An in vitro model for postoperative cranial nerve dysfunction and a proposed method of rehabilitation with N-acetylcysteine microparticles.

PURPOSE: When operating near cranial motor nerves, transient postoperative weakness of target muscles lasting weeks to months is often observed. As nerves are typically intact at a procedure's completion, paresis is hypothesized to result from a combination of neurapraxia and axonotmesis. As both neurapraxia and axonotmesis involve Schwann cell injury and require remyelination, we developed an in vitro RSC96 Schwann cell model of injury using hydrogen peroxide (H2O2) to induce oxidative stress and investigated the efficacy of candidate therapeutic agents to promote RSC96 viability. As a first step in developing a long-term local administration strategy, the most promising of these agents was incorporated into sustained-release microparticles and investigated for bioactivity using this assay. METHODS: The concentration of H2O2 which reduced viability by 50% was determined to establish a standard for inducing oxidative stress in RSC96 cultures. Fresh cultures were then co-dosed with H2O2 and the potential therapeutics melatonin, N-acetylcysteine, resveratrol, and 4-aminopyridine. Schwann cell viability was evaluated and the most efficacious agent, N-acetylcysteine, was encapsulated into microparticles. Eluted samples of N-acetylcysteine from microparticles was evaluated for retained bioactivity. RESULTS: 100 µM N-acetylcysteine improved the viability of Schwann cells dosed with H2O2. 100 µM Microparticle-eluted N-acetylcysteine also enhanced Schwann cell viability. CONCLUSION: We developed a Schwann cell culture model of iatrogenic nerve injury and used this to identify N-acetylcysteine as an agent to promote recovery. N-acetylcysteine was packaged into microparticles and demonstrated promise as a locally administrable agent to reduce oxidative stress in Schwann cells.

Inflight head stabilization associated with wingbeat cycle and sonar emissions in the lingual echolocating Egyptian fruit bat, Rousettus aegyptiacus.

Sensory processing of environmental stimuli is challenged by head movements that perturb sensorimotor coordinate frames directing behaviors. In the case of visually guided behaviors, visual gaze stabilization results from the integrated activity of the vestibuloocular reflex and motor efference copy originating within circuits driving locomotor behavior. In the present investigation, it was hypothesized that head stabilization is broadly implemented in echolocating bats during sustained flight, and is temporally associated with emitted sonar signals which would optimize acoustic gaze. Predictions from these hypotheses were evaluated by measuring head and body kinematics with motion sensors attached to the head and body of free-flying Egyptian fruit bats. These devices were integrated with ultrasonic microphones to record sonar emissions and elucidate the temporal association with periods of head stabilization. Head accelerations in the Earth-vertical axis were asymmetric with respect to wing downstroke and upstroke relative to body accelerations. This indicated that inflight head and body accelerations were uncoupled, outcomes consistent with the mechanisms that limit vertical head acceleration during wing downstroke. Furthermore, sonar emissions during stable flight occurred most often during wing downstroke and head stabilization, supporting the conclusion that head stabilization behavior optimized sonar gaze and environmental interrogation via echolocation.

Calbindin expression in adult vestibular epithelia.

The mammalian vestibular epithelia exhibit a remarkably stereotyped organization featuring cellular characteristics under planar cell polarity (PCP) control. PCP mechanisms are responsible for the organization of hair cell morphologic polarization vectors, and are thought to be responsible for the postsynaptic expression of the calcium-binding protein calretinin that defines the utricular striola and cristae central zone. However, recent analyses revealed that subtle differences in the topographic expression of oncomodulin, another calcium-binding protein, reflects heterogeneous factors driving the subtle variations in expression. Calbindin represents a third calcium-binding protein that has been previously described to be expressed in both hair cells and afferent calyces in proximity to the utricular striola and crista central zone. The objective of the present investigation was to determine calbindin's topographic pattern of expression to further elucidate the extent to which PCP mechanisms might exert control over the organization of vestibular neuroepithelia. The findings revealed that calbindin exhibited an expression pattern strikingly similar to oncomodulin. However, within calyces of the central zone calbindin was colocalized with calretinin. These results indicate that organizational features of vestibular epithelia are governed by a suite of factors that include PCP mechanisms as well others yet to be defined.

Models of vestibular semicircular canal afferent neuron firing activity.

