Vestibular Afferent Fibers Research Articles

Simultaneous Dual Recordings From Vestibular Hair Cells and Their Calyx Afferents Demonstrate Multiple Modes of Transmission at These Specialized Endings.

In the vestibular periphery, transmission via conventional synaptic boutons is supplemented by post-synaptic calyceal endings surrounding Type I hair cells. This review focusses on the multiple modes of communication between these receptors and their enveloping calyces as revealed by simultaneous dual-electrode recordings. Classic orthodromic transmission is accompanied by two forms of bidirectional communication enabled by the extensive cleft between the Type I hair cell and its calyx. The slowest cellular communication low-pass filters the transduction current with a time constant of 10–100 ms: potassium ions accumulate in the synaptic cleft, depolarizing both the hair cell and afferent to potentials greater than necessary for rapid vesicle fusion in the receptor and potentially triggering action potentials in the afferent. On the millisecond timescale, conventional glutamatergic quantal transmission occurs when hair cells are depolarized to potentials sufficient for calcium influx and vesicle fusion. Depolarization also permits a third form of transmission that occurs over tens of microseconds, resulting from the large voltage- and ion-sensitive cleft-facing conductances in both the hair cell and the calyx that are open at their resting potentials. Current flowing out of either the hair cell or the afferent divides into the fraction flowing across the cleft into its cellular partner, and the remainder flowing out of the cleft and into the surrounding fluid compartment. These findings suggest multiple biophysical bases for the extensive repertoire of response dynamics seen in the population of primary vestibular afferent fibers. The results further suggest that evolutionary pressures drive selection for the calyx afferent.

Context-independent encoding of passive and active self-motion in vestibular afferent fibers during locomotion in primates

The vestibular system detects head motion to coordinate vital reflexes and provide our sense of balance and spatial orientation. A long-standing hypothesis has been that projections from the central vestibular system back to the vestibular sensory organs (i.e., the efferent vestibular system) mediate adaptive sensory coding during voluntary locomotion. However, direct proof for this idea has been lacking. Here we recorded from individual semicircular canal and otolith afferents during walking and running in monkeys. Using a combination of mathematical modeling and nonlinear analysis, we show that afferent encoding is actually identical across passive and active conditions, irrespective of context. Thus, taken together our results are instead consistent with the view that the vestibular periphery relays robust information to the brain during primate locomotion, suggesting that context-dependent modulation instead occurs centrally to ensure that coding is consistent with behavioral goals during locomotion.

Calretinin Immunoreactivity in the VIIIth Nerve and Inner Ear Endorgans of Ranid Frogs.

Calcium-binding proteins are essential for buffering intracellular calcium concentrations, which are critical for regulating cellular processes involved in neuronal computations. One such calcium-binding protein, calretinin, is present in many neurons of the central nervous system as well as those which innervate cranial sensory organs, although often with differential distributions in adjacent cellular elements. Here, we determined the presence and distribution of calretinin-immunoreactivity in the peripheral vestibular and auditory system of ranid frogs. Calretinin-immunoreactivity was observed in ganglion cells innervating the basilar and amphibian papilla, and in a subpopulation of ganglion cells innervating the saccular epithelium. In contrast, none of the ganglion cells innervating the lagena, the utricle, or the three semicircular canals were calretinin-immunopositive, suggesting that this calcium-binding protein is a marker for auditory but not vestibular afferent fibers in the frog. The absence of calretinin in vestibular ganglion cells corresponds with the lack of type I hair cells in anamniote vertebrates, many of which in amniotes are contacted by the neurites of large, calyx-forming calretinin-immunopositive ganglion cells. In the sensory epithelia of all endorgans, the majority of hair cells were strongly calretinin-immunopositive. Weakly calretinin-immunopositive hair cells were distributed in the intermediate region of the semicircular canal cristae, the central part of the saccular macula, the utricular, and lagenar striola and the medial part of the amphibian papilla. The differential presence of calretinin in the frog vestibular and auditory sensory periphery might reflect a biochemical feature related to firing patterns and frequency bandwidths of self-motion versus acoustic stimulus encoding, respectively.

