletion from Type II hair cells triggered non-cell autonomous changes in vestibular afferent neurons; they retracted bouton terminals (normally present on only Type II cells) from transdifferentiating hair cells and replaced them with a calyx terminal (normally present on only Type I cells). These changes were accompanied by significant expansion of the utricle's central zone, called the striola. Our study presents the first example of a transcription factor required to maintain the type-specific hair cell phenotype in adult inner ears. Furthermore, we demonstrate that a single genetic change in Type II hair cells is sufficient to alter the morphology of their postsynaptic partners, the vestibular afferent neurons. [ABSTRACT FROM AUTHOR]

Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, we tested the hypothesis that a canal VI that transduces angular head velocity and provides this information to the brain via motion-modulated electrical stimulation of canal afferent nerves could improve the perception of angular head position relative to gravity in monkeys with severe vestibular damage. Using a subjective visual vertical task, we found that normal female monkeys accurately sensed the orientation of the head relative to gravity during dynamic tilts, that this ability was degraded following bilateral vestibular damage, and improved when the canal VI was used. These results demonstrate that a canal VI can improve graviception in vestibulopathic animals, suggesting that it could reduce the disabling perceptual and postural deficits experienced by patients with severe vestibular damage. [ABSTRACT FROM AUTHOR]

Detection of sound and head movement requires mechanoelectrical transduction (MET) channels at tips of hair-cell stereocilia. In vertebrates, the transmembrane channel-like (TMC) proteins TMC1 and TMC2 fulfill critical roles in MET, and substantial evidence implicates these TMCs as subunits of the MET channel. To identify developmental and functional roles of this Tmc subfamily in the zebrafish inner ear, we tested the effects of truncating mutations in tmcl, tmc2a, and tmc2b on in vivo mechanosensation at the onset of hearing and balance, before gender differentiation. We find that tmcl/2a/2b triple-mutant larvae cannot detect sound or orient with respect to gravity. They lack acoustic-evoked behavioral responses, vestibularinduced eye movements, and hair-cell activity as assessed with FM dye labeling and microphonic potentials. Despite complete loss of hair-cell function, tmc triple-mutant larvae retain normal gross morphology of hair bundles and proper trafficking of known MET components Protocadherin 15a (Pcdhl5a), Lipoma HMGIC fusion partner-like 5 (Lhfpl5), and Transmembrane inner ear protein (Tmie). Transgenic, hair cell-specific expression of Tmc2b-mEGFP rescues the behavioral and physiological deficits in tmc triple mutants. Results from tmc single and double mutants evince a principle role for Tmc2a and Tmc2b in hearing and balance, respectively, whereas Tmcl has lower overall impact. Our experiments reveal that, in developing cristae, hair cells stratify into an upper, Tmc2a-dependent layer of teardrop-shaped cells and a lower, Tmcl/2b-dependent tier of gourd-shaped cells. Collectively, our genetic evidence indicates that auditory/vestibular end organs and subsets of hair cells therein rely on distinct combinations of Tmcl/2a/2b. [ABSTRACT FROM AUTHOR]

Intrinsic plasticity of cerebellar Purkinje cells (PCs) has recently been demonstrated in cerebellar local circuits; however, its physiological impact on cerebellar learning and memory remains elusive. Here, we suggest that intrinsic plasticity of PCs is tightly involved in motor memory consolidation based on findings from PC-specific STIM1 knockout male mice, which show severe memory consolidation deficiency in vestibulo-ocular reflex memory. Gain-up training of the vestibulo-ocular reflex produced a decrease in the synaptic weight of PCs in both the WT and KO groups. However, intrinsic plasticity was impaired only in the knockout mice. Furthermore, the observed defects in the intrinsic plasticity of PCs led to the formation of aberrant neural plasticity in the vestibular nucleus neurons. Our results suggest that synergistic modulation of intrinsic and synaptic plasticity in PCs is required for the changes in downstream plasticity in the vestibular nucleus, and thereby contributing to the long-term storage of motor memory. [ABSTRACT FROM AUTHOR]

