Muscarinic Acetylcholine Receptors Modulate HCN Channel Properties in Vestibular Ganglion Neurons.

Efferent modulation of vestibular afferent excitability is linked to muscarinic signaling cascades that close low-voltage-gated potassium channels (i.e., KCNQ). Here, we show that muscarinic signaling cascades also depolarize the activation range of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We compared the voltage activation range and kinetics of HCN channels and induced firing patterns before and after administering the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine-M (Oxo-M) in dissociated vestibular ganglion neurons (VGNs) from rats of either sex using perforated whole-cell patch-clamp methods. Oxo-M depolarized HCN channels' half-activation voltage (V 1/2) and sped up the rate of activation near resting potential twofold. HCN channels in large-diameter and/or transient firing VGN (putative cell bodies of irregular firing neuron from central epithelial zones) had relatively depolarized V 1/2 in control solution and were less sensitive to mAChR activation than those found in small-diameter VGN with sustained firing patterns (putatively belonging to regular firing afferents). The impact of mAChR on HCN channels is not a direct consequence of closing KCNQ channels since pretreating the cells with Linopirdine, a KCNQ channel blocker, did not prevent HCN channel depolarization by Oxo-M. Efferent signaling promoted ion channel configurations that were favorable to highly regular spiking in some VGN, but not others. This is consistent with previous observations that low-voltage gated potassium currents in VGN are conducted by mAChR agonist-sensitive and -insensitive channels. Connecting efferent signaling to HCN channels is significant because of the channel's impact on spike-timing regularity and nonchemical transmission between Type I hair cells and vestibular afferents.SIGNIFICANCE STATEMENT Vestibular afferents express a diverse complement of ion channels. In vitro studies identified low-voltage activated potassium channels and hyperpolarization-activated cyclic-nucleotide gated (HCN) channels as crucial for shaping the timing and sensitivity of afferent responses. Moreover, a network of acetylcholine-releasing efferent neurons controls afferent excitability by closing a subgroup of low-voltage activated potassium channels on the afferent neuron. This work shows that these efferent signaling cascades also enhance the activation of HCN channels by depolarizing their voltage activation range. The size of this effect varies depending on the endogenous properties of the HCN channel and on cell type (as determined by discharge patterns and cell size). Simultaneously controlling two ion-channel groups gives the vestibular efferent system exquisite control over afferent neuron activity.

Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant.

BACKGROUND: Bilateral vestibular hypofunction is associated with chronic disequilibrium, postural instability, and unsteady gait owing to failure of vestibular reflexes that stabilize the eyes, head, and body. A vestibular implant may be effective in alleviating symptoms. METHODS: Persons who had had ototoxic (7 participants) or idiopathic (1 participant) bilateral vestibular hypofunction for 2 to 23 years underwent unilateral implantation of a prosthesis that electrically stimulates the three semicircular canal branches of the vestibular nerve. Clinical outcomes included the score on the Bruininks-Oseretsky Test of Motor Proficiency balance subtest (range, 0 to 36, with higher scores indicating better balance), time to failure on the modified Romberg test (range, 0 to 30 seconds), score on the Dynamic Gait Index (range, 0 to 24, with higher scores indicating better gait performance), time needed to complete the Timed Up and Go test, gait speed, pure-tone auditory detection thresholds, speech discrimination scores, and quality of life. We compared participants' results at baseline (before implantation) with those at 6 months (8 participants) and at 1 year (6 participants) with the device set in its usual treatment mode (varying stimulus pulse rate and amplitude to represent rotational head motion) and in a placebo mode (holding pulse rate and amplitude constant). RESULTS: The median scores at baseline and at 6 months on the Bruininks-Oseretsky test were 17.5 and 21.0, respectively (median within-participant difference, 5.5 points; 95% confidence interval [CI], 0 to 10.0); the median times on the modified Romberg test were 3.6 seconds and 8.3 seconds (difference, 5.1; 95% CI, 1.5 to 27.6); the median scores on the Dynamic Gait Index were 12.5 and 22.5 (difference, 10.5 points; 95% CI, 1.5 to 12.0); the median times on the Timed Up and Go test were 11.0 seconds and 8.7 seconds (difference, 2.3; 95% CI, -1.7 to 5.0); and the median speeds on the gait-speed test were 1.03 m per second and 1.10 m per second (difference, 0.13; 95% CI, -0.25 to 0.30). Placebo-mode testing confirmed that improvements were due to treatment-mode stimulation. Among the 6 participants who were also assessed at 1 year, the median within-participant changes from baseline to 1 year were generally consistent with results at 6 months. Implantation caused ipsilateral hearing loss, with the air-conducted pure-tone average detection threshold at 6 months increasing by 3 to 16 dB in 5 participants and by 74 to 104 dB in 3 participants. Changes in participant-reported disability and quality of life paralleled changes in posture and gait. CONCLUSIONS: Six months and 1 year after unilateral implantation of a vestibular prosthesis for bilateral vestibular hypofunction, measures of posture, gait, and quality of life were generally in the direction of improvement from baseline, but hearing was reduced in the ear with the implant in all but 1 participant. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02725463.).