Efferent Inputs Are Required for Normal Function of Vestibular Nerve Afferents

A group of vestibular afferent nerve fibers with irregular-firing resting discharges are thought to play a prominent role in responses to fast head movements and vestibular plasticity. We show that, in C57BL/6 mice (either sex, 4-5 weeks old), normal activity in the efferent vestibular pathway is required for function of these irregular afferents. Thermal inhibition of efferent fibers results in a profound inhibition of irregular afferents' resting discharges, rendering them inadequate for signaling head movements. In this way, efferent inputs adjust the contribution of the peripheral irregular afferent pathway that plays a critical role in peripheral vestibular signaling and plasticity.SIGNIFICANCE STATEMENT Vestibular end organs in the inner ear receive efferent inputs from the brainstem. Previously, electrical stimulation of efferents was linked to an increase in resting discharges of afferents and a decrease in their sensitivities. Here, we show that localized thermal inhibition of unmyelinated efferents results in a significant decrease in the activity of afferent nerve fibers, particularly those with irregular resting discharges implicated in responses to fast head movements and vestibular compensation. Thus, by upregulating and downregulating of afferent firing, particularly irregular afferents, efferents adjust neural activity sensitive to rapid head movements. These findings support the notion that peripheral vestibular end organs are not passive transducers of head movements and their sensory signal transmission is modulated by efferent inputs.

Impact of 4-aminopyridine on vestibulo-ocular reflex performance.

Vestibulo-ocular reflexes (VOR) are mediated by frequency-tuned pathways that separately transform the different dynamic and static aspects of head motion/position-related sensory signals into extraocular motor commands. Voltage-dependent potassium conductances such as those formed by Kv1.1 are important for the ability of VOR circuit elements to encode highly transient motion components. Here we describe the impact of the Kv1.1 channel blocker 4-aminopyridine (4-AP) on spontaneous and motion-evoked discharge of superior oblique motoneurons. Spike activity was recorded from the motor nerve in isolated preparations of Xenopus laevis tadpoles. Under static conditions, bath application of 1-10µM 4-AP increased the spontaneous firing rate and provoked repetitive bursts of spikes. During motion stimulation 4-AP also augmented and delayed the peak firing rate suggesting that this drug affects the magnitude and timing of vestibular-evoked eye movements. The exclusive Kv1.1 expression in thick vestibular afferent fibers in larval Xenopus at this developmental stage suggests that the altered extraocular motor output in the presence of 4-AP mainly derives from a firing rate increase of irregular firing vestibular afferents that propagates along the VOR circuitry. Clinically and pharmacologically, the observed 4-AP-mediated increase of peripheral vestibular input under resting and dynamic conditions can contribute to the observed therapeutic effects of 4-AP in downbeat and upbeat nystagmus as well as episodic ataxia type 2, by an indirect increase of cerebellar Purkinje cell discharge.

Neural circuits underlying jaw movements for the prey-catching behavior in frog: distribution of vestibular afferent terminals on motoneurons supplying the jaw.

Coordinated movement of the jaw is essential for catching and swallowing the prey. The majority of the jaw muscles in frogs are supplied by the trigeminal motoneurons. We have previously described that the primary vestibular afferent fibers, conveying information about the movements of the head, established close appositions on the motoneurons of trigeminal nerve providing one of the morphological substrates of monosynaptic sensory modulation of prey-catching behavior in the frog. The aim of our study was to reveal the spatial distribution of vestibular close appositions on the somatodendritic compartments of the functionally different trigeminal motoneurons. In common water frogs, the vestibular and trigeminal nerves were simultaneously labeled with different fluorescent dyes and the possible direct contacts between vestibular afferents and trigeminal motoneurons were identified with the help of DSD2 attached to an Andor Zyla camera. In the rhombencephalon, an overlapping area was detected between the incoming vestibular afferents and trigeminal motoneurons along the whole extent of the trigeminal motor nucleus. The vestibular axon collaterals formed large numbers of close appositions with dorsomedial and ventrolateral dendrites of trigeminal motoneurons. The majority of direct contacts were located on proximal dendritic segments closer than 300µm to the somata. The identified contacts were evenly distributed on rostral motoneurons innervating jaw-closing muscles and motoneurons supplying jaw-opening muscles and located in the caudal part of trigeminal nucleus. We suggest that the identified contacts between vestibular axon terminals and trigeminal motoneurons may constitute one of the morphological substrates of a very quick response detected in trigeminal motoneurons during head movements.

