Stephen M. Highstein - US grants

DESCRIPTION ( Adapted from applicant's abstract): The neural basis for the generation and control of vertical vestibular-induced eye movements, including the adaptive plasticity of the vestibulo-ocular reflex will be studied utilizing physiological, neurochemical and morphological techniques in squirrel monkeys. The vertical vestibulo-ocular reflex will be visually adapted by employing visual-vestibular mismatch stimuli and/or miniaturizing or magnifying lenses placed in a spectacle mount in front of the animals' eyes. Both the normal and adapted vestibulo-ocular reflex will be utilized as behavioral probes to elucidate the properties of discharge modulation of cerebellar floccular Purkinje cells and brainstem neurons. Previous work suggested that there are multiple brain sites for vestibulo-ocular reflex learning and memory, namely in the cerebellum and brainstem. We will adapt the vertical vestibulo-ocular reflex gain with paradigms designed to elucidate which of these sites encode signals that might be causal to the observed behaviors. We will also analyze the firing patterns of Purkinje cells by chemically inactivating sites known to carry components of the input signals to these cells., We will test our hypothesis that a major function of the cerebellum is to stabilize the vestibulo-ocular reflex during parametric gain changes. Our experiments should provide definitive data to discriminate between extant models of cerebellar function.

Primary vestibular afferent activity of the posterior semicircular canal of the toadfish will be recorded with a hook electrode or a glass microelectrode. The effects of the efferent vestibular system (electrically activated) will be assessed upon the ongoing spontaneous activity and naturally evoked activity of canal afferents. We will be cognisant of possible differential effects upon tonic and phasic afferents. Receptor-receptor interaction between various vestibular sensory areas and the posterior canal will be assessed by stimulation of each of these areas during recording of afferent activity from the posterior canal. The efferent adrenergic innervation of the labyrinth, described in our laboratory, will be further investigated. Efferent adrenergic receptors will be activated by bath application of noradrenalin and/or electric stimulation of the sympathetic system. Finally, intralabyrinthine dendritic morphology of posterior semicircular canal afferents will be elucidated by an approach employing intracellular labeling with horseradish peroxidase and subsequent reconstruction of labeled fibers using a drawing tube technique. These studies will correlate the dendritic morphology of the primary afferents with the physiological activity of the same afferents previously recorded. The mode of impulse initiation in these same phasic and tonic fibers will be examined.

The activation of the efferent vestibular system and its action upon information transfer via the primary afferents of the vestibular system will be studied during natural vestibular stimulation. We will use glass microelectrodes and extracellular recording in toadfish, Opsanus tau. The long-term goal of these studies is to understand the purpose, mode of action and role of this efferent system. We will address the action of the system upon the response dynamics of the horizontal semicircular canal afferents to angular acceleration and will perform a structure-function study of the distribution of efferents and afferents within the crista of the canal. We will assess the determinants of activation of the efferent system in tethered and free swimming fish. We will determine the central distribution of the thick and thin fiber components of the horizontal semicircular canal nerve as it pertains to the selective activation of components of this nerve by the efferent system. An isolated, in-vitro canal preparation will be utilized to determine the synaptic events in hair cells following stimulation of the efferent vestibular nerve. This experiment will be crucial to our understanding of efferent function because of the differential effects of efferent activation upon components of the canal nerve. Immunohistological procedures will be used to localize putative peptide neurotransmitters or modulators within the central and peripheral efferent vestibular system.

The activation of the efferent vestibular system and its action upon information transfer via the primary afferents of the vestibular system will be studied during natural vestibular stimulation. We will use glass microelectrodes and extracellular recording in toadfish, Opsanus tau. The long-term goal of these studies is to understand the purpose, mode of action and role of this efferent system. We will address the action of the system upon the response dynamics of the horizontal semicircular canal afferents to angular acceleration and will perform a structure-function study of the distribution of efferents and afferents within the crista of the canal. We will assess the determinants of activation of the efferent system in tethered and free swimming fish. We will determine the central distribution of the thick and thin fiber components of the horizontal semicircular canal nerve as it pertains to the selective activation of components of this nerve by the efferent system. An isolated, in-vitro canal preparation will be utilized to determine the synaptic events in hair cells following stimulation of the efferent vestibular nerve. This experiment will be crucial to our understanding of efferent function because of the differential effects of efferent activation upon components of the canal nerve. Immunohistological procedures will be used to localize putative peptide neurotransmitters or modulators within the central and peripheral efferent vestibular system.