Computations that require speed and temporal precision are implemented throughout the nervous system by neurons capable of firing at very high rates, rapidly encoding and transmitting a rich amount of information, but with substantial metabolic and physical costs. For economical fast spiking and high throughput information processing, neurons need to optimize multiple biophysical properties in parallel, but the mechanisms of this coordination remain unknown. We hypothesized that coordinated gene expression may underlie the coordinated tuning of the biophysical properties required for rapid firing and signal transmission. Taking advantage of the diversity of fast-spiking cell types in the medial vestibular nucleus of mice of both sexes, we examined the relationship between gene expression, ionic currents, and neuronal firing capacity. Across excitatory and inhibitory cell types, genes encoding voltage-gated ion channels responsible for depolarizing and repolarizing the action potential were tightly coexpressed, and their absolute expression levels increased with maximal firing rate. Remarkably, this coordinated gene expression extended to neurofilaments and specific presynaptic molecules, providing a mechanism for coregulating axon caliber and transmitter release to match firing capacity. These findings suggest the presence of a module of genes, which is coexpressed in a graded manner and jointly tunes multiple biophysical properties for economical differentiation of firing capacity. The graded tuning of fast-spiking capacity by the absolute expression levels of specific ion channels provides a counterexample to the widely held assumption that cell-type-specific firing patterns can be achieved via a vast combination of different ion channels. [ABSTRACT FROM AUTHOR]

Medial rectus motoneurons receive two main pontine inputs: abducens internuclear neurons, whose axons course through the medial longitudinal fasciculus (MLF), and neurons in the lateral vestibular nucleus, whose axons project through the ascending tract of Deiters (ATD). Abducens internuclear neurons are responsible for conjugate gaze in the horizontal plane, whereas ATD neurons provide medial rectus motoneurons with a vestibular input comprising mainly head velocity. To reveal the relative contribution of each input to the oculomotor physiology, single-unit recordings from medial rectus motoneurons were obtained in the control situation and after selective deafferentation from cats with unilateral transection of either the MLF or the ATD. Both MLF and AID transection produced similar short-term alterations in medial rectus motoneuron firing pattern, which were more drastic in MLF of animals. However, long-term recordings revealed important differences between the two types of lesion. Thus, while the effects of the MLF section were permanent, 2 months after ATD lesioning all motoneuronal firing parameters were similar to the control. These findings indicated a more relevant role of the MLF pathway in driving motoneuronal firing and evidenced compensatory mechanisms following the ATD lesion. Confocal immunocytochemistry revealed that MLF transection produced also a higher loss of synaptic boutons, mainly at the dendritic level. Moreover, 2 months after ATD transection, we observed an increase in synaptic coverage around motoneuron cell bodies compared with short-term data, which is indicative of a synaptogenic compensatory mechanism of the abducens internuclear pathway that could lead to the observed firing and morphological recovery. [ABSTRACT FROM AUTHOR]

Galvanic vestibular stimulation (GVS) uses modulated currents to evoke neuronal activity in vestibular endorgans in the absence of head motion. GVS is typically used for a characterization of vestibular pathologies; for studies on the vestibular influence of gaze, posture, and locomotion; and for deciphering the sensory-motor transformation underlying these behaviors. At variance with the widespread use of this method, basic aspects such as the activated cellular substrate at the sensory periphery or the comparability to motion-induced neuronal activity patterns are still disputed. Using semi-intact preparations of Xenopus laevis tadpoles, we determined the cellular substrate and the spatiotemporal specificity of GVS-evoked responses and compared sinusoidal GVS-induced activity patterns with motion-induced responses in all neuronal elements along the vestibulo-ocular pathway. As main result, we found that, despite the pharmacological block of glutamatergic hair cell transmission by combined bath-application of NMDA (7-chloro-kynurenic acid) and AMPA (CNQX) receptor blockers, GVS-induced afferent spike activity persisted. However, the amplitude modulation was reduced by ~30%, suggesting that both hair cells and vestibular afferent fibers are normally recruited by GVS. Systematic alterations of electrode placement with respect to bilateral semicircular canal pairs or alterations of the bipolar stimulus phase timing yielded unique activity patterns in extraocular motor nerves, compatible with a spatially and temporally specific activation of vestibulo-ocular reflexes in distinct planes. Despite the different GVS electrode placement in semi-intact X. laevis preparations and humans and the more global activation of vestibular endorgans by the latter approach, this method is suitable to imitate head/body motion in both circumstances. [ABSTRACT FROM AUTHOR]

