Arizona State University

The role of NMDA receptors in vestibular circuit function and balance

The vestibular cerebellum is the part of the brain that integrates signals that convey head, body and eye movements to coordinate balance. When this neural processing is disrupted by central or peripheral vestibular disorders, profound instability, vertigo, and balance errors result. We lack a basic understanding of the development and physiology of the first vestibular processing region in the cerebellum, the granule cell layer. This lack of knowledge is a major roadblock to the development of therapies that could ameliorate peripheral disorders such as Ménière’s disease. This project will look at a specific understudied cell type in the granule cell layer of the cerebellum, unipolar brush cells (UBCs). Our focus is particularly on the cells’ glutamate receptors, which control synaptic communication. It remains unclear how glutamate receptors assume their form and function during development, and we hypothesize that the NMDA-type glutamate receptors expressed by developing UBCs are necessary for the development of the remarkable dendritic brush of these cells, which slows and controls communication across the synapse, and the cells’ function in the circuit.

Arizona State University
The role of unipolar brush cells in vestibular circuit processing and in balance

The cerebellum receives vestibular sensory signals and is crucial for balance, posture, and gait. Disruption of the vestibular signals that are processed by the vestibular cerebellum, as in the case of Ménière’s disease, leads to profound disability. Our lack of understanding of the circuitry and physiology of this part of the vestibular system makes developing treatments for vestibular disorders extremely difficult. This project focuses on a cell type in the vestibular cerebellum called the unipolar brush cell (UBC). UBCs process vestibular sensory signals and amplify them to downstream targets. However, the identity of these targets and how they process UBC input is not understood. In addition, the role of UBCs in vestibular function must be clarified. The experiments outlined here will identify the targets of UBCs, their synaptic responses, and the role of UBCs in balance. A better understanding of vestibular cerebellar circuitry and function will help us identify the causes of vestibular disorders and suggest possible treatments for them.

Long-term goal: To develop a better understanding of the neural circuits that underlie vestibular function. A more complete understanding of the circuitry and physiology of the vestibular cerebellum is necessary to develop therapies for vestibular dysfunction caused by peripheral disorders such as Ménière’s disease.

UCLA David Geffen School of Medicine
Cellular and molecular biology of the microvasculature in the macula utricle of patients diagnosed with Ménière’s disease

To investigate the microscopic structure of the vasculature (blood vessel system) of balance organs from patients with intractable Ménière’s disease. Ishiyama’s hypothesis is that altered biochemical pathways affecting the vasculature of the blood labyrinthine barrier—which protects the inner ear from toxins and infections—may cause a dysfunction of the inner ear, leading to hearing loss and vertigo.

Ishiyama’s recent research revealed structural cellular changes in the blood labyrinthine barrier of the utricle, a balance organ, in Ménière’s patients. This project continues the work by detailing the cells and biochemical pathways that are altered in Ménière’s disease. This will provide greater information on the blood labyrinthine barrier and allow for the development of interventions that prevent the progression of hearing loss and stop the disabling vertigo in Ménière’s disease patients.

Missouri State University
Novel Ménière’s disease diagnosis: extratympanic simultaneous recording of ECochG and ABR to fast click rates using CLAD technique

Ménière’s disease is mainly diagnosed clinically with no available sensitive objective measures to confirm clinical diagnosis. Current auditory electrophysiologic measures such as standard electrocochleography (ECochG) to a slow click rate has low sensitivity that limits its clinical use. Also, standard ECochG to slow rate cannot measure neural adaptation phenomenon (decrease in the neural firing between the inner hair cells and auditory nerve) that occurs in response to continuous presentation of a fast acoustic stimulus. Although other technique modifications of ECochG such as maximum length sequence to fast rate seem to be promising, several limitations in extracting responses to very fast rates exist with this measure that hinder their clinical use for detection of Ménière’s disease. The new continuous loop averaging deconvolution (CLAD) algorithm is a promising technique to extract overlapping auditory evoked responses to very fast rates, providing valuable information about cochlear and neural function of clinical populations. Thus, the use of CLAD with fast rate ECochG and auditory brainstem response (ABR) has the potential to detect early Ménière’s disease by studying the neural adaptation phenomenon. It is hypothesized that Ménière’s disease may show abnormally fast neural adaptation that may manifest as fast degradation of AP and ABR response amplitudes and prolongation of latency as a function of click rate. The current objectives and the long-term goals of this project are to establish and advance ECochG and ABR measures using CLAD technique to identify the critical rate at which neural adaptation starts as a marker for early diagnosis, differential diagnosis and classification of Ménière’s disease.

