Brandon Walters, Ph.D.

Brandon Walters, Ph.D.

St. Jude Children's Research Hospital
Conditional Reprogramming of Otic Stem Cells: Development of a Novel In-Vitro Hair Cell Line

One of the major limitations in studies of hearing loss is the inability to study the phenomenon of hearing in a petri dish (in-vitro), thereby limiting the use of tools that are essential for understanding the causes of, and treatments for, hearing loss. In addition to this obvious limitation, the use of in-vitro studies is hindered primarily by technical limitations related to the low abundance of hair cells that are responsible for our sense of hearing. Researchers have attempted to overcome the issue of insufficient cell numbers by creating cell lines that mimic the properties of human hair cells, but success of these approaches have been limited. The goal of the proposed experiments is to utilize approaches from other fields to create a cell line that will allow for infinite proliferation of low abundance cells that can be turned into hair cells when needed, thus providing a limitless supply of hair cells for the study of hearing loss.

Research area: Hair Cells; Hearing Loss

Long-term goal of research: To identify drugs that can modulate the differentiation of hair cells, focusing primarily on compounds that promote hair cell formation, which we believe, will be of therapeutic benefit to people with hearing loss. To this end, we plan to utilize high throughput screening to test hundreds of thousands of compounds for potential effects on hair cell formation. We plan to combine the hair cell line that we create with various tools for tracking the developmental state of the cell to aid our evaluation of drugs that increase the number of all viable hair cells and to potentially extend our investigation to specific subtypes of hair cells that play distinct roles in hearing loss.

Ilse Wambacq, Ph.D.

Ilse Wambacq, Ph.D.

Montclair State University

Neurophysiological and psychoacoustic indices of binaural processing in adults

The overall goal of the proposed research is to investigate neurophysiological and psychoacoustic indices of binaural processing in adults with normal and impaired hearing. In order to develop and implement effective remediation for individuals with sensorineural hearing loss, it is essential to determine a straightforward means to identify binaural processing problems. It is particularly important to ascertain the relationship between neurophysiological and psychoacoustic measures because there are many individuals for whom it is difficult to obtain behavioral responses. In the proposed study we will evaluate the effect of sensorineural hearing loss on processing of interaural intensity differences (IIDs) and determine the relationship between neurophysiological and behavioral measures of sensitivity to IIDs. Results will provide the information necessary to assess binaural processing of IIDs and to develop remediation strategies for individuals with sensorineural hearing loss.

Guoqiang Wan, Ph.D.

Guoqiang Wan, Ph.D.

University of Michigan
Functions of supporting cell-derived neurotrophin-3 in noise-induced hearing loss

Emerging evidence shows that “benign” noise levels, initially thought to only result in temporary hearing impairment, can cause irreversible damage to the connections between hair cells the auditory neurons, and the synapses, which can lead to a permanent hearing decrease later in life. Currently, we have a limited understanding of how these synapses are maintained in the healthy cochlea and how they can be regenerated after noise overexposure. The overall goal of this study is to examine the potential of the neurotrophic factor, neurotrophin-3 (NT-3), to assist in preserving or regenerating these synaptic connections in cochlea after noise overexposure. We have generated genetic mouse models that allow us to remove or overproduce NT-3 from the supporting cells, which are the cells surrounding the sensory hair cells. We have found that NT-3 produced from the supporting cells is critical for regulation of hearing sensitivity and synaptic density in the cochlea. Based on this finding, we propose that NT-3 may present a novel therapeutic agent for NIHL. In this proposal, we will use these mouse models to address the following questions: does removing NT-3 exacerbate the damage to the loss of synapses and hearing sensitivity after noise overexposure? Does overproducing NT-3 prevent or promote recovery from noise-induced loss of synapses and hearing? These experiments will provide us with a better understanding of the pathophysiology of NIHL and the potential of neurotrophin-based therapeutics for treating hearing loss.

Bryan Ward, M.D.

Bryan Ward, M.D.

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.

Patricia A. White, Ph.D.

Patricia A. White, Ph.D.