Semicircular canal afferent neurons transmit information about head rotation to the brain. Mathematical models of how they do this have coevolved with concepts of how brains perceive the world. A 19th-century "camera" metaphor, in which sensory neurons project an image of the world captured by sense organs into the brain, gave way to a 20th-century view of sensory nerves as communication channels providing inputs to dynamical control systems. Now, in the 21st century, brains are being modeled as Bayesian observers who infer what is happening in the world given noisy, incomplete, and distorted sense data. The semicircular canals of the vestibular apparatus provide an experimentally accessible, low-dimensional system for developing and testing dynamical Bayesian generative models of sense data. In this review, we summarize advances in mathematical modeling of information transmission by semicircular canal afferent sensory neurons since the first such model was proposed nearly a century ago. Models of information transmission by vestibular afferent neurons may provide a foundation for developing realistic models of how brains perceive the world by inferring the causes of sense data.

Spaceflight-induced synaptic modifications within hair cells of the mammalian utricle.

Exposure to the microgravity conditions of spaceflight alleviates the load normally imposed by the Earth's gravitational field on the inner ear utricular epithelia. Previous ultrastructural investigations have shown that spaceflight induces an increase in synapse density within hair cells of the rat utricle. However, the utricle exhibits broad physiological heterogeneity across different epithelial regions, and it is unknown whether capabilities for synaptic plasticity generalize to hair cells across its topography. To achieve systematic and broader sampling of the epithelium than was previously conducted, we used immunohistochemistry and volumetric image analyses to quantify synapse distributions across representative utricular regions in specimens from mice exposed to spaceflight (a 15-day mission of the space shuttle Discovery). These measures were compared with similarly sampled Earth-bound controls. Following paraformaldehyde fixation and microdissection, immunohistochemistry was performed on intact specimens to label presynaptic ribbons (anti-CtBP2) and postsynaptic receptor complexes (anti-Shank1A). Synapses were identified as closely apposed pre- and postsynaptic puncta. Epithelia from horizontal semicircular canal cristae served as "within-specimen" controls, whereas utricles and cristae from Earth-bound cohorts served as experimental controls. We found that synapse densities decreased in the medial extrastriolae of microgravity specimens compared with experimental controls, whereas they were unchanged in the striolae and horizontal cristae from the two conditions. These data demonstrate that structural plasticity was topographically localized to the utricular region that encodes very low frequency and static changes in linear acceleration, and illuminates the remarkable capabilities of utricular hair cells for synaptic plasticity in adapting to novel gravitational environments.NEW & NOTEWORTHY Spaceflight imposes a radically different sensory environment from that in which the inner ear utricle normally operates. We investigated synaptic modifications in utricles from mice flown aboard a space shuttle mission. Structural synaptic plasticity was detected in the medial extrastriola, a region associated with encoding static head position, as decreased synapse density. These results are remarkably congruent with a recent report of decreased utricular function in astronauts immediately after returning from the International Space Station.

N-acetylcysteine microparticles reduce cisplatin-induced RSC96 Schwann cell toxicity.

Objectives: Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods: RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC50). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay. Results: The LC50 dose of cisplatin was determined to be 3.76 µM (p = 2.2 x 10-16). When co-dosed with cisplatin and a therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion: RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity. Level of Evidence: N/A Laryngoscope, 2023.

N-acetylcysteine Microparticles Reduce Cisplatin-induced RSC96 Schwann Cell Toxicity.

Objectives: Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods: RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC 50 ). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay. Results: The LC 50 dose of cisplatin was determined to be 3.76 µM (p=2.2 × 10 -16 ). When co-dosed with cisplatin and therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion: RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity. Lay Summary: Cisplatin is a chemotherapeutic agent known to cause balance and hearing problems through damage to the inner ear. This project explored cisplatin injury in a Schwann cell culture model and packaged an antioxidant into microparticles suitable for future drug delivery applications.

Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model.

HYPOTHESIS: The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear. BACKGROUND: Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents. METHODS: RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N -acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined. RESULTS: The estimated 50% lethal concentration dose for gentamicin was 805.6 µM, which was 46-fold higher than that for cisplatin (17.5 µM). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% ( p < 0.001) increase in cell viability when compared with cisplatin alone. However, this protective effect was not consistent across all trials. NAC was encapsulated into a PLGA microparticle and elution plateaued at 5 days. CONCLUSION: When dosed at their respective therapeutic ranges, cisplatin is more likely than gentamicin to induce damage to the Schwann cell model. Although NAC demonstrates an uncertain role in protecting against cisplatin-induced Schwann cell cytotoxicity, this study establishes a method to screen for other otoprotective medications to encapsulate into a tunable microparticle for localized drug delivery.