The activation of the efferent vestibular system and its action upon information transfer via the primary afferents of the vestibular system will be studied during natural vestibular stimulation. We will use glass microelectrodes and extracellular recording in toadfish, Opsanus tau. The long-term goal of these studies is to understand the purpose, mode of action and role of this efferent system. We will address the action of the system upon the response dynamics of the horizontal semicircular canal afferents to angular acceleration and will perform a structure-function study of the distribution of efferents and afferents within the crista of the canal. We will assess the determinants of activation of the efferent system in tethered and free swimming fish. We will determine the central distribution of the thick and thin fiber components of the horizontal semicircular canal nerve as it pertains to the selective activation of components of this nerve by the efferent system. An isolated, in-vitro canal preparation will be utilized to determine the synaptic events in hair cells following stimulation of the efferent vestibular nerve. This experiment will be crucial to our understanding of efferent function because of the differential effects of efferent activation upon components of the canal nerve. Immunohistological procedures will be used to localize putative peptide neurotransmitters or modulators within the central and peripheral efferent vestibular system.

Computer-aided reconstruction of normal, and regenerated individual vestibular primary afferent neurons will be employed in a study of the differential brainstem distribution of individual horizontal semicircular canal afferents in the toadfish, Opsanus tau. This canal nerve contains approximately 350 primary afferents. Each afferent carries a signal related to head movement. Utilizing adequate stimulation, these signals have been divided into three rough groups of: a) low gain velocity sensitive, b) high gain velocity sensitive, and 3) acceleration sensitive afferents. Preliminary studies indicate that each group of afferents terminate within discrete portions of the vestibular nuclei and cerebellum as well as in overlapping, common sites. The output from individual vestibular nuclei, as in all vertebrates, is directed to disparate sites within the neuraxis. There are rostrally projecting neurons innervating, e.g., the extra ocular motor nuclei, ipsi- and contralaterally projecting spinal neurons, projections to the ipsilateral and contralateral brainstem, and projections to other sites. for the present study, individual afferents, physiologically identified by their unique signals during adequate stimulation will be injected intra- axonally with HRP or biocytin to visualize their axons and collaterals, terminal fields, and somatic morphology. Afferent neurons will be computer-reconstructed and morphological information entered into digital memory for subsequent analysis. We will study relevant parameters such as soma size, axon diameter, number and mode of axonal branches, sites of axonal termination, and number of terminal boutons. Hypothesis 1 to be tested is that; in the transfer of information from the VIIIth nerve to its central targets the structure and terminal loci of fibers with diverse physiological signals parallels their diverse functions. Hypothesis 2 is that; functionally different physiological afferent signals will be transferred to appropriate secondary neurons. This will be tested by evaluating the response dynamics during rotation of identified secondary neurons. Intrasomatic electrophysiology following electric pulse stimuli of primary afferents will also be used to evaluate differences in mono- and poly- synaptic post synaptic potentials in different brainstem target neurons. Hypothesis 3 is that; following nerve section, regenerating afferents will find their appropriate brainstem targets and reconnect, transferring the appropriate physiological signals to the correct secondary neurons within the vestibular nuclei. The structure and function of regenerated afferents and their target neurons will be rigorously evaluated with the above mentioned morphological and physiological techniques.

DESCRIPTION (Principal Investigator's abstract): The neural basis for the generation and control of vertical vestibular-induced eye movements, including adaptive plasticity of the vestibulo-ocular reflex (VOR) will be studied utilizing physiological, morphological, neurochemical, and morphophysiological techniques. The vertical VOR will be visually adapted by employing both miniaturizing and/or magnifying lenses placed in a holder in front of the animals' eyes. Both the normal and adapted VORs will then be utilized as behavioral probes to elucidate the properties of brainstem and cerebellar neurons in vestibulo-ocular pathways. First, we will record extracellularly in alert animals, from Y-group, vestibular nucleus, and cerebellar neurons in normal monkeys and in those whose vertical VOR has been plastically adapted. We will quantify the responses of these cells to ascertain their roles, if any, in the normal VOR. Then, during VOR adaptation, we will ask if there are changes in neuronal firing that parallel the changes in reflex-induced eye movements. We hypothesize that eye movement plasticity is brought about by modified signals transmitted, pre-formed to the extra ocular motor nuclei. Y-group neurons are favorably situated to carry these signals. They are flocculus target neurons that are di- or polysynaptically activated by the VIIIth nerve and they project monosynaptically to the IIIrd and IVth nuclei. Discrete chemical lesions will also be employed in selected nuclear and cerebellar sites to temporarily silence them and then the normal and adapted VORs examined. The synaptic connectivity, morphology, and morphophysiology of neurons will be studied with anatomical tracers and intracellular injection to add information at the cellular and morphological levels that may shed light upon the function of this structure in gaze control. The Marr- Albus-Ito hypotheses and others will be critically tested. The neural basis for the integration of signals related to vertical eye movements will be studied in squirrel monkeys with physiological and morphological techniques. The axons of interstitial nucleus of Cajal neurons will be impaled in alert animals, physiologically characterized in relation to gaze, and injected with tracer to elucidate neuronal structure-function correlations. We will evaluate the organization of the vertical neural integrator to test hypotheses concerning its operation and the necessity for a bilateral structural organization.