House Ear Institute

“Forkhead box o” transcription factors and mammalian cochlear regeneration

To restore hearing to the deaf will require an understanding of the genes that regulate proliferation of adult supporting cells. While tumor suppressors, such as Cdkn1b, have well described functions in the cochlea, upstream regulators of such genes are not understood. White’s research will characterize the expression and function of Foxo3 (Forkhead box O3), a candidate regulator of Cdkn1b, in supporting cells.

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Ross Williamson, Ph.D.

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Ross Williamson, Ph.D.

University of Pittsburgh
Characterizing tinnitus-induced changes in auditory corticofugal networks

The irrepressible perception of sounds without an external sound source is a symptom that is present in a number of different auditory dysfunctions. It is the primary complaint of tinnitus sufferers, who report significant “ringing” in the ears, and it is one of the primary sensory symptoms present in schizophrenia sufferers who “hear voices.” Tinnitus is thought to reflect a disorder in gain: A loss of input at the periphery shifts the balance of excitation and inhibition throughout the auditory hierarchy leading to excess hyperexcitability, which then leads to the perception of phantom sounds. This project aims to quantify how such “phantom sound” signals are routed and broadcast across the entire brain, and to understand how these signals impact our ability to perceive sound. Identifying improper regulation of brain-wide neural circuits in this way will provide a foundation for the development of new treatments for tinnitus and other hearing disorders.

Daniel Winkowski, Ph.D.

Daniel Winkowski, Ph.D.

University of Maryland
Noise trauma induced reorganization of the auditory cortex

Tinnitus (‘ringing in the ears’) is a debilitating condition that is experienced by millions of people worldwide. Tinnitus is frequently seen after noise trauma to the ear. One of the core hypotheses of the etiology of tinnitus is that the percept of ‘ringing in the ears’ is generated by changes in patterns of neural activity in brain circuits at many levels of the auditory pathway. One brain area thought to be at least partly responsible for the tinnitus percept is the primary auditory cortex (A1). However, the precise changes in neural activity within local neuron populations have not been investigated directly. The goal of the proposed project is to probe how noise trauma affects both large- and local-scale organization of A1 brain circuits with unprecedented spatial and cellular resolution in an animal model of tinnitus. Proposed experiments will use state-of-the-art optical imaging approaches to investigate how entire auditory cortical areas (large-scale) and auditory cortical microcircuits (local-scale) are disrupted by noise trauma. A multi-level understanding of circuit dynamics underlying tinnitus (from single neurons to complete representations) will enhance our understanding of precisely how cortical circuits remodel after noise trauma and, in turn, develop and identify strategies by which this debilitating condition can be repaired.

Victor Wong, Ph.D.

Victor Wong, Ph.D.

Burke Neurological Institute, Weill Cornell Medicine
Targeting tubulin acetylation in spiral ganglion neurons for the treatment of hearing loss

Both the success of cochlear implants and of future therapeutic approaches critically depend on the integrity of spiral ganglion neurons and the availability of functional neurites (axons) for direct stimulation. Since very little is known about how to promote spiral ganglion neuron neurite growth, there is a critical need to understand how to reinforce these peripheral neurites to regenerate. Many of the molecular players that facilitate regeneration have been characterized in both the peripheral and central nervous systems. Among these are microtubules, which are a major mediator of the overall extension, consolidation, and navigation of the growing axon. In addition to providing structural support for the growth and targeting of axons, microtubules make up the major molecular “tracks” for transporting cargoes necessary for proper neurite function and growth. α-Tubulin, a major component of these tracks, can undergo a number of post-translational modifications which alter stability, intracellular transport, and axonal growth. α-Tubulin acetylation is an attractive target in particular since α-tubulin acetylation-promoting drugs have been found to increase neurite growth in injured neurons and to promote movement of intracellular cargoes such as mitochondria and mRNA. This project will examine how enhancing α-tubulin acetylation can alter the course of functional repair and regeneration of the molecular tracks after age-related and noise-induced hearing loss, thereby restoring auditory function.

Megan Beers Wood, Ph.D.

Megan Beers Wood, Ph.D.