P 11 Towards a human vestibular cortex – Manifold confounders hamper the delineation of vestibular responses in functional neuroimaging

Aim Galvanic vestibular stimulation (GVS) allows for robust vestibular responses and is therefore the gold standard in neuroimaging studies focusing on the central vestibular system. Nevertheless, there are several confounding side-effects which hinder the delineation of pure vestibular responses. Besides stimulating vestibular hair cells and afferent fibers [1] , mastoidal GVS also evokes somatosensory, vagal and nociceptive responses. Furthermore, GVS induces reflectory head movements leading to motion artefacts. Aim of our fMRI study was to assess and control for the impact of these confounders by means of local anaesthesia, optimized head fixation, and a sham-GVS stimulation with different current intensities. Methods We examined 44 right-handed healthy subjects (21 F; mean age 28 years) in three sessions (interval length between session > 24 h) with different conditions: GVS with 3.5 mA with/without local anaesthesia, sham-GVS with 3.5 mA/1 mA, and GVS with/without head fixation (headfixation system: Pearltec, Switzerland). Structural and functional images were obtained in a clinical 3T scanner (Siemens Magnetom Verio) with a 32-channel head coil. The protocol included a GVS stimulation session consisting of a T2*-weighted EPI sequence (TR 2s, 31 ascending slices, 3 mm in-plane resolution, slice thickness 3.5 mm), a MPRAGE sequence, and a resting-state session. Data analysis was performed using SPM 12 (Version 6407 Wellcome Department of Imaging Neuroscience, UK) and the motion fingerprint toolbox (Wilke, Neuroimage 2012) after standard preprocessing using DARTEL-based normalization. Results were considered significant at FDR p 0.05 (corrected at cluster level). Results Pain perception during GVS decreased significantly after local anesthesia (NRS-11 reduction from 4.5 to 1.7, Wilcoxon signed-rank test, Z = −3.79, p = 0.00). GVS with lidocaine evoked responses in the vestibular network, predominantly in right OP2 and the medial cingulate cortex bilaterally, which were absent during sham stimulation. Without anesthesia, confluent activation cluster were found in anterior and posterior insula-opercular regions. Activation of the insula was also shown bilaterally during sham-GVS, with a predominant effect in area OP1 and area PF with a current intensity of 3.5 mA. Sham-GVS with 1 mA led to bilateral responses in area Fp1, the precentral gyrus and the left posterior cingulum. Motion finger print analysis in GVS with and without head fixation revealed head motion predominantly in the roll plane, leading to inter-slice motion artefacts in temporo-parietal-opercular regions. These artefacts were eliminated using a new head fixation system. Conclusion In this fMRI study, we evaluated and minimized the effects of several confounders in GVS. Head motion artefacts as well as nociceptive and somatosensory responses may hinder the localization of actual vestibular response patterns, particularly in the insula and parietal operculum. Our results highlight the importance of controlling for these side-effects and lead the way towards a precise definition of the human vestibular cortical network.

Galvanic Vestibular Stimulation: Cellular Substrates and Response Patterns of Neurons in the Vestibulo-Ocular Network.

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. Galvanic vestibular stimulation is used frequently in clinical practice to test the functionality of the sense of balance. The outcome of the test that relies on the activation of eye movements by electrical stimulation of vestibular organs in the inner ear helps to dissociate vestibular impairments that cause vertigo and imbalance in patients. This study uses an amphibian model to investigate at the cellular level the underlying mechanism on which this method depends. The outcome of this translational research unequivocally revealed the cellular substrate at the vestibular sensory periphery that is activated by electrical currents, as well as the spatiotemporal specificity of the evoked eye movements, thus facilitating the interpretation of clinical test results.