In this project we will seek to resolve the origin of differences in tonic and phasic response output from the hair cell and cupula of the vestibular system. Specifically, we will determine if differences in encoded vestibular output is attributable to: (1) cupular motion and regional variation in hair cell stereociliary deflection; (2) afferents that are differentially (numerically and/or regionally) innervated by hair cells; and/or (3) that afferents may respond differentially to a transmitter quantum. This will be accomplished through a coordinated interdisciplinary effort encompassing digital video imaging image analysis, detailed electrophysiological recording and kinetic simulation studies described throughout this program project application. Silver's laboratory will focus upon the acquisition and analysis of images of stereociliary and cupular movements during head displacement, by developing a digital video light microscopic method for directly observation, analysis and relating movements of sub-cellular, cellular and supra-cellular structures in the vestibular end organ (VEO) related with vestibular function, using the toadfish (Opsanus tau) labyrinth as the model system, Reeves' group will focus upon advanced analytical imaging methods. High quality imagery of the performance of VEO components is needed to establish the structure- function relationships of these essential mechano-electrical transducers, especially in light of the advances made by the collaborating laboratories in hair cell electrophysiology and computational displacements of these transducers obtained on-line during an actual experiment is lacking. Recently, Silver, in collaboration with Highstein, accomplished direct video light microscopic imaging microscope capable of video observation and recording of stereociliary and cupular movements in situ in concert with concurrent electrophysiological recordings; (2) describe the sub-micrometer displacements of these structures during VEO movements via computational representations of image data (i.e., processed imagery, isosurfaces and isovolume) to aid in testing for the parity correspondence among actual VEO movements (this work), electrophysiological performance (Highstein and Boyle) and kinetic simulations (Rabbit, Miller). Integration of the information developed will facilitate assessment of normal and dysfunctional VEO performance in normal, and microgravity environments.

The overall goals of the proposal are to characterize the determinants of the response dynamics of the horizontal semicircular canal and to study the mechanisms and sequels of the efferent vestibular systems manipulation of these determinants. The response dynamics of the horizontal semicircular canal nerve have been documented in this species. There are three broad classes of afferent based upon their response dynamics across the frequency and amplitude spectrum studied. There are frequency and amplitude dependent non-linearities represented within the responses of certain classes of afferent. The contributions and significance of the putative differential motion of the center and periphery of the cupula and of hair cell receptor current frequency and amplitude dependent non-linearities to those in the primary afferents will be evaluated. Whole cell patch clamp techniques will be applied to hair cells isolated from defined functional regions of the crista to study the magnitude and kinetics of activation, inactivation, and deactivation of potassium currents. The current clamp responses to perturbing currents of these cells will be determined. Differential efferent action upon the various classes of primary afferent has also been documented. The implications and mechanisms of this differential action will be studied with morphological and physiological techniques. The amplitudes and shapes of miniature (m) EPSPs recorded from primary afferents will be measured before and during stimulation of efferents to assess the significance of the efferent evoked changes in EPSP characteristics to the output of the system. The activation sequelae of the efferent vestibular system upon horizontal canal afferents in free swimming fish will be studied utilizing multi-channel electrodes, under water acoustic telemetry and under water video. Thus, we hope to arrive at a general theory of efferent action in this species. Studies of the cellular and systems science aspects of the vestibular system and its efferent control add information about function and may bear upon possible future therapies and mechanisms for the control of motion sickness.