Johns Hopkins University School of Medicine
Type II auditory nerve fibers as instigators of the cochlear immune response after acoustic trauma

A subset of patients with hyperacusis experience pain in the presence of typically tolerated sound. Little is known about the origin of this pain. One hypothesis is that the type II auditory nerve fibers (type II neurons) of the inner ear may act as pain receptors after exposure to damaging levels of noise (acoustic damage). Our lab has shown that type II neurons share key characteristics with pain neurons: They respond to tissue damage; they are hyperactive after acoustic damage; and they express genes similar to pain neurons, such as the gene for CGRP-alpha. However, type II neurons are not the only cell types that respond to acoustic damage. The immune system responds quickly after damaging noise exposure. In other systems of the body such as the skin, CGRP-alpha can affect immune cell function. This project looks at the expression of CGRP-alpha in type II neurons after noise exposure. CGRP-alpha will be blocked during noise exposure to see if this affects the immune response to tissue damage.

Julian R A Wooltorton, Ph.D.

Julian R A Wooltorton, Ph.D.

University of Pennsylvania

Probing the inner hair cell bundle displacement-quantal synaptic response transfer function

How do submicron displacements of hair bundles on inner hair cells lead to a neural code perceived as sound? This proposal investigates the critical relationship (or transfer function) between hair bundle displacements and afferent fiber bouton responses in the gerbil cochlea. Understanding how we encode the acoustic wave into sound is vital to hearing research. By investigating the relationship between the response to acoustic waves of sensory cells in the cochlea and the resulting postsynaptic neuronal response, we will provide vital information on how the first synapse in the auditory pathway works. This is the basic step carried out by cochlear prostheses. Further insight into the biological details of this encoding step promise new insight into how to improve the design and performance of cochlear prostheses, and help to further ameliorate hearing loss and deafness. Mechanical energy of an acoustic wave enters the ear en route to the cochlea where it is translated into the electrical signals of the auditory nerve. This process involves numerous steps dependent upon the unique architecture of the mammalian ear and various specialized cellular processes to maintain fidelity in reporting frequency, amplitude, timing, and range of auditory stimuli. The inner hair cell processes acoustic waves in the cochlea. A hair bundle atop this cell senses acoustic stimulus and allows current to flow into the hair cell. This ultimately results in neurotransmitter release onto an afferent fiber bouton and subsequent sound perception. One of the true wonders of the biological world is the ability of the auditory system to detect the nearly molecular scale displacements of the hair bundle that result from acoustic wave stimulation. How these tiny displacements lead to a neural code that we perceive as sound is poorly understood. In this application, we propose to define the quantitative relationship (transfer function) between inner hair cell bundle displacement and the quantal response in the afferent fiber bouton.

Calvin Wu, Ph.D.

Calvin Wu, Ph.D.

University of Michigan
Development and transmission of the tinnitus neural code

Noise overexposure is a common risk factor of tinnitus, and is thus used as a common tinnitus inducer in animal research. However, noise exposure does not always cause tinnitus, and researchers would rely on behavioral testing to infer an animal’s subjective pathology. However, behavioral tests only work under the assumption that tinnitus is unchanging during the long testing period, which does not reflect the dynamic nature of tinnitus as well as ignoring variability. This inability to measure tinnitus within a short time window impedes our understanding of its emergence and progression. The project addresses these limitations through bypassing behavioral testing and directly identifying and locating an objective code for tinnitus in real-time spiking neurons. Using a novel data-driven approach, we can pinpoint exactly when/where tinnitus emerges and examine how noise trauma triggers and transmits the tinnitus signal throughout the auditory pathway.

Hsiao-Huei (Juli) Wu, Ph.D.

Hsiao-Huei (Juli) Wu, Ph.D.

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Ruili Xie, Ph.D.

Ruili Xie, Ph.D.