Modulated discharge of Purkinje and stellate cells persists after unilateral loss of vestibular primary afferent mossy fibers in mice

Cerebellar Purkinje cells are excited by two afferent pathways: climbing and mossy fibers. Climbing fibers evoke large "complex spikes" (CSs) that discharge at low frequencies. Mossy fibers synapse on granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of "simple spikes" (SSs). Both afferent systems convey vestibular information to folia 9c-10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8-10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c-10, to which vestibular primary afferents project, and in folia 8-9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL-induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In summary, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. Whereas vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the nonspecific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers.

Bidirectional Plasticity Gated by Hyperpolarization Controls the Gain of Postsynaptic Firing Responses at Central Vestibular Nerve Synapses

Linking synaptic plasticity with behavioral learning requires understanding how synaptic efficacy influences postsynaptic firing in neurons whose role in behavior is understood. Here, we examine plasticity at a candidate site of motor learning: vestibular nerve synapses onto neurons that mediate reflexive movements. Pairing nerve activity with changes in postsynaptic voltage induced bidirectional synaptic plasticity in vestibular nucleus projection neurons: long-term potentiation relied on calcium-permeable AMPA receptors and postsynaptic hyperpolarization, whereas long-term depression relied on NMDA receptors and postsynaptic depolarization. Remarkably, both forms of plasticity uniformly scaled synaptic currents evoked by pulse trains, and these changes in synaptic efficacy were translated into linear increases or decreases in postsynaptic firing responses. Synapses onto local inhibitory neurons were also plastic but expressed only long-term depression. Bidirectional, linear gain control of vestibular nerve synapses onto projection neurons provides a plausible mechanism for motor learning underlying adaptation of vestibular reflexes.

Development and organization of polarity-specific segregation of primary vestibular afferent fibers in mice

A striking feature of vestibular hair cells is the polarized arrangement of their stereocilia as the basis for their directional sensitivity. In mammals, each of the vestibular end organs is characterized by a distinct distribution of these polarized cells. We utilized the technique of post-fixation transganglionic neuronal tracing with fluorescent lipid soluble dyes in embryonic and postnatal mice to investigate whether these polarity characteristics correlate with the pattern of connections between the endorgans and their central targets; the vestibular nuclei and cerebellum. We found that the cerebellar and brainstem projections develop independently from each other and have a non-overlapping distribution of neurons and afferents from E11.5 on. In addition, we show that the vestibular fibers projecting to the cerebellum originate preferentially from the lateral half of the utricular macula and the medial half of the saccular macula. In contrast, the brainstem vestibular afferents originate primarily from the medial half of the utricular macula and the lateral half of the saccular macula. This indicates that the line of hair cell polarity reversal within the striola region segregates almost mutually exclusive central projections. A possible interpretation of this feature is that this macular organization provides an inhibitory side-loop through the cerebellum to produce synergistic tuning effects in the vestibular nuclei. The canal cristae project to the brainstem vestibular nuclei and cerebellum, but the projection to the vestibulocerebellum originates preferentially from the superior half of each of the cristae. The reason for this pattern is not clear, but it may compensate for unequal activation of crista hair cells or may be an evolutionary atavism reflecting a different polarity organization in ancestral vertebrate ears.

Vestibular afferents to the motoneurons of glossopharyngeal and vagus nerves in the frog, Rana esculenta

The aim of this work was to study whether the vestibular afferent fibers establish direct connections with the motoneurons of glossopharyngeal and vagus nerves of the frog, Rana esculenta. In anaesthetized animals the vestibulocochlear nerve and the common root of glossopharyngeal-vagus and accessory (IX-X-XI) nerves were simultaneously labeled with fluorescein dextran amine (vestibulocochlear nerve) and tetramethylrhodamine dextran amine (IX-X-XI). With a confocal laser scanning microscope we could detect close appositions between the vestibular afferent fibers and somatodendritic components of the general and special visceral motoneurons of the ambiguus nucleus of IX-X nerves. The direct impulse transmission may provide a quick and immediate response of cardiovascular and gastrointestinal system upon body displacement.