Massachusetts Eye and Ear, Harvard Medical School
Characterization of endolymphatic sac anatomy in early and late onset Ménière's disease: a clinical radiologic study

Ménière’s disease is an inner ear disease that affects the vestibular organs of the inner ear and presents with various symptoms such as vertigo, hearing loss, and tinnitus. There is no known cause, but it is believed that Ménière’s can be associated with an abnormal accumulation of fluid in the inner ear, called endolymphatic hydrops, which is produced in an appendix to the vestibular system, called the endolymphatic sac. Currently, diagnosis of Ménière’s is entirely based on clinical symptoms, and since these can vary greatly in patients and even mimic other diseases, it has made identifying Ménière’s difficult, delaying treatment of symptoms. Previously, using radiologic imaging, we had found striking differences in the vestibular aqueduct, a bony canal that the sac traverses, among those with either early or late-onset Ménière’s. This project is to confirm whether the shape and course of the vestibular aqueduct can act as a reliable biomarker to identify distinct types of Ménière’s in patients.

University of Colorado Denver
The role of K+ conductances in coding vestibular afferent responses

Approximately 615,000 people in the United States suffer from Meniere’s disease, a disorder of the inner ear that causes episodic vertigo, tinnitus and progressive hearing loss. The underlying etiology of the disease is not known but may include defects in ion channels and alterations in inner ear fluid potassium (K+) ion concentration. Specialized hair cells inside the ear detect head movement in the vestibular system and sound signals in the cochlea. A rich variety of channels is found on the membranes of hair cells as well as on the afferent nerve endings that form connections (synapses) with hair cells. Many of these channels selectively allow the passage of K+ ions and are thought to be important for maintaining the appropriate balance of K+ ions in inner ear fluids. I study an unusual type of nerve ending called a calyx, found at the ends of afferent nerves that form synapses with type I hair cells of the vestibular system. These nerves send electrical signals to the brain about head movements. My goal is to use immunocytochemistry and electrophysiology to identity K+ channels on the calyx membrane and to explore their role in regulating electrical activity and K+ levels in inner ear fluid. I will identify potential routes for K+ entry that could influence calyx properties. I will investigate whether altered ionic concentrations in inner ear fluid change the buffering capacity of K+ channels and whether this affects the signals that travel along the afferent vestibular nerve to the brain. Meniere’s disease is a disorder of the entire membranous labyrinth of the inner ear and thus affects both the vestibular sensory organs and the cochlea. Similar K+ ion channels are expressed in vestibular and auditory afferent neurons. Studying ion channels present in both auditory and vestibular systems will reveal properties common to both systems and will increase our understanding of the importance of ion channels in Meniere’s disease.

University of California, Los Angeles
Cellular modifications of the vestibular labyrinth: Intrinsic mechanisms following unilateral aminoglycoside treatment for Meniere’s disease

Intra-tympanic gentamicin is a widely used treatment for unilateral Meniere’s disease, primarily to reduce the activity in the affected ear and thereby reduce the frequency and severity of vertigo attacks. Though the treatments are applied to only one ear, the adaptive effects in the untreated ear have not been widely studied. At the same time, there is evidence indicating that the vestibular receptors exhibit intrinsic capabilities for modification or adaptation to alterations from the normal operating conditions. For example, the inner ear vestibular receptors may undergo a form of “sensory learning” when exposed to changes in the ambient operating conditions associated with spaceflight. An investigation of the contralateral labyrinth following treatments comparable to that associated with intra-tympanic gentamicin may provide clues as to alterations in the conserved ear. These capabilities may be recruited through rehabilitative measures (pharmacologic, physical therapy) to accelerate recovery to normal vestibular function. We propose to study the activity of individual neurons projecting to the conserved vestibular receptors, thereby providing a direct measure of the output of these neurons and by comparisons to our large database of untreated specimens, as well as to determine whether alterations in this activity ensues following adaptation to administration of gentamicin to the contralateral ear.