Suppression of delayed rectifier K+ channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons.

Aminoglycoside antibiotics, such as gentamicin, are known to have vestibulotoxic effects, including ataxia and disequilibrium. To date, however, the underlying cellular and molecular mechanisms are still unclear. In this study, we determined the role of gentamicin in regulating the sustained delayed rectifier K+ current (IDR) and membrane excitability in vestibular ganglion (VG) neurons in mice. Our results showed that the application of gentamicin to VG neurons decreased the IDR in a concentration-dependent manner, while the transient outward A-type K+ current (IA) remained unaffected. The decrease in IDR induced by gentamicin was independent of G-protein activity and led to a hyperpolarizing shift of the inactivation Vhalf. The analysis of phospho-c-Jun N-terminal kinase (p-JNK) revealed that gentamicin significantly stimulated JNK, while p-ERK and p-p38 remained unaffected. Blocking Kv1 channels with α-dendrotoxin or pretreating VG neurons with the JNK inhibitor II abrogated the gentamicin-induced decrease in IDR. Antagonism of JNK signaling attenuated the gentamicin-induced stimulation of PKA activity, whereas PKA inhibition prevented the IDR response induced by gentamicin. Moreover, gentamicin significantly increased the number of action potentials fired in both phasic and tonic firing type neurons; pretreating VG neurons with the JNK inhibitor II and the blockade of the IDR abolished this effect. Taken together, our results demonstrate that gentamicin decreases the IDR through a G-protein-independent but JNK and PKA-mediated signaling pathways. This gentamicin-induced IDR response mediates VG neuronal hyperexcitability and might contribute to its pharmacological vestibular effects.

Persistent and resurgent Na+ currents in vestibular calyx afferents.

Vestibular afferent neurons convey information from hair cells in the peripheral vestibular end organs to central nuclei. Primary vestibular afferent neurons can fire action potentials at high rates and afferent firing patterns vary with the position of nerve terminal endings in vestibular neuroepithelia. Terminals contact hair cells as small bouton or large calyx endings. To investigate the role of Na+ currents (INa) in firing mechanisms, we investigated biophysical properties of INa in calyx-bearing afferents. Whole cell patch-clamp recordings were made from calyx terminals in thin slices of gerbil crista at different postnatal ages: immature [postnatal day (P)5-P8, young (P13-P15), and mature (P30-P45)]. A large transient Na+ current (INaT) was completely blocked by 300 nM tetrodotoxin (TTX) in mature calyces. In addition, INaT was accompanied by much smaller persistent Na+ currents (INaP) and distinctive resurgent Na+ currents (INaR), which were also blocked by TTX. ATX-II, a toxin that slows Na+ channel inactivation, enhanced INaP in immature and mature calyces. 4,9-Anhydro-TTX (4,9-ah-TTX), which selectively blocks Nav1.6 channels, abolished the enhanced INa in mature, but not immature, calyces. Therefore, Nav1.6 channels mediate a component of INaT and INaP in mature calyces, but are minimally expressed at early postnatal days. INaR was expressed in less than one-third of calyces at P6-P8, but expression increased with development, and in mature cristae INaR was frequently found in peripheral calyces. INaR served to increase the availability of Na+ channels following brief membrane depolarizations. In current clamp, the rate and regularity of action potential firing decreased in mature peripheral calyces following 4,9-ah-TTX application. Therefore, Nav1.6 channels are upregulated during development, contribute to INaT, INaP, and INaR, and may regulate excitability by enabling higher mean discharge rates in a subpopulation of mature calyx afferents.NEW & NOTEWORTHY Action potential firing patterns differ between groups of afferent neurons innervating vestibular epithelia. We investigated the biophysical properties of Na+ currents in specialized vestibular calyx afferent terminals during postnatal development. Mature calyces express Na+ currents with transient, persistent, and resurgent components. Nav1.6 channels contribute to resurgent Na+ currents and may enhance firing in peripheral calyx afferents. Understanding Na+ channels that contribute to vestibular nerve responses has implications for developing new treatments for vestibular dysfunction.