The posterior vermis of the cerebellum is considered to be critically involved in saccadic adaptation. However, recent evidence suggests that the adaptive decrease (backward adaptation) and the adaptive increase (forward adaptation) of saccade amplitude rely on partially separate neural substrates. We investigated whether the posterior cerebellum could be differentially involved in backward and forward adaptation by using transcranial direct current stimulation (TDCS). To do so, participants' saccades were adapted backward or forward while they received anodal, cathodal, or sham TDCS. In two extra groups, subjects underwent a nonadaptation session while receiving anodal or cathodal TDCS to control for the direct effects of TDCS on saccadic execution. Surprisingly, cathodal stimulation tended to increase the extent of both forward and backward adaptations, while anodal TDCS strongly impaired forward adaptation and, to a smaller extent, backward adaptation. Forward adaptation was accompanied by a greater increase in velocity with cathodal stimulation, and reduced duration of change for anodal stimulation. In contrast, the expected velocity decrease in backward adaptation was noticeably weaker with anodal stimulation. Stimulation applied during nonadaptation sessions did not affect saccadic gain, velocity, or duration, demonstrating that the reported effects are not due to direct effects of the stimulation on the generation of eye movements. Our results demonstrate that cerebellar excitability is critical for saccadic adaptation. Based on our results and the growing evidence from studies of vestibulo-ocular reflex and saccadic adaptation, we conclude that the plasticity at the level of the oculomotor vermis is more fundamentally important for forward adaptation than for backward adaptation. [ABSTRACT FROM AUTHOR]

Previous experiments have shown that the vestibulo-ocular reflex (VOR) is partially suppressed during large head-free gaze (gaze = eye-in-head + head-in-space) shifts when both the eyes and head are moving actively, on a fixed body, or when the eyes are moving actively and the head passively on a fixed body. We tested, in human subjects, the hypothesis that the VOR is also suppressed during gaze saccades made with en bloc, head and body together, rotations. Subjects made saccades by following a target light. During some trials, the chair rotated so as to move the entire body passively before, during, or after a saccade. The modulation of the VOR was a function of both saccade amplitude and the time of the head perturbation relative to saccade onset. Despite the perturbation, gaze remained accurate. Thus, VOR modulation is similar when gaze changes are programmed for the eyes alone or for the eyes and head moving together. We propose that the brain always programs a change in gaze using feedback based on gaze and head signals, rather than on separate eye and head trajectories. [ABSTRACT FROM AUTHOR]

The learning of motor skills is thought to occur largely through trial and error; however, the error signals and rules controlling the induction of motor learning have not been fully elucidated. We evaluated the learning rules that translate the sensory and motor cues available during training into learned changes in the gain and phase of the vestibulo-ocular reflex (VOR) of mice. Contrary to previous theories, neither the phase of retinal image motion relative to head motion nor the phase of retinal image motion relative to eye movement could consistently predict the direction of the learned change in the gain of the VOR across all training conditions tested. Instead, the phase of the gaze movement relative to head motion during training was the best predictor of whether learning would increase or decrease the gain of the VOR. Learned changes in the phase of the VOR were best predicted by a different cue-the phase of the eye movement relative to head motion during training. These results provide new constraints on the neural mechanisms implementing the adaptive calibration of the VOR by cerebellum-dependent motor learning. [ABSTRACT FROM AUTHOR]

