Medical University of South Carolina
Age and hearing loss effects on subcortical envelope encoding
Generously funded by Royal Arch Research Assistance
Elizabeth McCullagh, Ph.D.
University of Colorado
The role of the MNTB in sound localization impairments in autism spectrum disorder
The processing of sound location and the establishment of spatial channels to separate several simultaneous sounds is critical for social interaction, such as carrying on a conversation in a noisy room or focusing on a person speaking. Impairments in sound localization can often result in central auditory processing disorders (CAPD). A form of CAPD is also observed clinically in all autism spectrum disorders, and is a significant to quality-of-life issues in autistic patients.
The circuit in charge of initially localizing sound sources and establishing spatial channels is located in the auditory brain stem and functions with precisely integrated neural excitation and inhibition. A recent theory posits that autism may be caused by an imbalance of excitatory and inhibitory synapses, particularly in sensory systems. An imbalance of excitation and inhibition would lead to a decreased ability to separate competing sound sources. While the current excitation to inhibition model of autism assumes that most inhibition in the brain is GABAergic, the sound localization pathway in the brainstem functions primarily with temporally faster and more precise glycinergic inhibition.
The role of glycinergic inhibition has never been studied in autism disorders, and could be a crucial component of altered synaptic processing in autism. The brainstem is a good model to address this question since the primary form of inhibition is through glycine, and the ratio of excitation to inhibition is crucial for normal processing.
Melissa McGovern, Ph.D.
University of Pittsburgh
Hair cell regeneration in the mature cochlea: investigating new models to reprogram cochlear epithelial cells into hair cells
Sensory hair cells in the inner ear detect mechanical auditory stimulation and convert it into a signal that the brain can interpret. Hair cells are susceptible to damage from loud noises and some medications. Our lab investigates the ability of nonsensory cells in our inner ears to be able to regenerate lost hair cells. We regenerate cells in the ear by converting nonsensory cells into sensory cells through genetic reprogramming. Key hair cell-inducing program genes are expressed in non-hair cells and partially convert them into hair cells. There are multiple types of nonsensory cells in the inner ear and they are all important for different reasons. In addition, they are in different locations relative to the sensory hair cells. In order to better understand the ability of different groups of cells to restore hearing, we need to be able to isolate different populations of cells. The funded project will allow us to create a new model to target specific nonsensory cells within the inner ear to better understand how these cells can be converted into hair cells. By using this new model, we can specifically investigate cells near the sensory hair cells and understand how they can be reprogrammed. Our lab is also very interested in how the partial loss of genes in the inner ear can affect cellular identities. In addition to targeting specific cells in the ear, we will investigate whether the partial loss of a protein in nonsensory cells may improve their ability to be converted into sensory cells. This information will allow us to further explore possible therapeutic targets for hearing restoration.
Kathleen McNerney, Ph.D.
University at Buffalo, SUNY
The vestibular evoked myogenic potential: unanswered questions regarding stimulus and recording parameters
The vestibular evoked myogenic potential (VEMP) is a response that can be recorded from the sternocleidomastoid (SCM) muscle as well as other neck muscles such as the trapezius. It is believed to be generated by the saccule, which is a part of our vestibular system that is normally responsible for our sense of balance. Recent studies have shown that it is also responsive to sound. Three types of stimuli that are used to elicit the VEMP are air-conducted (AC) stimuli, bone-conducted (BC) stimuli, and galvanic (electrical) stimuli. Although there are several universal findings that have held true throughout previous studies, there are several questions which remain unanswered. The present study will attempt to address these issues by making a direct comparison between the three types of stimuli listed above, within the same subjects. In addition, input/output functions will be defined for all three types of stimuli. Finally, we will be looking at the repeatability of the three types of stimuli across subjects as well as address the inconsistencies that have been found between monaural and binaural stimulation. This study will not only provide us with a better understanding of the VEMP, it will also enhance its clinical utility.
Anahita Mehta, Ph.D.
University of Michigan
Effects of age on interactions of acoustic features with timing judgments in auditory sequences
Imagine being at a busy party where everyone is talking at once, yet you can still focus on your friend’s voice. This ability to discern important sounds from noise involves integrating different features, such as the pitch (how high or low a sound is), location, and timing of these sounds. As we age, even with good hearing, this integration may become harder, affecting our ability to understand speech in noisy environments. Our brains must combine these features to make sense of our surroundings, a process known as feature integration. However, it’s not entirely clear how these features interact, especially when they conflict. For example, how does our brain handle mixed signals regarding pitch and sound location?