Bilirubin-induced neurotoxic and ototoxic effects in rat cochlear and vestibular organotypic cultures.

Exposure to high levels of bilirubin in hyperbilirubinemia patients and animal models can result in sensorineural deafness. However, the mechanisms underlying bilirubin-induced damage to the inner ear, including the cochlear and vestibular organs, remain unknown. The present analyses of cochlear and vestibular organotypic cultures obtained from postnatal day 3 rats exposed to bilirubin at varying concentrations (0, 10, 50, 100, or 250 µM) for 24 h revealed that auditory nerve fibers (ANFs) and vestibular nerve endings were destroyed even at low doses (10 and 50 µM). Additionally, as the bilirubin dose increased, spiral ganglion neurons (SGNs) and vestibular ganglion neurons (VGNs) exhibited gradual shrinkage in conjunction with nuclei condensation or fragmentation in a dose-dependent manner. The loss of cochlear and vestibular hair cells (HCs) was only evident in explants treated with the highest concentration of bilirubin (250 µM), and bilirubin-induced major apoptosis most likely occurred via the extrinsic apoptotic pathway. Thus, the present results indicate that inner ear neurons and fibers were more sensitive to, and exhibited more severe damage following, bilirubin-induced neurotoxicity than sensory HCs, which illustrates the underlying causes of auditory neuropathy and vestibulopathy in hyperbilirubinemia patients.

Functional Expression of an Osmosensitive Cation Channel, Transient Receptor Potential Vanilloid 4, in Rat Vestibular Ganglia.

Transient receptor potential vanilloid (TRPV) 4 is a nonselective cation channel expressed in sensory neurons such as those in the dorsal root and trigeminal ganglia, kidney, and inner ear. TRPV4 is activated by mechanical stress, heat, low osmotic pressure, low pH, and phorbol derivatives such as 4α-phorbol 12,13-didecanoate (4α-PDD). We investigated the expression of TRPV4 in rat vestibular ganglion (VG) neurons. The TRPV4 gene was successfully amplified from VG neuron mRNA using reverse-transcription polymerase chain reaction. Furthermore, immunoblotting showed positive expression of TRPV4 protein in VG neurons. Immunohistochemistry indicated that TRPV4 was localized predominantly on the plasma membrane of VG neurons. Calcium (Ca2+) imaging of VG neurons showed that 4α-PDD and/or hypotonic stimuli caused an increase in intracellular Ca2+ concentration ([Ca2+]i) that was almost completely inhibited by ruthenium red, a selective antagonist of TRPV channels. Interestingly, a [Ca2+]i increase was evoked by both hypotonic stimuli and 4α-PDD in approximately 38% of VG neurons. These data indicate that TRPV4 is functionally expressed in VG neurons as an ion channel and that TRPV4 likely participates in VG neurons for vestibular neurotransmission as an osmoreceptor and/or mechanoreceptor.

Analysis of signal processing in vestibular circuits with a novel light-emitting diodes-based fluorescence microscope.

