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.

Mass Eye and Ear

Auditory and vestibular phenotype characterization of a Ménière’s disease model in humans and mice with X-linked hypophosphatemia

Our group has begun to segregate the pool of Ménière’s disease patients into distinct subtypes based upon specific clinical characteristics and morphologic features of the inner ear endolymphatic sac and vestibular aqueduct. One cohort—designated MDhp—demonstrated on histopathology and radiologic imaging an incompletely developed (hypoplastic) endolymphatic sac and vestibular aqueduct and had a high comorbid prevalence of X-linked hypophosphatemia. XLH is a genetic phosphate metabolism and bone growth disorder caused by a loss-of-function variant in the Phex gene. The high coincidence of XLH in the MDhp cohort led to the hypothesis that the two disorders may have etiologic similarities. Our preliminary studies suggest that the Phex gene-deficient XLH mouse also recapitulates clinical features of the MDhp cohort: hearing loss and balance dysfunction, endolymphatic hydrops, and hypoplasia of the endolymphatic sac and vestibular aqueduct. During this project we will determine whether the inner ear phenotype of humans with XLH generally resembles that of MDhp, and whether the XLH mouse model also exhibits an MDhp phenotype. Characterizing the MDhp phenotype within the context of patients with XLH and a Phex-deficient mouse model is a critical first step toward investigating the pathophysiology of MD and elucidating the genetic etiology of the MDhp subgroup. This research may demonstrate that the Phex gene-deficient mouse can be used as a reliable animal model of the MDhp subtype, which will pave the way for future studies of the role of the Phex gene mutation in MD patients and, more generally, the genetic basis of this complex disease. 

University of Pennsylvania, Perelman School of Medicine

Defining the role of EYA4 risk variants in the pathogenesis of Ménière’s disease.

Ménière’s disease is a disabling inner-ear condition that can cause sudden episodes of spinning dizziness, changing hearing loss, ringing in the ears, and a feeling of pressure or fullness. Although these symptoms can be severe and unpredictable, we still do not understand why most people develop the disease.

Our recent large genetic study—comparing nearly 9,000 people with Ménière’s disease with more than 1.9 million people without it— identified several DNA regions associated with disease risk. Two of the strongest signals lie near a gene called EYA4, which is active in the inner ear and is already known to be important for hearing. The DNA differences associated with Ménière’s disease are likely not changing the EYA4 protein itself. Instead, they may act like altered “dimmer switches,” changing when, where, or how strongly EYA4 is turned on in the cells that support hearing and balance.

This project will determine which of these DNA differences are most likely to cause increased disease risk and test how they affect EYA4 activity in the inner ear. We will use advanced genetic analyses to narrow the list of possible causal variants, then test human DNA regulatory sequences in mice to see whether risk-associated versions behave differently from non-risk versions in the living inner ear.

We will also investigate what happens when EYA4 is disrupted in specific inner-ear cell types in adult mice. By measuring balance behavior, hearing, inner-ear function, and tissue changes, we will test whether loss of EYA4 produces key features of Ménière’s disease, including vertigo, progressive hearing loss, and abnormal fluid buildup in the inner ear.

Together, these studies will convert newly discovered genetic clues into a clearer explanation of disease biology. The work may identify the molecular changes that make some people more susceptible to Ménière’s disease and establish experimental models needed to develop better risk prediction, prevention strategies, and ultimately more precise treatments.

Columbia University

Enhanced cochlear endolymphatic hydrops imaging for Ménière’s disease with intracochlear MRI contrast delivery via microneedle

Ménière’s disease is a chronic inner ear disorder that causes episodes of vertigo, hearing loss, tinnitus, and aural fullness. These symptoms are thought to arise from endolymphatic hydrops (EH)—a buildup of fluid in the inner ear. Current MRI methods can visualize EH but are limited by long wait times, high contrast doses, and inconsistent image quality. This project introduces a new microneedle-based technique that delivers MRI contrast agents directly into the cochlea through a minimally invasive injection. By bypassing systemic delivery, this method allows faster, more reliable imaging with smaller doses of contrast. The project also integrates advanced 3D image segmentation powered by artificial intelligence (AI) to automatically and accurately measure EH. Through safety testing in animal models and development of an automated 3D segmentation pipeline, this research will establish a foundation for clinical translation. The ultimate aim is to create a precise, safe, and efficient imaging approach for early diagnosis and monitoring of Meniere’s disease, improving treatment decisions and patient outcomes.

Rice University
Understanding the biophysics and protein biomarkers of Ménière’s disease via optical coherence tomography imaging

Our sense of hearing and balance depends on maintaining proper fluid balance in a specialized fluid in the inner ear called the endolymph. Ménière’s disease is an inner ear disorder associated with increased fluid pressure in the endolymph that involves dizziness, hearing loss, and tinnitus. Ménière’s disease is difficult to diagnose and treat clinically, which is a source of frustration for both physicians and patients. Part of the barrier to diagnosing and treating Ménière’s disease is the lack of imaging tools to study the inner ear and a poor understanding of the underlying causes. The goal of this research is to develop an approach to noninvasively image the inner ear and study the internal structures in the vestibular system in typical and disease states. We will utilize optical coherence tomography (OCT), a technique capable of imaging through bone, and observe changes in the fluid compartments in the inner ear. The expected outcome of this research will be the establishment of a powerful non-invasive imaging platform of the inner ear that will enable us to test hypotheses, in living animals, on how ion transport regulates the endolymph, how disorders of ion transport cause disruption of endolymphatic fluid, and how the expression of different biomarkers lead to disorders of ion transport.