The neuroactive peptide calcitonin-gene related peptide (CGRP) is known to act at efferent synapses and their targets in hair cell organs, including the cochlea and lateral line. CGRP is also expressed in vestibular efferent neurons as well as a number of central vestibular neurons. Although CGRP-null (-/-) mice demonstrate a significant reduction in cochlear nerve sound-evoked activity compared with wild-type mice, it is unknown whether and how the loss of CGRP influence vestibular system function. Vestibular function was assessed by quantifying the vestibulo-ocular reflex (VOR) in alert mice. The loss of CGRP in (-/-) mice was associated with a reduction of the VOR gain of 50% without a concomitant change in phase. Using immunohistochemistry, we confirmed that, although CGRP staining was absent in the vestibular end-organs of null (-/-) mice, cholinergic staining appeared normal, suggesting that the overall gross development of vestibular efferent innervation was unaltered. We further confirmed that the observed deficit in vestibular function of null (-/-) mice was not the result of nontargeted effects at the level of the extraocular motor neurons and/or their innervation of extraocular muscles. Analysis of the relationship between vestibular quick phase amplitude and peak velocity revealed that extraocular motor function was unchanged, and immunohistochemistry revealed no abnormalities in motor endplates. Together, our findings show that the neurotransmitter CGRP plays a key role in ensuring VOR efficacy. [ABSTRACT FROM AUTHOR]

For learning to occur through trial and error, the nervous system must effectively detect and encode performance errors. To examine this process, we designed a set of oculomotor learning tasks with more than one visual object providing potential error cues, as would occur in a natural visual scene. A task-relevant visual target and a task-irrelevant visual background both influenced vestibulo-ocular reflex learning in rhesus monkeys. Thus, motor learning does not identify a single error cue based on behavioral relevance, but can be simultaneously influenced bymorethanonecue. Moreover, the relative weighting of the different cues could vary. If the speed of the visual target'smotiononthe retinawas low (≪1°/s), background motion dominated learning, but if target speed was high, the effects of the background were suppressed. The target and background motion had similar, nonlinear effects on the putative neural instructive signals carried by cerebellar climbing fibers, but with a stronger influence of the background on the climbing fibers than on learning. Incontrast, putative neural instructive signals carried by the simple spikes of Purkinje cells were influenced solely by the motion of the visual target. Because they are influenced by different cues during training, joint control of learning by the climbing fibers and Purkinje cells may expand the learning capacity of the cerebellar circuit. [ABSTRACT FROM AUTHOR]

Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions. [ABSTRACT FROM AUTHOR]

In addition to the well-known signals of retinal image slip, floccular complex spikes (CSs) also convey nonvisual signals. Were corded eye movement and CS activity from Purkinje cells in awake rabbits sinusoidally oscillated in the dark on a vestibular turntable. The stimulus frequency ranged from 0.2 to 1.2 Hz, and the velocity amplitude ranged from 6.3 to 50°/s. The average CS modulation was evaluated at each combination of stimulus frequency and amplitude. More than 75% of the Purkinje cells carried nonvisual CS signals. The amplitude of this modulation remained relatively constant over the entire stimulus range. The phase response of the CS modulation in the dark was opposite to that during the vestibulo-ocular reflex (VOR) in the light. With increased frequency, the phase response systematically shifted from being aligned with contraversive head velocity toward peak contralateral head position. At fixed frequency, the phase response was dependent on peak head velocity, indicating a system nonlinearity. The nonvisual CS modulation apparently reflects a competition between eye movement and vestibular signals, resulting in an eye movement error signal inferred from nonvisual sources. The combination of this error signal with the retinal slip signal in the inferior olive results in a net error signal reporting the discrepancy between the actual visually measured eye movement error and the inferred eye movement error derived from measures of the internal state. The presence of two error signals requires that the role of CSs in models of the floccular control of VOR adaption be expanded beyond retinal slip. [ABSTRACT FROM AUTHOR]