University of North Carolina at Chapel Hill

Synaptic transmission in the principal cells of the anteroventral cochlear nucleus during age-related hearing loss

Age-related hearing loss (AHL) is a common disorder that affects most individuals as they age and causes conditions from deteriorated hearing sensitivity to complete deafness. Anatomical and physiological changes in the auditory system during AHL underlie the perceptual loss of hearing. Changes in cochlear nucleus, which is the first processing center of the central auditory system, are of special interest in studying AHL. However, little is known about the changes of synaptic transmission in principal cells of the cochlear nucleus during AHL except a pioneering study from this lab. This project will utilize DBA/2j mice as the animal model for AHL to study the changes of synaptic transmission in principal cells of anteroventral cochlear nucleus (AVCN) during AHL. Specifically, the study will use whole-cell recording techniques to evaluate the glycinergic transmission in bushy cells as well as both glycinergic and glutamatergic transmission in stellate cells of the AVCN in brain slices prepared from DBA/2j mice at three age groups, which represent three different developmental stages of AHL (normal hearing, intermediate hearing loss, and complete hearing loss). The study seeks to identify physiological changes in synaptic transmission in the principal cells of AVCN during AHL that may underlie the perceptual loss of hearing.

Kathleen T. Yee, Ph.D.

Kathleen T. Yee, Ph.D.

Tufts University School of Medicine

The role of Neuregulin1 signaling in the developing cochlear nucleus

The long-term objective of this study is to understand the genetics of cochlear nucleus neuronal differentiation and specification to examine how information-transmitting cells in the brain (neurons) obtain their identity and acquire specific characteristics that endow them to perform very specific functions.

Eunyoung Yi, Ph.D.

Eunyoung Yi, Ph.D.

Johns Hopkins University School of Medicine

Dopaminergic modulation of inner hair cell afferent synaptic transmission

In the inner ear, the inner hair cells convert sound information into electrical signals. Auditory nerve fibers pick up information from the hair cells via the hair cell afferent synapse and transmit the sound signal to the brain. Interesting, auditory nerve fiber activity can be modulated by feedback mechanisms from the brain. Lateral efferent fibers originating in the auditory brainstem innervate auditory nerve fibers at their endings, directly where they contact the inner hair cells. Dopamine is one of the neurotransmitters found in lateral efferent endings and dopamine release is thought to provide a protective role against noise-trauma. However, the cellular mechanisms underlying this process are not well understood. In this project, we will use histological techniques to identify the cellular locations and subtypes of dopamine receptors at the inner hair cell afferent synapse. We will also use electrophysiological techniques to measure electrical impulses in auditory nerve fiber endings at the hair cell afferent synapse in an excised cochlear preparation. We will apply drugs that specifically imitate or inhibit the actions of dopamine, and investigate the mechanisms and intracellular targets by which dopamine receptors modulate the signals at the inner hair cell afferent synapse.

Yasheng Yuan, Ph.D.

Yasheng Yuan, Ph.D.

Massachusetts Eye and Ear Infirmary
Regeneration of auditory neurons using stem cells

Hearing loss is usually permanent, and there are no effective interventions available to reverse symptoms by repair of damage. The overall goal of this research is to develop a cell-based therapy to replace auditory neurons. We have shown that neural progenitor cells derived from mouse embryonic stem (ES) cells transplanted into the auditory nerve send out fibers that grow to hair cells and to the cochlear nucleus. In this proposal, we will specifically address this issue through the use of a new mouse ES cell line for tracing the grafted cells and new procedures for detection of the synapses. We will connect the location of the new synapses with auditory function throughout the frequency range of the cochlea. Our study is composed of two related, specific aims. In the first aim we will assess auditory function after cell transplantation. In the second aim we will connect the synaptic counts to functional improvement in specific frequency regions.

Research areas: sensorineural hearing loss, stem cells and regeneration

Long-term goal of research: to find biological treatments for hearing loss. Hearing loss has lifelong consequences for individuals and their family. Hearing is mediated by hair cells, which convert sound vibrations into electric signals that are conveyed to the brain through the auditory nerve. Damage to hair cells and the auditory nerve result in hearing loss. Since mammals lack the regenerative capacity to replace hair cells and auditory nerve, hearing loss is usually permanent and there is no effective intervention to reverse the loss of these cells. Our previous work has demonstrated that neurons derived from stem cells can survive and re-innervate the cochlea. The proposed work will investigate a new approach to cell transplantation that will allow us to directly measure cell replacement and its effect on hearing.