Optical visualization of neural network activity is limited by imaging system-dependent technical tradeoffs. To overcome these constraints, we have developed a powerful low-cost and flexible imaging system with high spectral variability and unique spatio-temporal precision for simultaneous optical recording and manipulation of neural activity of large cell groups. The system comprises eight high-power light-emitting diodes, a camera with a large metal-oxide-semiconductor sensor and a high numerical aperture water-dipping objective. It allows fast and precise control of excitation and simultaneous low noise imaging at high resolution. Adjustable apertures generated two independent areas of variable size and position for simultaneous optical activation and image capture. The experimental applicability of this system was explored in semi-isolated preparations of larval axolotl (Ambystoma mexicanum) with intact inner ear organs and central nervous circuits. Cyclic galvanic stimulation of semicircular canals together with glutamate- and γ-aminobutyric acid (GABA)-uncaging caused a corresponding modulation of Ca(2+) transients in central vestibular neurons. These experiments revealed specific cellular properties as well as synaptic interactions between excitatory and inhibitory inputs, responsible for spatio-temporal-specific sensory signal processing. Location-specific GABA-uncaging revealed a potent inhibitory shunt of vestibular nerve afferent input in the predominating population of tonic vestibular neurons, indicating a considerable impact of local and commissural inhibitory circuits on the processing of head/body motion-related signals. The discovery of these previously unknown properties of vestibular computations demonstrates the merits of our novel microscope system for experimental applications in the field of neurobiology.

Developmental increase in hyperpolarization-activated current regulates intrinsic firing properties in rat vestibular ganglion cells.

The primary vestibular neurons convey afferent information from hair cells in the inner ear to the vestibular nuclei and the cerebellum. The intrinsic firing properties of vestibular ganglion cells (VGCs) are heterogeneous to sustained membrane depolarization, and undergo marked developmental changes from phasic to tonic types during the early postnatal period. Previous studies have shown that low-voltage-activated potassium channels, Kv1 and Kv7, play a critical role in determining the firing pattern of VGCs. In the present study, we explored the developmental changes in the properties of hyperpolarization-activated current (Ih) in rat VGCs and the role played by Ih in determining the firing properties of VGCs. Tonic firing VGCs showed a larger current density of Ih as compared to phasic firing VGCs, and tonic firing VGCs became phasic firing in the presence of ZD7288, an Ih channel blocker, indicating that Ih contributes to control the firing pattern of VGCs. The amplitude of Ih increased and the activation kinetics of Ih became faster during the developmental period. Analysis of developmental changes in the expression of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels revealed that expression of HCN1 protein and its mRNA increased during the developmental period, whereas expression of HCN2-4 protein and its mRNA did not change. Our results suggest that HCN1 channels as well as Kv1 channels are critical in determining the firing pattern of rat VGCs and that developmental up-regulation of HCN1 transforms VGCs from phasic to tonic firing phenotypes.

Clonidine treatment delays postnatal motor development and blocks short-term memory in young mice.

During the development of the nervous system, the perinatal period is particularly sensitive as neuronal connections are still forming in the brain of the neonate. Alpha2-adrenergic receptors are overexpressed temporarily in proliferative zones in the developing brain, reaching a peak during the first postnatal week of life. Both stimulation and blocking of these receptors during this period alter the development of neural circuits, affecting synaptic connectivity and neuronal responses. They even affect motor and cognitive skills later on in the adult. It's especially important to look for the early neurological consequences resulting from such modifications, because they may go unnoticed. The main objective of the present study has been to reaffirm the importance of the maturation of alpha-adrenergic system in mice, by carrying out a comprehensive examination of motor, behavioral and cognitive effects in neonates, during early postnatal development, following chronic administration of the drug Clonidine, an alpha2 adrenergic system agonist. Our study shows that mice treated postnatally with clonidine present a temporal delay in the appearance of developmental markers, a slow execution of vestibular reflexes during first postnatal week of life and a blockade of the short term memory in the novel object recognition task. Shortly after the treatment the startle response is hyperreactive.

Functional expression of TRPV1 and TRPA1 in rat vestibular ganglia.