Translations of Steinhausen's Publications Provide Insight Into Their Contributions to Peripheral Vestibular Neuroscience.

The quantitative relationship between angular head movement and semicircular canal function is most often referenced to the well-known torsion-pendulum model that predicts cupular displacement from input head acceleration. The foundation of this model can be traced back to Steinhausen's series of papers between 1927 and 1933 whereby he endeavored to document observations of cupular displacements that would directly infer movement of the endolymph resulting from angular rotation. He also was the first to establish the direct relationship between cupular displacement and compensatory eye movements. While the chronology of these findings, with their successes and pitfalls, are documented in Steinhausen's work, it reflects a fascinating journey that has been inaccessible to the non-German speaking community. Therefore, the present compilation of translations, with accompanying introduction and discussion, was undertaken to allow a larger component of the vestibular scientific community to gain insight into peripheral labyrinthine mechanics provided by this historical account.

Implantable Drug Reservoir Devices for Inner Ear Delivery of Pharmacotherapeutics.

OBJECTIVE: Cisplatin is a platinum-based chemotherapeutic drug that secondarily induces toxicity in inner ear sensory epithelia, contributing to auditory and vestibular dysfunction. We describe the creation of a drug reservoir device (DRD) to combat this ototoxicity for the duration of chemotherapy. As ototoxic side effects of chemotherapy may limit an oncologist's ability to prescribe first-line agents such as cisplatin, mitigating such devastating effects through prolonged topical therapy would be tremendously valuable. STUDY DESIGN: We investigated (1) the ability of an electrospun polylactic acid DRD to provide prolonged delivery of the posited otoprotectant metformin and (2) the development of an in vitro model utilizing Sh-Sy5y human neuroblastoma cells to assess the efficacy of metformin in reducing cisplatin-induced toxicity. SETTING: Neurophysiology laboratory. METHODS: Basic science experiments were performed to assess DRD properties and metformin's effects on cisplatin toxicity in culture. RESULTS: We found that DRDs with increasing polylactic acid concentrations exhibited metformin release for up to 8 weeks. In modeling elution across the round window in vitro, continued elution of metformin was observed for at least 6 weeks, as quantified by spectrophotometry. Unfortunately, metformin did not exhibit protective efficacy in this model using Sh-Sy5y cells. CONCLUSION: While metformin was not found to be protective in Sh-Sy5y cells, these results suggest that an electrospun DRD can provide a tailorable drug delivery system providing medication for the duration of chemotherapy treatment. This represents a novel drug delivery system and efficacy screening assay with broad clinical applications in personalized delivery of inner ear therapies.

Genome-wide screening for genetic loci associated with noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is one of the more common sources of environmentally induced hearing loss in adults. In a mouse model, Castaneous (CAST/Ei) is an inbred strain that is resistant to NIHL, while the C57BL/6J strain is susceptible. We have used the genome-tagged mice (GTM) library of congenic strains, carrying defined segments of the CAST/Ei genome introgressed onto the C57BL/6J background, to search for loci modifying the noise-induced damage seen in the C57BL/6J strain. NIHL was induced by exposing 6-8-week old mice to 108 dB SPL intensity noise. We tested the hearing of each mouse strain up to 23 days after noise exposure using auditory brainstem response (ABR). This study identifies a number of genetic loci that modify the initial response to damaging noise, as well as long-term recovery. The data suggest that multiple alleles within the CAST/Ei genome modify the pathogenesis of NIHL and that screening congenic libraries for loci that underlie traits of interest can be easily carried out in a high-throughput fashion.

On the Legacy of Genetically Altered Mouse Models to Explore Vestibular Function: Distribution of Vestibular Hair Cell Phenotypes in the Otoferlin-Null Mouse.