Xiping Zhan, Ph.D.

Xiping Zhan, Ph.D.

Howard University
Dopaminergic activity in modulation of noise-induced tinnitus

Tinnitus is a major challenge for public health because it is a condition that is associated with hearing loss and can contribute to debilitating emotional stress, anxiety, and mental fatigue. Dr. Zhan’s interest is focused on the mechanisms that generate tinnitus and modulate tinnitus associated anxiety and depression using an animal model. His studies focus on dopaminergic activity in the limbic midbrain. Dopamine and its receptors play an important role in human mood behavior. Recently, dopamine has been suggested to be involved in tinnitus. Dr. Zhan’s research is designed to find out how dopamine neurons are communicating with other neurons to contribute to tinnitus generation. In addition, he also investigates how the functions of dopamine cells are modified during the development of tinnitus following noise exposures. These studies will shed light on the cellular mechanisms of tinnitus and offer a novel avenue for drug therapy.

Ning Zhou, Ph.D.

Ning Zhou, Ph.D.

East Carolina University
Place specificity of electrical stimulation with a cochlear implant and its relationship to neural survival and speech recognition

Modern cochlear implants code a speech signal by dividing it into spectral channels and modulating trains of biphasic electrical pulses with the low-frequency temporal envelope from each channel. Perception with a cochlear implant therefore is dependent on two factors: the acuity of processing the low frequency amplitude modulations and the place specificity of excitation. Cochlear implant users have demonstrated amplitude modulation detection similar to that found in normal hearing ears with larger individual variability, nonetheless the challenge of the prosthesis lies with the poor place specificity. Ideally, the output of an electrode should target a specific population of nerve fibers. However spread of excitation is often large, leading to neural interactions between channels. The first aim of the research is to investigate whether the underlying cause of channel interaction is the status of neural survival near the stimulation sites. The hypothesis is that excitation is more likely to spread further from a stimulation site in the cochlea when the density of surviving spiral ganglion cells is sparse. Neural status of a stimulation site will be estimated using a non-invasive psychophysical measure that correlates with the count of spiral ganglion cells in implanted animals. Place specificity of excitation will be measured by a psychophysical forward-masking procedure that is widely used to assess spatial tuning in electrical hearing. The second aim of the research is to examine the effects of place specificity on speech perception that requires mainly the spectral cues. The rationale is that poor place specificity would cause a reduction in spectral resolution or smearing of spectral speech cues. Proposed speech recognition tasks that demand good spatial tuning are perception of sine-wave speech, also known as the spectral skeleton of speech, and perception of speech presented in background noises.

Research area: Cochlear Implants

Long-term goal of research: If the proposed hypothesis is correct, that is, poor neural survival predicts poor spatial tuning, we will seek to ask the question whether the temporal processing acuity of the activated neurons at the site with low cell density would also be compromised. Once the relationship between temporal and spatial acuity is determined, we will examine the relative importance of the temporal and spatial acuity for speech recognition. The two acuities might not be equally important, or that they might be contributing to different aspects of speech recognition. With this information, the long term goal is to optimize implant user’s speech processing MAPs by strengthening the perception acuity that is the most important for speech recognition in the ear.

Junhuang Zou, Ph.D.

Junhuang Zou, Ph.D.

University of Utah
Understanding the function of PDZD7 in hair cells

Usher syndrome is a devastating genetic disease affecting both hearing and vision. It is the leading genetic cause of combined deafness and blindness in the world. Usher syndrome is clinically and genetically heterozygous. It is classified into three clinical types according to the severity of hearing and vestibular symptoms. Zou's studies focus on type 2, which is the dominant form of Usher syndrome and characterized by congenital moderate degree of hearing loss, normal vestibular function, and retinitis pigmentosa. PDZD7 was recently reported to exacerbate the symptoms and contribute the digenic form of Usher syndrome type 2 when patients carry heterozygous PDZD7 mutations. Zou has successfully generated a Pdzd7 knockout mouse. Using this animal model, Zou plans to investigate the function of PDZD7 during hair bundle development in the cochlea. This study will be significant for the future diagnosis and treatments for Usher syndrome type 2.

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