Previous research shows that when cues from different senses, like hearing and sight, occur simultaneously, our performance improves. But if they are out of sync, it becomes harder. Less is known about how our brains integrate conflicting cues within the same sense, such as pitch and spatial location in hearing. Our study aims to explore how this ability changes with age and develop a simple test that could be used as an easy task of feature integration, especially for older adults. This research may lead to better rehabilitation strategies, making everyday listening tasks easier for everyone.
Frances Meredith, Ph.D.
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.
Iain M. Miller, Ph.D.
Ohio University
The distribution of glutamate receptors in the turtle utricle: a confocal and electron microscope study
When stimulated by acceleration and head tilt (gravity), sensory hair cells in the turtle utricle, an organ in the inner ear, transmit information about these stimuli to the brain. The long term goal of this research is to understand what role synaptic structure and composition play in the observed spatially heterogeneous and diverse discharge properties of afferents supplying the vestibular end organs, and in particular, the utricle. This knowledge is central for accurate diagnosis and rational treatment strategies for vestibular dysfunction.
Srikanta Mishra, Ph.D.
New Mexico State University
Medial Efferent Mechanisms in Auditory Processing Disorders
Many individuals experience listening difficulty in background noise despite clinically normal hearing and no obvious auditory pathology. This condition has often received a clinical label called auditory processing disorder (APD). However, the mechanisms and pathophysiology of APD are poorly understood. One mechanism thought to aid in listening-in-noise is the medial olivocochlear (MOC) inhibition— a part of the descending auditory system. The purpose of this translational project is to evaluate whether the functioning of the MOC system is altered in individuals with APD. The benefits of measuring MOC inhibition in individuals with APD are twofold: 1) it could be useful to better define APD and identify its potential mechanisms, and 2) it may elucidate the functional significance of MOC efferents in listening in complex environments. The potential role of the MOC system in APD pathophysiology, should it be confirmed, would be of significant clinical interest because current APD clinical test batteries lack mechanism-based physiologic tools.
Rahul Mittal, Ph.D.
University of Miami Miller School of Medicine
Deciphering the role of Slc22a4 in the development of stria vascularis, and to determine the effect of supplementation of its antioxidant substrate ergothioneine, on age-related hearing loss
Since mutations in the SLC22 gene family have been implicated in various pathological conditions, there has been a renewed interest in understanding their role in the maintenance of normal physiological functions of cells. SLC22A4 is ubiquitously expressed in the body and transports across the cellular plasma membrane various compounds, including acetylcholine and carnitine as well as the naturally occurring antioxidant ergothioneine (ERGO). In addition, SLC22A4 is abundantly expressed in the stria vascularis (SV), but its role in SV biology is not known.
This project will help in understanding how SLC22A4 contributes to SV development, atrophy, and dysfunction of the cochlea, leading to hearing loss. The project also aims to determine whether ERGO supplementation can prevent SV atrophy and ameliorate age-related hearing loss (presbycusis) in a mouse model.
Sharlen Moore, Ph.D.
Johns Hopkins University
Modulation of neuro-glial cortical networks during tinnitus
My long term goals are to understand the complexity and temporal sequencing of tinnitus effectors with an integrative perspective, considering the interplay of the diverse cell types that might promote the development and maintenance of tinnitus to provide an updated interpretation of this disorder. Additionally, to use glial cells as a key therapeutic target to treat tinnitus.
Generously funded by the Les Paul Foundation
Clive Morgan, Ph.D.
Oregon Health & Science University
Characterization of Usher syndrome 1F protein complexes
Much of our current knowledge on the molecular makeup of the hair bundle has origins in genetic studies. Several key genes have been discovered but are limited to those genes that are absolutely required for hearing and dispensable in other systems. Many independent genetic mutations also occur in a handful of genes, so that finding new genes can be quite difficult and expensive. My colleague Peter Barr-Gillespie, Ph.D., has pioneered the use of hair bundle isolation techniques to allow studies of the hair bundle proteome, allowing us to uncover many of the features of the hair bundle in single experiments. The next step is to look at how these proteins interact to fulfill the functions of a mechanically sensitive hair bundle and the effects of genetic abnormalities on the whole bundle proteome (set of proteins). In this project I will analyze individual protein complexes using a new hair bundle isolation strategy that allows us to isolate and analyze protein complexes from the hair bundle. I will perform a comparative analysis of the makeup of all Usher syndrome protein complexes. This will shed new light on the proteins involved directly in mechanotransduction.