The middle temporal (MT) and medial superior temporal (MST) areas are successive stations of the visual motion-processing stream and project in parallel to the pontine nucleus, which is closely associated with rapid stabilization of gaze. We recorded the neural activities of MTand MST neurons of monkeys during short-latency ocular following responses (OFRs) elicited by large-field sinusoidal gratings with different spatial frequencies drifting at different temporal frequencies, and examined the dependence on spatiotemporal frequency. The results indicate that most MT/MST neurons were tuned almost separately for spatial and temporal frequencies of motion stimuli. The difference between MT and MST neurons was particularly striking for the optimal spatial frequency (higher for MT and lower for MST). The spatiotemporal frequency dependence of the OFRs could be reproduced by a weighted sum of the population activities of theMTand MSTneurons. We conclude thatMTandMSTneurons work as spatiotemporal frequency sensors that extract motions of finer and coarser visual features and that both areas contribute to generation of OFRs. [ABSTRACT FROM AUTHOR]

Synaptic plasticity in the cerebellum is thought to contribute to motor learning. In particular, long-term depression (LTD) at parallel fiber (PF) to Purkinje neuron (PN) excitatory synapses has attracted much attention of neuroscientists as a primary cellular mechanism for motor learning. In contrast, roles of plasticity at cerebellar inhibitory synapses in vivo remain unknown. Here, we have investigated the roles of long-lasting enhancement of transmission at GABAergic synapses on a PN that is known as rebound potentiation (RP). Previous studies demonstrated that binding of GABAA receptor with GABAA receptor-associated protein (GABARAP) is required for RP, and that a peptide that blocks this binding suppresses RP induction. To address the functional roles of RP, we generated transgenic mice that express this peptide fused to a fluorescent protein selectively in PNs using the PN-specific L7 promoter. These mice failed to show RP, although they showed no changes in the basal amplitude or frequency of miniature IPSCs. The transgenic mice also showed no abnormality in gross cerebellar morphology, LTD, or other excitatory synaptic properties, or intrinsic excitability of PNs. Next, we attempted to evaluate their motor control and learning ability by examining reflex eye movements. The basal dynamic properties of the vestibuloocular reflex and optokinetic response, and adaptation of the latter, were normal in the transgenic mice. In contrast, the transgenic mice showed defects in the adaptation of vestibulo-ocular reflex, a model paradigm of cerebellum-dependent motor learning. These results together suggest that RP contributes to a certain type of motor learning. [ABSTRACT FROM AUTHOR]

Multisensory visuo-vestibular cortical areas are important for spatial orientation and facilitate the control of the brainstem-mediated vestibular ocular reflex (VOR). Despite reports of visual input and cognitive tasks modulating the VOR through cortical control, it is unknown whether higher-order visual stimuli such as bistable perception and attention tasks involving visual imagery have an effect on the VOR. This is a possibility since such stimuli recruit cortical areas overlapping with those engaged during vestibular activation. Here we used a novel paradigm in which human subjects view bistable perceptual stimuli or perform complex attention tasks during concurrent vestibular stimulation. Bistable perceptual phenomena and attention tasks asymmetrically modulated the VOR but only if they involved a visuospatial component (e.g., binocular motion rivalry but not color rivalry). Strikingly, the lateralization effect was dependent upon the subjects' handedness, making this report the first behavioral demonstration that vestibular cortical processing is strongly lateralized to the non-dominant hemisphere. Furthermore, we show that perceptual transitions can modulate the dynamics of the vestibular system contingent upon the presence of a spatial component in the perceptual transition stimuli. Both perceptual transitions and attentional tasks are thought to invoke a redirection of spatial attention. We infer that such redirection of spatial attention engages multisensory vestibular cortical areas that modulate low-level vestibular function which, in turn, may contribute to spatial orientation. [ABSTRACT FROM AUTHOR]

Identification of marker genes expressed in specific cell types is essential for the genetic dissection of neural circuits. Here we report a new strategy for classifying heterogeneous populations of neurons into functionally distinct types and for identifying associated marker genes. Quantitative single-cell expression profiling of genes related to neurotransmitters and ion channels enables functional classification of neurons; transcript profiles for marker gene candidates identify molecular handles for manipulating each cell type. We apply this strategy to the mouse medial vestibular nucleus (MVN), which comprises several types of neurons subserving cerebellar-dependent learning in the vestibulo-ocular reflex. Ion channel gene expression differed both qualitatively and quantitatively across cell types and could distinguish subtle differences in intrinsic electrophysiology. Single-cell transcript profiling of MVN neurons established six functionally distinct cell types and associated marker genes. This strategy is applicable throughout the nervous system and could facilitate the use of molecular genetic tools to examine the behavioral roles of distinct neuronal populations. [ABSTRACT FROM AUTHOR]