The overall goals of the Program Project are to study the neural and cellular bases of labyrinthine function, relevant to balance and equilibrium. The investigators will pursue a multifaceted, interdisciplinary research approach to test the central hypothesis of this Program, that the origins of diverse primary vestibular afferent response dynamics can be found distributed among the steps of the transduction cascade from head acceleration to afferent discharge modulation. Those steps are (1) biomechanics, (2) mechano-transduction, (3) basolateral currents, (4) hair cell synapses, and (5) postsynaptic factors. The proposed studies will evaluate the contributions of each of these categories to the differential response dynamics of individual canal nerve afferents, utilizing the vertebrate fish Opsanus tau (toadfish) as the model experimental system for all proposed experiments. Specifically, cupular structure, and the relative motion of the cupula and single hair cell stereocilia in response to mechanical stimuli will be evaluated. Transduction will be investigated through voltage clamp studies of semicircular canal hair cells in-situ. These experiments will examine the regional differences in membrane currents generated in response to hair bundle motion, and will test the hypothesis that such differences influence the construction of individual nerve response dynamics. The relationships of transduction voltage and/or current to membrane and endolymphatic potentials will be measured, to establish a working model for the generation of transduction in-vivo. Results from these studies will establish the electro-chemical characteristics of hair cell apical transduction. Other experiments will document the transcupular pressure differentials that drive cupular motion. Cupular deformation, and stereociliary coupling to the cupula will be observed with video microscopy and quantitated by image analysis. Afferent nerve responses will be further evaluated in plugged semicircular canals. The ultrastructural organization and synaptology of functionally-characterized, biocytin-injected primary afferents will be characterized and quantified using light and electron microscopy. The effects of efferent vestibular nuclei stimulation on hair cell receptor and membrane potentials, and upon transmitter release as measured by mEPSPs will be determined. These experiments will provide a systematic study of the origins of primary vestibular afferent response dynamics in a single vertebrate species. As such, the work will offer new insights into labyrinthine function, and is thereby critical for the development of effective therapies for motion sickness and peripheral vestibular disorders

The overall goals of the proposal are to characterize the determinants of the response dynamics of the horizontal semicircular canal and to study the mechanisms and sequels of the efferent vestibular systems manipulation of these determinants. The response dynamics of the horizontal semicircular canal nerve have been documented in this species. There are three broad classes of afferent based upon their response dynamics across the frequency and amplitude spectrum studied. There are frequency and amplitude dependent non-linearities represented within the responses of certain classes of afferent. The contributions and significance of the putative differential motion of the center and periphery of the cupula and of hair cell receptor current frequency and amplitude dependent non-linearities to those in the primary afferents will be evaluated. Whole cell patch clamp techniques will be applied to hair cells isolated from defined functional regions of the crista to study the magnitude and kinetics of activation, inactivation, and deactivation of potassium currents. The current clamp responses to perturbing currents of these cells will be determined. Differential efferent action upon the various classes of primary afferent has also been documented. The implications and mechanisms of this differential action will be studied with morphological and physiological techniques. The amplitudes and shapes of miniature (m) EPSPs recorded from primary afferents will be measured before and during stimulation of efferents to assess the significance of the efferent evoked changes in EPSP characteristics to the output of the system. The activation sequelae of the efferent vestibular system upon horizontal canal afferents in free swimming fish will be studied utilizing multi-channel electrodes, under water acoustic telemetry and under water video. Thus, we hope to arrive at a general theory of efferent action in this species. Studies of the cellular and systems science aspects of the vestibular system and its efferent control add information about function and may bear upon possible future therapies and mechanisms for the control of motion sickness.

Vestibular research has seen recent major advances with the advent of new tools,
techniques and ideas. These advances have been realized in studies of both the
central and peripheral vestibular systems and in studies performed in both
terrestrial and micro-gravity. Advances have been made in the understanding of
the contributions of biomechanics, including intralabyrinthine pressure and the
stiffness and elastic restoring forces of the stereocilia and cupula to the
formation of the response dynamics of the semicircular canal nerves
The conference should be of interest to broad areas of neuroscience,
including developmental biology, physiology and pharmacology, space biology,
bioengineering, and the medical fields of neurology, otolaryngology, and
neurosurgery. The conference will be held in the Eric P. Newman Center for Continuing
Education of the Washington University School of Medicine from Thursday November
16 through Saturday November 18, 2000 under the direction of Drs. Stephen M.
Highstein, Chair and Joel Goebel, Co-Chair. Speakers have been chosen by Drs.
Highstein and Goebel with the advice of the advisory panel and others prominent
in vestibular research. While many of the speakers have national and
international reputations as leaders of their fields, an emphasis has been
placed on the contributions of younger workers wherever possible. Women are
also represented to the maximum extent possible. We are interested in bringing
existing controversies to light, and adequate time will be provided for
discussion and resolution of differing viewpoints. An effort has been made to
provide an outlet for research that is new and on the cutting edge in a poster
session.