Frequency-Independent Synaptic Transmission Supports a Linear Vestibular Behavior

The vestibular system is responsible for transforming head motion into precise eye, head, and body movements that rapidly stabilize gaze and posture. How do central excitatory synapses mediate behavioral outputs accurately matched to sensory inputs over a wide dynamic range? Here we demonstrate that vestibular afferent synapses in vitro express frequency-independent transmission that spans their in vivo dynamic range (5-150 spikes/s). As a result, the synaptic charge transfer per unit time is linearly related to vestibular afferent activity in both projection and intrinsic neurons of the vestibular nuclei. Neither postsynaptic glutamate receptor desensitization nor saturation affect the relative amplitude or frequency-independence of steady-state transmission. Finally, we show that vestibular nucleus neurons can transduce synaptic inputs into linear changes in firing rate output without relying on one-to-one calyceal transmission. These data provide a physiological basis for the remarkable linearity of vestibular reflexes.

Functions of Interneurons in Mouse Cerebellum

The output signal of Purkinje cells is conveyed by the modulated discharge of simple spikes (SSs) often ascribed to mossy fiber-granule cell-parallel fiber inputs to Purkinje cell dendrites. Although generally accepted, this view lacks experimental support. We can address this view by controlling afferent signals that reach the cerebellum over climbing and mossy fiber pathways. Vestibular primary afferents constitute the largest mossy fiber projection to the uvula-nodulus. The discharge of vestibular primary afferent mossy fibers increases during ipsilateral roll tilt. The discharge of SSs decreases during ipsilateral roll tilt. Climbing fiber discharge [complex spikes (CSs)] increases during ipsilateral roll tilt. These observations suggest that the modulation of SSs during vestibular stimulation cannot be attributed directly to vestibular mossy fiber afferents. Rather we suggest that interneurons driven by vestibular climbing fibers may determine SS modulation. We recorded from cerebellar interneurons (granule, unipolar brush, Golgi, stellate, basket, and Lugaro cells) and Purkinje cells in the uvula-nodulus of anesthetized mice during vestibular stimulation. We identified all neuronal types by juxtacellular labeling with neurobiotin. Granule, unipolar brush, stellate, and basket cells discharge in phase with ipsilateral roll tilt and in phase with CSs. Golgi cells discharge out of phase with ipsilateral roll tilt and out of phase with CSs. The phases of stellate and basket cell discharge suggests that their activity could account for the antiphasic behavior of CSs and SSs. Because Golgi cells discharge in phase with SSs, Golgi cell activity cannot account for SS modulation. The sagittal array of Golgi cell axon terminals suggests that they contribute to the organization of discrete parasagittal vestibular zones.

Vestibulotrigeminal pathways in the frog, Rana esculenta

The aim of this study was to investigate whether primary vestibular afferent fibers establish direct connections with the motor and sensory trigeminal system in the brainstem of the frog. The experiments were carried out on Rana esculenta. In anaesthetized animals the trigeminal and vestibular nerves were prepared, and their proximal stumps were labeled either with fluorescein binding dextran amine (trigeminal nerve) or tetramethylrhodamine dextran amine (vestibulocochlear nerve). With a confocal laser scanning microscope we could detect close connections between the vestibular fibers and branches of the dorsal dendritic array of the jaw-closing motoneurons, suggestive of monosynaptic contacts. In the other parts of the brainstem, vestibular terminals were detected in the termination areas of the mesencephalic trigeminal nucleus and of the Gasserian (Vth) ganglion and they were probably involved in polysynaptic connections. In agreement with the results obtained in mammalian species, the present findings suggest that the vestibulotrigeminal relationship is quite complex and uses multiple pathways to connect the vestibular apparatus with the motor and sensory nuclei of the trigeminal nerve in the anurans as well.