The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles. Using a combination of anatomical tracing and electrophysiological recordings in transgenic mouse lines, we identified several classes of neurons in the medial vestibular nucleus that receive Purkinje cell synapses from the cerebellar flocculus. Glycinergic and glutamatergic flocculus target neurons (FTNs) with somata densely surrounded by Purkinje cell terminals projected axons to the ipsilateral abducens and oculomotor nuclei, respectively. Of three additional types of FTNs that were sparsely innervated by Purkinje cells, glutamatergic and glycinergic neurons projected to the contralateral and ipsilateral abducens, respectively, and GABAergic neurons projected to contralateral vestibular nuclei. Densely innervated FTNs had high spontaneous firing rates and pronounced postinhibitory rebound firing, and were physiologically homogeneous, whereas the intrinsic excitability of sparsely innervated FTNs varied widely. Heterogeneity in the molecular expression, physiological properties, and postsynaptic targets of FTNs implies that Purkinje cell activity influences the neural control of eye movements in several distinct ways. These results indicate that the cerebellum regulates a simple reflex behavior via at least five different cell types that are postsynaptic to Purkinje cells. [ABSTRACT FROM AUTHOR]

Conceptual and practical advantages of pavlovian eyelid conditioning facilitate analysis of cerebellar computation and learning. Even so, eyelid conditioning procedures are unrealistic in an important way. The error signal to the olivocerebellar system does not decrease as learning adapts response amplitude or gain. This inherently limits the utility of eyelid conditioning for studies investigating how cerebellar learning mechanisms acquire and store an adaptive response amplitude. We report the development and characterization of a training procedure in which conditioned response amplitude is brought under experimental control with contingencies that more closely parallel natural conditions. In this procedure, the delivery of the unconditioned stimulus (US) is made contingent on conditioned response amplitude: the US is delivered for responses that fail to reach a specified target amplitude and is omitted for responses that meet or exceed the target. We find that rabbits trained with either a tone or with mossy fiber stimulation as the conditioned stimulus learn responses that approach target amplitudes ranging from 2 to 5 mm. Inactivating the interpositus nucleus with muscimol infusions abolished these conditioned responses, indicating that cerebdllar involvement in eyelid conditioning is not tied explicitly to the use of pavlovian procedures. Together with previous studies, these data suggest that response amplitude is learned and encoded in the cerebellum during eyelid conditioning. As such, these results provide a foundation for systematic and controlled investigations of the cerebellar mechanisms that learn and encode the proper amplitude of adaptive movements. [ABSTRACT FROM AUTHOR]

Motor learning is required for the reacquisition of skills that have been compromised as a result of brain lesion or disease, as well as for the acquisition of new skills. Behaviors with well characterized anatomy and physiology are required to yield significant insight into changes that occur in the brain during motor learning. The vestibulo-ocular reflex (VOR) is well suited to establish connections between neurons, neural circuits, and motor performance during learning. Here, we examined the linkage between neuronal and behavioral VOR responses in alert behaving monkeys (Macaca mulatta) during the impressive recovery that occurs after unilateral vestibular loss. We show, for the first time, that motor learning is characterized by the dynamic reweighting of inputs from different modalities (i.e., vestibular vs extravestibular) at the level of the single neurons that constitute the first central stage of vestibular processing. Specifically, two types of information, which did not influence neuronal responses before the lesion, had an important role during compensation. First, unmasked neck proprioceptive inputs played a critical role in the early stages of this process demonstrated by faster and more substantial recovery of vestibular responses in proprioceptive sensitive neurons. Second, neuronal and VOR responses were significantly enhanced during active relative to passive head motion later in the compensation process (>3 weeks). Together, our findings provide evidence linking the dynamic regulation of multimodal integration at the level of single neurons and behavioral recovery, suggesting a role for homeostatic mechanisms in VOR motor learning. [ABSTRACT FROM AUTHOR]