Bruna Mussoi, Au.D., Ph.D.
University of Tennessee
Auditory neuroplasticity following experience with cochlear implants
Cochlear implants provide several benefits to older adults, though the amount of benefit varies across people. The greatest improvements in speech understanding abilities usually happen within the first 6 months after implantation. It is generally accepted that these gains in performance are a result of neural changes in the auditory system, but while there is strong evidence of neural changes following cochlear implantation in children, there is limited evidence in adults with hearing loss in both ears. This study will examine how neural responses change as a function of the amount of cochlear implant use, when compared to longstanding hearing aid use. Listeners who are candidates for a cochlear implant (who either decide to pursue implantation or to keep wearing hearing aids) will be tested at several time points, from pre-implantation and up to 6 months after implantation. The results of this project will improve our understanding of the impact of cochlear implant use on neural responses in older adults, and their relationship with the ability to understand speech.
Mirna Mustapha-Chaib, Ph.D.
University of Michigan
Determine the functional role of the unique amino terminus of MYO15 in hearing using genetically engineered mice
Assessing the role of the N-terminus of MYO15 in structural development of hair cells and in the neurosensory process of hearing is expected to provide basic information about the process of hearing at the molecular level. Long term, we expect proteins that interact with the N-terminus of MYO15 will also be defective in some forms of hearing loss. Models similar to the one we propose have been used as proof of principle for gene therapy. Mutations in humans indicate that the N-terminal portion of MYO15 is required in some way for hearing. Using our resources and experience in genetically engineered mice will advance the understanding of the specific molecular function of the N-terminus of Myo15 in mammalian hearing and determine the consequences on morphological development and signal transduction within the cochlear hair cells. Thus, these studies will immediately make a contribution to the rapidly advancing field of molecular hearing research. The next step will be to identify the proteins that interact with the N-terminus, screen pedigrees for mutations in these genes and work towards therapeutic intervention for genes that are common causes of deafness.
Vijaya Prakash Krishnan Muthaiah, Ph.D.
University at Buffalo, the State University of New York
Potential of inhibition of poly ADP-ribose polymerase as a therapeutic approach in blast-induced cochlear and brain injury
Many potential drugs in the preclinical phase for treating different types of noise-induced hearing loss (from blast and non-blast noise) revolve around targeting oxidative stress or interfering in the cell death cascade. Though noise-induced oxidative stress and cell death is well studied in the auditory periphery, the effects of noise exposure on the central auditory system remains understudied, especially in blast noise exposure where both auditory and non-auditory structures in the brain are affected. Impulsive noise (blast wave)-induced hearing loss is different from continuous noise exposure as it is more likely to be accompanied by accelerated cognitive deficits, depression, anxiety, dementia, and brain atrophy. It is well established that poly ADP-ribose polymerase (PARP) is a key mediator of cell death and it is overactivated by oxidative stress. Thus this project will explore the potential of PARP inhibition as a potential therapeutic approach for blast-induced cochlear and brain injury. The dampening of PARP overactivation by its inhibitor 3-aminobenzamide is expected to both mitigate blast noise-induced oxidative stress and to interfere with the cell death cascade, thereby reducing cell death in both the peripheral and central auditory system.
Gowri Nayak, Ph.D.
Cincinnati Children’s Hospital Medical Center
Signaling defects due to Tricellulin deficiency
Mutations in a protein called Tricellulin lead to hereditary hearing loss in humans and degeneration of cochlear sensory cells and deafness in mice. In the inner ear, Tricellulin is found in the sensory epithelia at sites where three epithelial cells meet. The localization of Tricellulin at the junction between cells gives it the potential to respond to external cues and transmit the signals to the cell interior. The current project aims at uncovering the potential cellular signaling roles of Tricellulin by determining the gene expression changes in the inner ear of Tricellulin mutant mice compared to wild-type mice. The results of this study will not only add to the existing knowledge of the inner ear development and maintenance but also will examine the direct effects of losing a protein that helps preserve our hearing.
Research area: Fundamental Auditory Research
Long-term goal of research: To determine the role of cell junction proteins in the inner ear function and elucidate the biological processes that are affected by genetic mutations in these proteins. As tight junctions are also the focus of drug delivery studies, it is valuable to realize the cellular functions of the associated proteins so that they can be manipulated for therapeutic purposes.