Antiphasic Purkinje cell responses in mouse uvula-nodulus are sensitive to static roll–tilt and topographically organized

Two vestibular pathways converge at the uvula-nodulus to modulate the discharge of Purkinje cell complex and simple spikes (CSs and SSs). In the mouse, vestibular primary afferent mossy fibers originate from each of the end organs of the ipsilateral labyrinth and terminate in the granule cell layers of folia 9c–10. Vestibular climbing fiber projections originate from the contralateral β-nucleus and dorsomedial cell column (dmcc) and terminate directly on Purkinje cells. CSs and SSs could be regulated independently or they could be co-dependent. Here we examine how the discharges of CSs and SSs are modulated by sinusoidal and static roll–tilt in the uvula-nodulus of mice anesthetized with either chloralose–urethane or ketamine–xylazine. All vestibularly-driven CSs and SSs were sensitive to static roll–tilt. None were sensitive to horizontal vestibular stimulation. CSs were modulated in phase with ipsilateral roll–tilt. SSs were modulated out of phase. Spontaneous discharges of CSs were followed by a pause in SSs. Phase leads of CSs and SSs with respect to sinusoidal roll–tilt were advanced by ketamine–xylazine anesthesia relative to chloralose–urethane anesthesia by ∼45°. The antiphasic modulation of CSs and SSs was independent of anesthetic. Chloralose–urethane, but not ketamine–xylazine, induced spontaneous oscillations of CSs and SSs in 16% of Purkinje cells. Optimal planes of CSs in folia 9c–10 Purkinje cells were organized topographically into sagittal zones whose widths were approximately 400 μm. Purkinje cells with optimal planes in the posterior quadrant of the ipsilateral hemi-field were located in a medial zone. Purkinje cells with optimal planes in the anterior quadrant of the ipsilateral hemi-field were located in a lateral zone. The CS-associated pause in SSs establishes a vector-specific SS output. The amplitude of SS modulation may depend on parallel fiber-mediated signals to Purkinje cells as well as on the state of cerebellar interneurons.

Acid-Sensing Ionic Channels in the Rat Vestibular Endorgans and Ganglia

Acid-sensing ionic channels (ASICs) are members of the epithelial Na+ channel/degenerin (ENaC/DEG) superfamily. ASICs are widely distributed in the central and peripheral nervous system. They have been implicated in synaptic transmission, pain perception, and the mechanoreception in peripheral tissues. Our objective was to characterize proton-gated currents mediated by ASICs and to determine their immunolocation in the rat vestibular periphery. Voltage clamp of cultured afferent neurons from P7 to P10 rats showed a proton-gated current with rapid activation and complete desensitization, which was carried almost exclusively by sodium ions. The current response to protons (H+) has a pH0.5 of 6.2. This current was reversibly decreased by amiloride, gadolinium, lead, acetylsalicylic acid, and enhanced by FMRFamide and zinc, and negatively modulated by raising the extracellular calcium concentration. Functional expression of the current was correlated with smaller-capacitance neurons. Acidification of the extracellular pH generated action potentials in vestibular neurons, suggesting a functional role of ASICs in their excitability. Immunoreactivity to ASIC1a and ASIC2a subunits was found in small vestibular ganglion neurons and afferent fibers that run throughout the macula utricle and crista stroma. ASIC2b, ASIC3, and ASIC4 were expressed to a lesser degree in vestibular ganglion neurons. The ASIC1b subunit was not detected in the vestibular endorgans. No acid-pH-sensitive currents or ASIC immunoreactivity was found in hair cells. Our results indicate that proton-gated current is carried through ASICs and that ionic current activated by H+ contributes to shape the vestibular afferent neurons' response to its synaptic input.