A unique feature of the cerebellar architecture is that Purkinje cells in the cerebellar cortex each receive input from a single climbing fiber. In mice deficient in the γ isoform of protein kinase C (PKCγ-/- mice), this normal architecture is disrupted so that individual Purkinje cells receive input from multiple climbing fibers. These mice have no other known abnormalities in the cerebellar circuit. Here, we show that PKCγ-/- mice are profoundly impaired in vestibulo-ocular reflex (VOR) motor learning. The PKCγ-/- mice exhibited no adaptive increases or decreases in VOR gain at training frequencies of 2 or 0.5 Hz. This impairment was present across a broad range of peak retinal slip speeds during training. We compare the results for VOR motor learning with previous studies of the performance of PKCγ-/- mice on other cerebellum-dependent learning tasks. Together, the results suggest that single climbing fiber innervation of Purkinje cells is critical for some, but not all, forms of cerebellum-dependent learning, and this may depend on the region of the cerebellum involved, the organization of the relevant neural circuits downstream of the cerebellar cortex, as well as the timing requirements of the learning task. [ABSTRACT FROM AUTHOR]

Translational self-motion disturbs the stability of retinal images by inducing a pattern of retinal optic flow that cannot be compensated globally by a single eye movement. The eyes must rotate by different amounts, depending on which spatial location needs to be stabilized on the retina. However, compensatory eye movements during steady fixation are always such as to maintain visual acuity on the fovea at the expense of significant image slip on the peripheral retina. We investigated whether such a foveal visual strategy during translation is hard-wired or whether it embeds enough flexibility to also allow for behaviorally relevant objects outside the foveae to be stabilized preferentially on the retinas. Monkeys were moved forward or backward and leftward or rightward passively in darkness while planning a saccade or bar release to peripheral dimmed targets. By comparing the eye movements made during these tasks with those under conditions of steady fixation, we found that the motion-induced eye movements depended only on current fixation. This was true even during the last milliseconds just before a saccade to the peripheral target. We conclude that the foveal stabilization strategy is invariant and solely dependent on current eye position, a strategy that is optimal for both processing speed and efficiency in the extraction of heading information from retinal flow during self-motion. [ABSTRACT FROM AUTHOR]

The basis for the consolidation of memory is a controversial topic, particularly in the case of motor memory. One view is that motor memory is transferred, partially or completely, to a new location during the consolidation process ("systems consolidation"). We investigated this possibility in a primitive motor system, the vestibulo-ocular reflex (VOR). In the simple circuitry of the VOR, there are relatively few possible storage sites for memory. We partially blocked excitatory neurotransmission in the cerebellar cortex of cats with the glutamate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). If CNQX was injected immediately after 60 min of rotation under conditions that induced a learned decrease in the gain of the VOR, gain was returned to its baseline value. Expression of the new memory could also be disrupted by rotation in darkness, suggesting that consolidation had not taken place; however, after learning had continued for 3 d, expression of the learned change was diminished only slightly by blockade and was unaffected by rotation in darkness. Our interpretation of these results is that learning may take place initially in the cerebellar cortex and that during consolidation, motor memories are converted to a more distributed representation that includes the cerebellar cortex and another site. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that abnormal visual experience early in life induces ocular motor abnormalities. The purpose of this study was to determine how visual deprivation alters the function and gene expression profile of the ocular motor system in mice. We measured the effect of dark rearing on eye movements, gene expression in the oculomotor nucleus, and contractility of isolated extraocular muscles. In vivo eye movement recordings showed decreased gains for optokinetic and vestibulo-ocular reflexes, confirming an effect of dark rearing on overall ocular motor function. Saccade peak velocities were preserved, however, arguing that the quantitative changes in these reflexes were not secondary to limitations in force generation. Using microarrays and quantitative PeR, we found that dark rearing shifted the oculomotor nucleus transcriptome to a state of delayed/arrested development. The expression of 132 genes was altered by dark rearing; these genes fit in various functional categories (signal transduction, transcription/translation control, metabolism, synaptic function, cytoskeleton), and some were known to be associated with neuronal development and plasticity. Extraocular muscle contractility was impaired by dark rearing to a greater extent than expected from the in vivo ocular motility studies: changes included decreased force and shortening speed and evidence of abnormal excitability. The results indicate that normal development of the mouse ocular motor system and its muscles requires visual experience. The transcriptional pattern of arrested development may indicate that vision is required to establish the adult pattern, but it also may represent the plastic response of oculomotor nuclei to abnormal extraocular muscles. [ABSTRACT FROM AUTHOR]