Both TRPV1 and TRPA1 are non-selective cation channels. They are co-expressed, and interact in sensory neurons such as dorsal root ganglia (DRG) and trigeminal ganglia (TG), and are involved in nociception, being activated by nociceptive stimuli. Immunohistological localization of TRPV1 in vestibular ganglion (VG) neurons has been reported. Although TRPA1 is co-expressed with TRPV1 in DRG and TG neurons, it is unclear whether TRPA1 channels are expressed in VG neurons. Moreover, it is unknown whether TRPV1 and TRPA1 channels are functional in VG neurons. We investigated the expression of TRPV1 and TRPA1 in rat VG neurons by RT-PCR, in situ hybridization, immunohistochemistry, and Ca(2+) imaging experiments. Both TRPV1 and TRPA1 RT-PCR products were amplified from the mRNA of rat VG neurons. In situ hybridization experiments showed TRPV1 and TRPA1 mRNA expression in the majority of VG neurons. Immunohistochemistry experiments confirmed TRPV1 protein expression. In Ca(2+) imaging experiments, capsaicin, a TRPV1 agonist, induced a significant increase in intracellular calcium ion concentration ([Ca(2+)]i) in rat primary cultured VG neurons, which was almost completely blocked by capsazepine, a TRPV1-specific antagonist. Cinnamaldehyde, a TRPA1 agonist, also caused an increase in [Ca(2+)]i, which was completely inhibited by HC030031, a TRPA1-specific antagonist. Moreover, in some VG neurons, a [Ca(2+)]i increase was evoked by both capsaicin and cinnamaldehyde in the same neuron. In summary, our histological and physiological studies reveal that TRPV1 and TRPA1 are expressed in VG neurons. It is suggested that TRPV1 and TRPA1 in VG neurons might participate in vestibular function and/or dysfunction such as vertigo.

Expression of calcitonin gene-related peptide in efferent vestibular system and vestibular nucleus in rats with motion sickness.

UNLABELLED: Motion sickness presents a challenge due to its high incidence and unknown pathogenesis although it is a known fact that a functioning vestibular system is essential for the perception of motion sickness. Recent studies show that the efferent vestibular neurons contain calcitonin gene-related peptide (CGRP). It is a possibility that the CGRP immunoreactivity (CGRPi) fibers of the efferent vestibular system modulate primary afferent input into the central nervous system; thus, making it likely that CGRP plays a key role in motion sickness. To elucidate the relationship between motion sickness and CGRP, the effects of CGRP on the vestibular efferent nucleus and the vestibular nucleus were investigated in rats with motion sickness. METHODS: An animal model of motion sickness was created by subjecting rats to rotary stimulation for 30 minutes via a trapezoidal stimulation pattern. The number of CGRPi neurons in the vestibular efferent nucleus at the level of the facial nerve genu and the expression level of CGRPi in the vestibular nucleus of rats were measured. Using the ABC method of immunohistochemistry technique, measurements were taken before and after rotary stimulation. The effects of anisodamine on the expression of CGRP in the vestibular efferent nucleus and the vestibular nucleus of rats with motion sickness were also investigated. RESULTS AND DISCUSSION: Both the number of CGRPi neurons in the vestibular efferent nucleus and expression level in the vestibular nucleus increased significantly in rats with motion sickness compared to that of controls. The increase of CGRP expression in rats subjected to rotary stimulation 3 times was greater than those having only one-time stimulation. Administration of anisodamine decreased the expression of CGRP within the vestibular efferent nucleus and the vestibular nucleus in rats subjected to rotary stimulation. In conclusion, CGRP possibly plays a role in motion sickness and its mechanism merits further investigation.

TRPV4 channels mediate the infrared laser-evoked response in sensory neurons.

Infrared laser irradiation has been established as an appropriate stimulus for primary sensory neurons under conditions where sensory receptor cells are impaired or lost. Yet, development of clinical applications has been impeded by lack of information about the molecular mechanisms underlying the laser-induced neural response. Here, we directly address this question through pharmacological characterization of the biological response evoked by midinfrared irradiation of isolated retinal and vestibular ganglion cells from rodents. Whole cell patch-clamp recordings reveal that both voltage-gated calcium and sodium channels contribute to the laser-evoked neuronal voltage variations (LEVV). In addition, selective blockade of the LEVV by micromolar concentrations of ruthenium red and RN 1734 identifies thermosensitive transient receptor potential vanilloid channels as the primary effectors of the chain reaction triggered by midinfrared laser irradiation. These results have the potential to facilitate greatly the design of future prosthetic devices aimed at restoring neurosensory capacities in disabled patients.

Members of the BMP, Shh, and FGF morphogen families promote chicken statoacoustic ganglion neurite outgrowth and neuron survival in vitro.