Research area: Meniere's disease; Ototoxicity

Long-term goal of research: The proposed work is based on the intra-tympanic gentamicin treatment currently used for Ménière’s disease, but the implications of this study could have an even greater impact. Better understanding of the vestibular system’s ability to respond to damage reveals the possibility of retraining the non-lesioned ear, akin to physical therapy. Though most animal studies use unilateral labyrinthectomy as their disease model, such complete loss is rare in the clinical setting. The intra-tympanic gentamicin treatment for Ménière’s disease is not the same as a labyrinthectomy, as the lesions are likely to be partial. Thus, the experiment described here, a direct test of whether peripheral plasticity ensues following partial lesions, is more translationally realistic compared to the labyrinthectomy. Therefore, an investigation into the effects of a less severe lesion, such as the gentamicin regimen proposed here which preserves spontaneous neuronal activity, would be of significant translational value.

Harvard Medical School
Development and Physiology of the Endolymphatic Duct and Sac in Zebrafish

Abnormalities in our sense of hearing and balance are incapacitating in the extreme, and, when subtle, cause psychological distress. Meniere’s disease is an inner ear disease with unclear causes that is inferred from episodes of vertigo, hearing loss, tinnitus, and the sensation of fullness in the ear that can last two to four hours. An unstable inner ear environment is believed to underlie Meniere’s disease. Recently, Swinburne has developed methods to image the live development and physiology of the portion of the Zebrafish ear conserved in humans and believed to be dysfunctional in Meniere’s disease: the endolymphatic duct and sac. With these methods, Ian hopes to gain basic understanding of how the inner ear’s environment is normally maintained and how a defect can lead to a disease.

Classifying the endolymphatic duct and sac cell types and their gene sets using high-throughput single-cell transcriptomics

To understand how the inner ear endolymphatic duct and sac stabilize the inner ear’s environment and to identify ways to restore or elevate this function to mitigate or cure Ménière's disease. The endolymphatic duct and sac play important roles in stabilizing a fluid composition necessary for sensing sound and balance. The recurrent vertigo in Ménière's is likely caused by a malfunction of the endolymphatic sac, causing volume or pressure changes in the inner ear.

Swinburne recently found that the typical-functioning endolymphatic sac periodically inflates and deflates like a balloon, and that specialized cell structures in the sac appear to transiently open, causing the deflation of the endolymphatic sac. The sac, then, appears to act as a relief valve to maintain a consistent volume and pressure within the inner ear. This project will generate a list of endolymphatic sac cell types and the genes governing their function, which will aid in Ménière's diagnosis (which can be delayed due to the range of fluctuating symptoms) and the development of a targeted drug or gene therapy.

Johns Hopkins University School of Medicine
The effect of fluid volume on vestibular function and adaptation in patients with Ménière’s disease

Individuals with Ménière’s disease experience spontaneous attacks of spinning vertigo, ear fullness, tinnitus, and hearing loss. We do not know the pathophysiology of Ménière’s disease. On some tests of the inner ear, individuals with Ménière’s have responses indicating inner ear balance is not functioning well (absent caloric responses), but other tests suggesting it is (head impulse testing). The reason for this is debated. Strong magnetic resonance imaging (MRI) scanners cause dizziness and nystagmus (back-and-forth beating of the eyes from inner ear stimulation) in all healthy humans due to magnetic vestibular stimulation (MVS). The combination of MVS and MRI imaging provides a unique opportunity to better understand the physiology of patients with Ménière’s disease. This project will assess nystagmus in strong MRI machines in individuals with Ménière’s and compare this to tests of vestibular function and to imaging of the inner ear.