OBJECTIVES: Early in his career, David Lim recognized the scientific impact of genetically anomalous mice exhibiting otoconia agenesis as models of drastically compromised vestibular function. While these studies focused on the mutant pallid mouse, contemporary genetic tools have produced other models with engineered functional modifications. Lim and colleagues foresaw the need to analyze vestibular epithelia from pallid mice to verify the absence of downstream consequences that might be secondary to the altered load represented by otoconial agenesis. More generally, however, such comparisons also contribute to an understanding of the susceptibility of labyrinthine sensory epithelia to more widespread cellular changes associated with what may appear as isolated modifications. METHODS: Our laboratory utilizes a model of vestibular hypofunction produced through genetic alteration, the otoferlin-null mouse, which has been shown to exhibit severely compromised stimulus-evoked neurotransmitter release in type I hair cells of the utricular striola. The present study, reminiscent of early investigations of Lim and colleagues that explored the utility of a genetically altered mouse to explore its utility as a model of vestibular hypofunction, endeavored to compare the expression of the hair cell marker oncomodulin in vestibular epithelia from wild-type and otoferlin-null mice. RESULTS: We found that levels of oncomodulin expression were much greater in type I than type II hair cells, though were similar across the 3 genotypes examined (ie, including heterozygotes). CONCLUSION: These findings support the notion that modifications resulting in a specific component of vestibular hypofunction are not accompanied by widespread morphologic and cellular changes in the vestibular sensory epithelia.

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola.

Oncomodulin (OCM, aka ß-parvalbumin) is an EF-hand calcium binding protein that is expressed in a restricted set of hair cells in the peristriolar region of the mammalian utricle. In the present study, we determined the topologic distribution of OCM among hair cell phenotypes to advance our understanding of the cellular organization of the striola and the relationship of these phenotypes with characteristics of tissue polarity. The distributions of OCM-positive (OCM+) hair cells were quantified in utricles of mature C57Bl/6 mice. Immunohistochemistry was conducted using antibodies to OCM, calretinin, and ß3-tubulin. Fluorophore-conjugated phalloidin was used to label hair cell stereocilia, which provided the basis for determining hair cell counts and morphologic polarizations. We found OCM expression in striolar types I and II hair cells, though the distributions were dissimilar to the native striolar type I and II distributions, favoring type I hair cells. The distribution of OCM immunoreactivity among striolar type I hair cells also reflected nonrandom distribution among type Ic and Id phenotypes (i.e., those receiving calretinin-positive and calretinin-negative calyces, respectively). However, many OCM+ hair cells were found lateral to the striola, and within the epithelial region encompassing OCM+ hair cells, the distributions of OCM+ types Ic and Id hair cells were similar to the native distributions of Ic and Id in this region. Summarily, these data provide a quantitative perspective supporting the existence of different underlying factors driving the topologic expression of OCM in hair cells than those responsible for tissue polarity characteristics associated within the utricular striola, including calretinin expression in afferent calyces.

Partial Aminoglycoside Lesions in Vestibular Epithelia Reveal Broad Sensory Dysfunction Associated with Modest Hair Cell Loss and Afferent Calyx Retraction.

Although the effects of aminoglycoside antibiotics on hair cells have been investigated for decades, their influences on the dendrites of primary afferent neurons have not been widely studied. This is undoubtedly due to the difficulty in disassociating pathology to dendritic processes from that resulting from loss of the presynaptic hair cell. This was overcome in the present investigation through development of a preparation using Chinchilla laniger that enabled direct perilymphatic infusion. Through this strategy we unmasked gentamicin's potential effects on afferent calyces. The pathophysiology of the vestibular neuroepithelia after post-administration durations of 0.5 through 6 months was assessed using single-neuron electrophysiology, immunohistochemistry, and confocal microscopy. Hair cell densities within cristae central zones (0.5-, 1-, 2-, and 6-months) and utricle peri- and extrastriola (6-months) regions were determined, and damage to calretinin-immunoreactive calyces was quantified. Gentamicin-induced hair cell loss exhibited a profile that reflected elimination of a most-sensitive group by 0.5-months post-administration (18.2%), followed by loss of a second group (20.6%) over the subsequent 5.5 months. The total hair cell loss with this gentamicin dose (approximately 38.8%) was less than the estimated fraction of type I hair cells in the chinchilla's crista central zone (approximately 60%), indicating that viable type I hair cells remained. Extensive lesions to afferent calyces were observed at 0.5-months, though stimulus-evoked modulation was intact at this post-administration time. Widespread compromise to calyx morphology and severe attenuation of stimulus-evoked afferent discharge modulation was found at 1 month post-administration, a condition that persisted in preparations examined through the 6-month post-administration interval. Spontaneous discharge was robust at all post-administration intervals. All calretinin-positive calyces had retracted at 2 and 6 months post-administration. We found no evidence of morphologic or physiologic recovery. These results indicate that gentamicin-induced partial lesions to vestibular epithelia include hair cell loss (ostensibly reflecting an apoptotic effect) that is far less extensive than the compromise to stimulus-evoked afferent discharge modulation and retraction of afferent calyces (reflecting non-apoptotic effects). Additionally, calyx retraction cannot be completely accounted for by loss of type I hair cells, supporting the possibility for direct action of gentamicin on the afferent dendrite.