Vestibular research has seen recent major advances with the advent of new tools, techniques and ideas. These advantages have been realized in studies of both the central and peripheral vestibular systems in studies performed on both terrestrial and microgravity. Advances have been made in the understanding of the contributions of biomechanics, including intra labyrinthine pressure to the formation of the response dynamics of the semicircular canal nerves. Experiments have also revealed that canal dynamics of the semicircular canal nerves Experiments have also revealed that canal plug does not completely inactivate the response of the plugged canal but shifts the phase and gain (dynamics) of the response. There have been advances in the study of the metabolism and formation of the otolith that is no longer regarded as a static entity but is viewed as a structure in the dynamic flux of remodeling. The concept of a "fragile" otolith has emerged to explain why there can be the occurrence of benign paroxsismal positional vertigo thought due to gravitational responses of the semicircular canals when otolithnic particles break off and become lodged upon the cupula. Studies in microgravity have bearing on the tilt-translation hypothesis of otolithic organ function. Concepts of the function of the vestibular nuclei have been completely revised by studies showing that signals related to head motion that are expressed in the nuclei are not seen when the head is free and the animal makes a voluntary movement. Finally, new tools have allowed scientists to begin to examine the frames of reference relative to the gravitoinertial vector in head free experiments. Clinical testing of peripheral labyrinthine function has also been revolutionized as it is now possible to test the function of single semicircular canals as well as the integrity of some central pathways using simple head thrust procedures. Therefore we desire to hold a forum paring basic scientists and clinicians on the same panel to discus and point out these advances and their meaning. To promote the educational aspects of the conference we hope to award up to 30 fellowships to students and postdoctoral fellows to acquaint them with the exciting new developments in vestibular research.

DESCRIPTION (Provided By Applicant): An international meeting entitled Recent Progress in Cerebellar Research is proposed. The gathering will last three days, from November 16-18, 2001, and be held in the Eric P. Newman Center of the Washington University School of Medicine in St. Louis, Missouri immediately following the Society for Neuroscience Meeting. We will bring together the international community of cerebellar researchers to discuss the current status of the field. Progress in cerebellar physiology has proceeded at a rapid pace, and a meeting to exchange new results and concepts seems timely. This meeting will serve to cross-fertilize efforts between various factions in the field in the understanding of cerebellar function. Washington University has been chosen as a venue because of its central location. Seven sequential panel sessions, each with an organized and moderated discussion period, two plenary lectures reviewing the history of landmark discoveries, and a poster session will be presented over a three-day period to consider the following topics that are important for understanding cerebellar function. 1) The cerebellum as a device for coordination of movement; 2) Relative roles of the cerebellar cortex and nuclei; 3) Parallel fiber beams. What do they do? 4) Climbing fiber inputs to the cerebellum. What is signaled? 5) Cognitive processing by the cerebellum; 6) LTD, LTP and molecular mechanisms of learning and memory; 7) Models of cerebellar function.

This three-day conference will bring together the international community of cerebellar researchers to discuss the current status of the field. Progress in cerebellar physiology has proceeded at a rapid pace and a meeting to exchange new results and concepts seems timely. This meeting will serve to cross-fertilize efforts between various factions in the field in the understanding of cerebellar function. Seven sequential panel sessions, each with an organized and moderated discussion period, two plenary lectures the history of landmark discoveries, and a poster session will be presented over a three-day period to consider the following topics that are important for understanding cerebellar function. 1) The cerebellum as a device for coordination of movement; 2) Relative roles of the cerebellar cortex and nuclei; 3) Parallel fiber beams. What do they do? 4) Climbing fiber inputs to the cerebellum. What is signaled? 5) Cognitive processing by the cerebellum; 6) LTD, LTP and molecular mechanisms of learning and memory; 7) Models of cerebellar function. It is expected that attendees of the meeting will be informed of the very latest progress and research in the cerebellar field. Because cerebellar research is presently extremely active, and because many of the speakers use state of the art technology such as optical recording and multiple electrode recording techniques, attendees will also be informed of the state of the art of methodology related to the neurosciences. The open format of the poster session will provide the opportunity for active, intimate discussion.