Mechanosensory hair cells of the chicken inner ear are innervated by the peripheral processes of statoacoustic ganglion (SAG) neurons. Members of several morphogen families are expressed within and surrounding the chick inner ear during stages of SAG axon outgrowth and pathfinding. On the basis of their localized expression patterns, we hypothesized that bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and sonic hedgehog (Shh) may function as guidance cues for growing axons and/or may function as trophic factors once axons have reached their targets. To test this hypothesis, three-dimensional collagen cultures were used to grow Embryonic Day 4 (E4) chick SAG explants for 24 h in the presence of purified proteins or beads soaked in proteins. The density of neurite outgrowth was quantified to determine effects on neurite outgrowth. Explants displayed enhanced neurite outgrowth when cultured in the presence of purified BMP4, BMP7, a low concentration of Shh, FGF8, FGF10, or FGF19. In contrast, SAG neurons appeared unresponsive to FGF2. Collagen gel cultures were labeled with terminal dUTP nick-end labeling and immunostained with anti-phosphohistone H3 to determine effects on neuron survival and proliferation, respectively. Treatments that increased neurite outgrowth also yielded significantly fewer apoptotic cells, with no effect on cell proliferation. When presented as focal sources, BMP4, Shh, and FGFs -8, -10, and -19 promoted asymmetric outgrowth from the ganglion in the direction of the beads. BMP7-soaked beads did not induce this response. These results suggest that a subset of morphogens enhance both survival and axon outgrowth of otic neurons.

Responsiveness of rat vestibular ganglion neurons to exogenous neurotrophic factors during postnatal development in dissociated cultures.

We examined the responsiveness of rat vestibular ganglion neurons (VGNs) to exogenous neurotrophic factors, BDNF, NT-3, and GDNF, during postnatal development in dissociated cultures. VGNs were obtained from postnatal days (P) 1, 3, 7, and 14. After two days in culture, the survival of VGNs in control cultures without any exogenous neurotrophic factors was greater in younger (P1 or 3) rats than older (P7 or 14) rats. None of the three neurotrophic factors used facilitated survival of VGNs from older rats while only BDNF facilitated survival of VGNs from younger rats. BDNF was also effective both for increasing neurite sprouting in VGNs from younger rats and for neurite extension in VGNs from each of the postnatal ages. VGNs from P1 rats showed responsiveness to all three neurotrophic factors in their neurite sprouting. Developmental changes of VGNs in their responsiveness to exogenous neurotrophic factors should be considered in treating or preventing neuronal degeneration caused by peripheral vestibular lesions.

[The use of artificial neural networks in evaluation of posturographic data]. / Die Anwendung künstlicher neuronaler Netze bei der Auswertung posturografischer Messungen.

BACKGROUND: Posturography methods have been applied in clinical neurootology to evaluate the equilibrium function of patients. Methods of statistical analysis play an important role for improving data processing and to support the interpretation of the results. In contrast to conventional statistics, artificial neural networks are model-free and non-parametric. The aim of the presented study was to investigate how accurately these methods are able to discriminate between healthy and equilibrium-disturbed subjects. PATIENTS AND METHODS: 51 healthy volunteers participated in this study. 2 static posturography measurements were recorded before and 40 min after alcohol intake (0.4‰-0.6‰). Recorded signals were processed by 4 different methods in order to estimate power spectral densities (0 Hz-25 Hz). 11 different methods of artificial neural networks were investigated. The ability of artificial neural networks for classification was evaluated in patients with an acute unilateral vestibular loss. RESULTS: It turned out that estimating power spectral densities by means of autoregressive modelling and subsequent classification by Support-Vector Machine or by Learning Vector Quantization Networks are most accurate. Validation analysis yielded mean classification errors for the test set of 4.2 ± 2.2%. CONCLUSIONS: Analysis of neurootological data by artificial neural networks proved to be a sensitive recognition method of even small changes of the postural system.

Betahistine treatment improves the recovery of static symptoms in patients with unilateral vestibular loss.