Afferent synapses are present in utricular hair cells from otoconia-deficient mice.

The head tilt mouse (het/het, abbr. het) is a naturally occurring mutant whose salient phenotypic traits include the complete absence of otoconia in both the utricle and saccule. Cursory histologic evaluation has indicated that the neuroepithelia exhibit a normal appearance. Though evidence exists indicating that utricular function is severely if not completely compromised in these animals, it is not yet known whether afferent synapses exist within utricular hair cells of otoconia-deficient mutants. The absence of synapses would be suggestive of a trophic relationship between stimulus-evoked hair cell activation and the afferent synapse. To address this question, we have conducted an ultrastructural survey of utricular sensory epithelia from confirmed het mice. The specific objective was to determine whether utricular hair cells made synaptic contact with afferent neurons. We found that both type I and II hair cells from utricles of het mice exhibited afferent synapses that were found at numerous sites distributed throughout the utricle. These results indicate that afferent synapses within vestibular hair cells do not critically depend upon stimulus-evoked activity.

Fiber diameter distributions in the chinchilla's ampullary nerves.

A morphometric study of the chinchilla's ampullary nerves was conducted to produce an unbiased accounting of the diameter distribution of their constituent fibers. Diameter analyses were determined from 1 microm plastic-embedded nerve sections taken at a plane immediately proximal to the sensory epithelium. We found these nerves to be composed of 2094+/-573 fibers, having diameters that ranged from 0.5 to 8 microm. The distributions of diameters were positively skewed, where approximately 75% of the fibers were found to have diameters less than 3.5 microm. An analysis of the spatial distribution of diameters within the nerve section revealed that the lateralmost areas of the nerve contained larger fractions of fibers within the smallest diameter quintiles, and the central area harbored greater proportions of the larger diameter quintiles. However, significant fractions of all quintiles were found in all areas. These data were integrated with available data of Fernandez et al. (1998) to produce diameter estimates of calyx, dimorphic, and bouton morphology subpopulations. In view of a general relationship between diameter, innervation locus, and an afferent's physiologic characteristics, these data provide the basis for developing a perspective for the in situ distribution of afferent response dynamics.

Dynamics and the single spike.

Responses of vestibular primary afferent neurons to head rotation exhibit fractional-order dynamics. As a consequence, the head tends to be in a localized region of its state-space at spike times of a particular neuron during arbitrary head movements, and single spikes can be interpreted as state measurements. We are developing a model of neural computations underlying trajectory prediction and control tasks, based on this experimental observation. This is a step toward a formal neural calculus in which single spikes are modeled realistically as the operands of neural computation.

Distribution of high-conductance calcium-activated potassium channels in rat vestibular epithelia.

Voltage- and calcium-activated potassium channels (BK) are important regulators of neuronal excitability. BK channels seem to be crucial for frequency tuning in nonmammalian vestibular and auditory hair cells. However, there are a paucity of data concerning BK expression in mammalian vestibular hair cells. We therefore investigated the localization of BK channels in mammalian vestibular hair cells, specifically in rat vestibular neuroepithelia. We find that only a subset of hair cells in the utricle and the crista ampullaris express BK channels. BK-positive hair cells are located mainly in the medial striolar region of the utricle, where they constitute at most 12% of hair cells, and in the central zone of the horizontal crista. A majority of BK-positive hair cells are encapsulated by a calretinin-positive calyx defining them as type I cells. The remainder are either type I cells encapsulated by a calretinin-negative calyx or type II hair cells. Surprisingly, the number of BK-positive hair cells in the utricle peaks in juvenile rats and declines in early adulthood. BK channels were not found in vestibular afferent dendrites or somata. Our data indicate that BK channel expression in the mammalian vestibular system differs from the expression pattern in the mammalian auditory and the nonmammalian vestibular system. The molecular diversity of vestibular hair cells indicates a functional diversity that has not yet been fully characterized. The predominance of BK-positive hair cells within the medial striola of juvenile animals suggests that they contribute to a scheme of highly lateralized coding of linear head movements during late development.