The vestibulo-ocular reflex (VOR) comprises an outstanding system to perform studies that probe possible cerebellar roles in motor learning. Novel VOR gains can be induced (learned) by the wearing of minifying or magnifying lenses, and learning requires the presence of the cerebellum. Previously, it was shown that Purkinje cells change their head velocity sensitivities with learning and that this change was thought to be inappropriate to be causal for the changed behavior. We now demonstrate that Purkinje cells also change their eye position, eye velocity, and head velocity sensitivities after learning. These combined changes at the Purkinje cell level contribute to a net modulation that is appropriate to support the new VOR gains. Importantly, the changes in the eye position parameter, reported for the first time, suggest the involvement of the neuronal integrator pathways in VOR learning. We provide evidence that all of these changes are necessary for VOR behavior and can explain learning deficits after cerebellar removal. [ABSTRACT FROM AUTHOR]

The ability to simultaneously move in the world and maintain stable visual perception depends critically on the contribution of vestibuloocular reflexes (VORs) to gaze stabilization. It is traditionally believed that semicircular canal signals drive compensatory responses to rotational head disturbances (rotational VOR), whereas otolith signals compensate for translational movements [translational VOR (TVOR)]. However, a sensory ambiguity exists because otolith afferents are activated similarly during head translations and reorientations relative to gravity (i.e., tilts). Extra-otolith cues are, therefore, necessary to ensure that dynamic head tilts do not elicit a TVOR. To investigate how extra-otolith signals contribute, we characterized the temporal and viewing distance-dependent properties of a TVOR elicited in the absence of a lateral acceleration stimulus to the otoliths during combined translational/rotational motion. We show that, in addition to otolith signals, angular head position signals derived by integrating sensory canal information drive the TVOR. A physiological basis for these results is proposed in a model with two distinct integration steps. Upstream of the well known oculomotor velocity-to-position neural integrator, the model incorporates a separate integration element that could represent the "velocity storage integrator," whose functional role in the oculomotor system has so far remained controversial. We propose that a key functional purpose of the velocity storage network is to temporally integrate semicircular canal signals, so that they may be used to extract translation information from ambiguous otolith afferent signals in the natural and functionally relevant bandwidth of head movements. [ABSTRACT FROM AUTHOR]

Presents a study that investigated rapid motor learning behavior in the translational vestibulo-ocular reflex (TVOR) of a controlled group of monkeys. Observation of learned changes in the TVOR; Investigation of the locality of learning sites; Suggestions with regard to the underlying cellular mechanisms of the dependence of learning on both head motion and evoked eye movement.

Presents a study which compared the three-dimensional kinematics associated with the translational vestibulo-ocular reflex with those of the rotational vestibulo-ocular reflex and pursuit eye movements as a simple test for a more general conceptual property regarding the functional role of vestibular-evoked eye movements during translation. Materials and methods; Results and discussion.

The article presents a critical review of papers related to a functional vestibular prosthesis. J. M. Goldberg states the role of two types of vestibular reflexes including vestibularocular reflex which helps to reduce retinal image motion, and vestibulocolic reflex to stabilize head in space. As per R. F. Lewis vestibular prosthesis based on the electrical stimulation of the semicircular canals affects the restoration function in patients with damaged vestibular system.