Localization of TREK-1, a two-pore-domain K + channel in the peripheral vestibular system of mouse and rat

The distribution of two-pore-domain (2P-domain) K + channels of the TREK subfamily was studied using immunocytochemistry in the peripheral vestibular system of mouse and rat. Using RT-PCR, the mRNA for TREK-1, but not for TREK-2 or TRAAK, were detected in mouse vestibular endorgans and ganglia. The TREK-1 channel protein was immunodetected in both nerve fibers and nerve cell bodies in the vestibular ganglion, both afferent fibers and nerve calyces innervating type I hair cells in the utricle and cristae. The post-synaptic localization in afferent calyces may suggest a neuroprotective role in glutamatergic excitotoxicity during ischemic conditions. In non-neuronal cells, TREK-1 was immunodetected in the apical membrane of dark cells and transitional cells, both of which are involved in endolymph K + secretion and recycling. TREK-1 may subserve some neuroprotective function in afferent nerve fibers as well as play a role in endolymph potassium homeostasis.

Dissociating self-generated from passively applied head motion: neural mechanisms in the vestibular nuclei.

The ability to distinguish sensory inputs that are a consequence of our own actions from those that result from changes in the external world is essential for perceptual stability and accurate motor control. To accomplish this, it has been proposed that an internal prediction of the consequences of our actions is compared with the actual sensory input to cancel the resultant self-generated activation. Here, we provide evidence for this hypothesis at an early stage of processing in the vestibular system. Previous studies have shown that neurons in the vestibular nucleus, which receive direct inputs from vestibular afferent fibers, are responsive to passively applied head movements. However, these same neurons do not reliably encode head velocity resulting from self-generated movements of the head on the body. In this study, we examined the mechanism that underlies the selective elimination of vestibular sensitivity to active head-on-body rotations. Individual neurons were recorded in monkeys making active head movements. The correspondence between intended and actual head movement was experimentally controlled. We found that a cancellation signal was gated into the vestibular nuclei only in conditions in which the activation of neck proprioceptors matched that expected on the basis of the neck motor command. This finding suggests that vestibular signals that arise from self-generated head movements are inhibited by a mechanism that compares the internal prediction of the sensory consequences by the brain to the actual resultant sensory feedback. Because self-generated vestibular inputs are selectively cancelled early in processing, we propose that this gating is important for the computation of spatial orientation and control of posture by higher-order structures.

Activity‐Related Postlesional Vestibular Reorganization

The synaptic convergence patterns of semicircular canal and macular afferent nerve inputs onto second-order vestibular neurons reorganize in adult frogs after a change in the activity of vestibular nerve afferent fibers. Axotomized afferent nerve fibers become silent after a vestibular nerve lesion, and second-order vestibular target neurons become disfacilitated. These changes initiate an activity-related process that was studied in detail in vitro two months after a section of the ramus anterior (RA) of N. VIII. The postlesional reaction results in an expansion of signals, preferentially from intact, remaining afferent nerve fibers, but also from excitatory commissural and spinal ascending fibers. This process of expansion takes weeks, is graded in its extent, and reversible in case of a nerve regeneration, but is not competitive, i.e., the synaptic contacts from axotomized afferent nerve fibers are maintained without a change in their efficacy. Postlesional synaptic reorganization in the brainstem is restricted to the operated side, underlies the improved responsiveness of disfacilitated second-order vestibular neurons, but also their altered spatial response tuning. The functional consequences of this reorganization were studied in vivo two months after RA nerve section by recording abducens nerve responses during linear or angular accelerations. The vector orientations of best responses of the abducens nerve of chronic RA frogs evoked by linear or angular acceleration differed from the vector orientations of controls. In chronic RA frogs, linear acceleration evoked contralesional abducens nerve responses that originated from the utricle on the intact side and from the lagena, a vertical macular organ in frogs. Such an inadequate lagenar response component was absent in controls and in the ipsi-lesional abducens nerve of chronic RA frogs. Similar differences were detected in the direction of abducens nerve responses of chronic RA frogs during angular acceleration. Thus, compensatory vestibulo-ocular reflexes of chronic RA frogs became more symmetric in gain, but less precise in direction.