Vestibular loss induces a combination of postural, oculomotor, and perceptive symptoms that are compensated over time. The aim of this study was to analyze the influence of betahistine dihydrochloride on vestibular compensation. A randomized, double-blind, placebo-controlled study was performed in Menière's disease patients who underwent a curative unilateral vestibular neurotomy (UVN). The effects of betahistine treatment were investigated on a broad spectrum of vestibular-induced changes resulting from vestibular loss: body sway, head orientation, ocular cyclotorsion, spontaneous nystagmus, verticality perception, and self-evaluation of the postural stability. The time course of the recovery was compared in 16 patients who received either a placebo or betahistine (24 mg b.i.d.) from 3 days up to 3 months after UVN. Patients were examined before (day -1) and after UVN (days 7, 30, and 90). Results indicate that betahistine reduces the time to recovery by 1 month or more depending on the tested functions. Betahistine was effective as soon as 4 days after treatment administration, and the effect remained during the whole compensation period (up to 3 months). The observed clinical effects may be attributed to an action of betahistine in rebalancing the neuronal activity between contralateral vestibular nuclei.

Melatonin attenuates the vestibulosympathetic but not vestibulocollic reflexes in humans: selective impairment of the utricles.

Melatonin has been reported to decrease nerve activity of medial vestibular nuclei in the rat and is associated with attenuated muscle sympathetic nerve activity (MSNA) responses to baroreceptor unloading in humans. The purpose of this study was to determine if melatonin alters the vestibulosympathetic reflex (VSR) and vestibulocollic reflex (VCR) in humans. In study 1, MSNA, arterial blood pressure, and heart rate were measured in 12 healthy subjects (28 ± 1 yr; 6 men, 6 women) during head-down rotation (HDR) before and 45 min after ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the opposite treatment (melatonin or placebo). Melatonin significantly attenuated MSNA responses during HDR compared with placebo (burst frequency Δ 4 ± 1 vs. Δ 7 ± 1 bursts/min, and total MSNA Δ 51 ± 20 and Δ 96 ± 15%, respectively; P < 0.02). In study 2, vestibular evoked myogenic potentials (VEMP) were measured in 10 healthy subjects (26 ± 1 yr; 4 men and 6 women) before and after ingestion of 3 mg melatonin. Melatonin did not alter the timing of the p13 and n23 peaks (pre-melatonin 13.2 ± 0.4 and 21.3 ± 0.6 ms vs. post-melatonin 13.5 ± 0.4 and 21.4 ± 0.7 ms, respectively) or the p13-n23 interpeak amplitudes [pre-melatonin 22.5 ± 4.6 arbitrary units (au) and post-melatonin 22.7 ± 4.6 au]. In summary, melatonin attenuates the VSR and supports the concept that melatonin negatively affects orthostatic tolerance. However, melatonin does not alter the VCR in humans suggesting melatonin's effect on the VSR appears to be mediated by the utricles.

Effects of gentamicin on guinea pig vestibular ganglion function and on substance P and neuropeptide Y.

Previous studies have demonstrated that following intratympanic gentamicin application in the guinea pigs, vestibular evoked myogenic potentials (VEMPs) were absent regardless of stimulation mode using either air-conducted sound (ACS) stimuli or galvanic vestibular stimulation (GVS). Ultrastructurally, both type I hair cells and their calyx terminals were distorted in the saccular macula. However, little is known about the toxic effects of gentamicin on the vestibular ganglion (VG). In this study, absent ACS- and GVS-VEMPs were noted in all the gentamicin-treated ears (100%), which were confirmed by the substantial loss of sensory hair cells in the saccular macula. Moreover, dramatic up-regulation of growth associated protein-43 (GAP-43) expression was detected in the ipsilateral VG neurons. The mean percentage of substance P-like immunoreactive (SP-LI) neurons in the treated VG (81.8±1.9%) was significantly higher than that in the control VG (68.6±3.3%). Conversely, the mean percentage of neuropeptide Y-like immunoreactive (NPY-LI) neurons in the treated VG (13.7±3.8%) was dramatically lower than that in the control VG (49.0±3.8%). Double labeling results shown 82% of SP-LI and 16% of NPY-LI neurons coexpressed with GAP-43, suggested that SP accumulating coincided with NPY decreasing in regenerating VG neurons after gentamicin treatment. Overall, the changes in SP and NPY expression in VG neurons after gentamicin treatment were like to those in the superior cervical ganglion following sympathectomy.