A complete vestibular evaluate system including a multi axis vestibular motion system, an eye movement measurement system, an animal stabilization device, a single unit amplifier, and a data acquisition system is requested. The instrument will be utilized by each of the Principle investigators to evaluate vestibular function. The instrument is capable of performing behavioral tests including linear and angular acceleration and off vertical rotary testing. Some investigator and the transgenic core will examine vestibular-evoked eye movements and others will determine the response dynamics of single vestibular afferent nerve fibers. The unit will be housed within the Old Shriner's Hospital at Washington University one floor above the transgenic mouse core and will also serve as a screening device for vestibular deficits in mutant mice. The humans who complain of subjective vertigo or balance difficulties objective vestibular deficits are often subtle and can only be revealed by behavioral tests in a clinical laboratory setting. Eye movements have been extremely useful in this regard. For example, nystagmus produced during head positioning tests is diagnostic for benign positional paroxysmal vertigo and head-thrusting tests can reveal subtle specific semicircular canal dysfunction. Mice lack the capability of speech; therefore if we hope to provide mouse models for specific vestibular defects it is necessary to implement sophisticated tests to document these defects. We desire to standardized the vestibulo-ocular responses to angular and linear acceleration in the mouse. To that end we need a device that can provide specified angular and linear acceleration as well as off vertical axis rotation. Such a platform will enable the evaluation of vestibulo-ocular reflexes over the entire relevant range of frequencies and amplitudes. Further, in the likely scenario of the necessity to test specific therapeutic agents a normative database which to evaluate the action of pharmacological agents will be invaluable. Existing tests such as the vestibular evoked response are not nearly as sensitive as neural recording.

DESCRIPTION (provided by applicant): In the vestibular system, as in the auditory and visual systems, stimuli are transduced and neural signals processed prior to transmission to the brain. Our research and that of others has clearly shown that the afferent responses from the semicircular canal deviate from canal biomechanics, and has implicated signal processing by the hair cell-primary afferent synapse in shaping the afferent response. Our overarching hypothesis is that the spatial distribution of an ensemble of transmitter and receptor phenotypes on hair cells and the afferent terminal arbors form processing entities that transform hair cell receptor potentials into the frequency code seen in the nerve discharge. The goal of the proposed research is to measure and quantify the contributions of these entities to the adaptation and frequency-dependent responses of vestibular semicircular canal afferents. We have demonstrated that there are three hair cell transmitter phenotypes: GABAergic, glutamatergic and cells that express both transmitters. We propose that specific combinations of hair cells and afferent terminals operating in feed-forward and feedback configurations dictate the transformation of canal biomechanical responses into the neural codes of individual primary afferent fibers. This proposal focuses on four categories of synaptic and/or extrasynaptic factors putatively involved in signal processing: (1) hair cell transmitter phenotype(s) impinging on a given ending, including the possibility of a diversity of hair cell transmitter phenotypes and post-synaptic receptor distributions interacting at a given terminal, (2) potential feedback between the calyx and hair cell, including feedback from hair cell-released transmitter to the hair cell itself, (3) the rate of transmitter release and subsequent synaptic current dynamics, governed by pre- and post-synaptic ionic currents present at a particular synapse, and (4) the integrative properties of the afferent dendrite. Understanding the complexity of the signal processing performed by afferent terminals is a necessary step toward developing treatments for vestibular disorders. Basic science adds information that is important in understanding normal and abnormal function. Once the precise mechanisms involved in shaping afferent dynamics are more thoroughly understood, appropriate and specific pharmacological agents may be developed to reduce abnormal bursts of afferent neural activity, thereby mitigating the severity of vertiginous symptoms in disorders such as M[unreadable]ni[unreadable]re's syndrome. PUBLIC HEALTH RELEVANCE The inner ear contains the organs of hearing, balance and equilibrium. We study synaptic communication by chemical transmitter between hair cells (the primary mechanical sensors) and their innervated nerve fibers. Results from these investigations are expected to support the development of targeted therapies for peripheral vestibular disorders such as M[unreadable]ni[unreadable]re's syndrome and benign paroxysmal positional vertigo.