Tenzin Ngodup, Ph.D.
Oregon Health & Science University
Discovery of novel inhibitory cell types in the cochlear nucleus
Excessive neuronal electrical activity, or hyperactivity, is believed to underlie tinnitus. While many studies on hyperactivity have focused on a region called the dorsal cochlear nucleus, an auditory processing region in the brainstem, very little attention has been given to the ventral cochlear nucleus (VCN). This is surprising since the VCN is likely required for the activation of higher auditory centers in the brain. One likely cause of hyperexcitability is an imbalance between excitatory and inhibitory neuronal connections, or synapses. With the use of genetically modified mouse lines, we are able to reveal that the diversity of inhibitory cell types and circuitry within the VCN is far richer than previously described. Our primary goal is to discover and study the functional significance of these novel inhibitory neurons in the VCN whose inhibitory action, if compromised, could lead to hyperactivity and auditory dysfunction.
Kirill Vadimovich Nourski, M.D., Ph.D.
University of Iowa
Temporal Processing in the Human Auditory Cortex
My research area is the function of the auditory cortex—the hearing center in the brain. Some neurosurgical patients undergo an operation in which arrays of electrodes are temporarily implanted in the brain for clinical diagnostic purposes. This provides a unique opportunity to study how the auditory cortex works, by measuring its activity (“brain waves”) directly from the brain. My personal project involves measuring the brain’s responses to the timing information of sounds and the ability of the brain to accurately follow this timing and use this information to build a coherent percept of the environment. I want to understand where and how, specifically, timing cues are processed in the auditory cortex. Patients with cochlear implants are largely dependent on timing and rhythm cues to understand speech and communicate. On the other hand, people who have auditory processing disorders, may be impaired in their ability to process that kind of information. In order to come up with new ways of assisting people with auditory processing disorders, it’s important to understand how the timing and rhythm of speech is usually handled by the brain.
Research area: fundamental auditory research
Long-term goal of research: Beyond this study, my long term goal is to better understand how the different areas that comprise the auditory cortex in humans are organized and what specific roles they play in processing information about sounds, particularly, as it relates to perception of speech. Ultimately, this knowledge will contribute to finding new and/or improved solutions for people with hearing loss and auditory processing disorders.
Kevin K. Ohlemiller, Ph.D.
Washington University
Cellular and Genetic Bases of Age-Associated Strial Degeneration and EP decline in NOD congenic mice
The electric currents that run through cochlear sensory cells are largely driven by a specialized cochlear structure called the stria vascularis. The work of the stria requires a lot of energy, so that it is densely vascularized (hence the name). Loss of strial blood vessels is thought to be a common cause of age-related hearing loss. Not everyone shows signs of this kind of pathology, however, so that there must be forms of certain genes carried by some people that act as ‘risk’ genes. People who carry ‘risk’ genes may be more likely to experience loss of strial blood vessels, and ultimately loss of the stria itself. In 2008 we discovered that a particular breed of mice (NOD mice) start out with a normal stria, but then show loss of strial vessels, followed by loss of the stria beginning from both ends of the cochlea and progressing toward the middle. These changes were accompanied by other distinctive anatomic features that may tell us something about the process, or may be unrelated. By crossing these mice with another strain that does not show pathology, we will be able to determine what pathologic features are inherited together (thus caused by the same genes), how many genes are involved, and their approximate locations. Any gene(s) we find may have human counterparts that exert similar effects.
Research areas: auditory physiology/pathophysiology, cell biology of hearing and deafness
Long-term goal of research: Finding ‘risk’ genes may not point directly to cures or allow us to predict who will lose their hearing. Nevertheless, identifying the genes, gene networks, and gene products will help pinpoint key reactions that can be tweaked pharmacologically. We are among the first to seek out mouse strains with pathology of the stria vascularis and to use these to uncover genes that promote strial degeneration in mice, and possibly in humans.
Peihan Orestes, Ph.D.
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.
Carolyn P. Ojano-Dirain, Ph.D.
University of Florida College of Medicine
Prevention of aminoglycoside-induced hearing loss with the mitochondria-targeted antioxidant MitoQ
Aminoglycoside antibiotics, such as gentamicin, are commonly used to treat serious infections due to bacteria. However, these drugs can cause hearing loss. At present, there is no solution to prevent hearing loss caused by aminoglycoside antibiotics. This research will determine if the antioxidant MitoQ will prevent hearing loss induced by aminoglycoside antibiotics.
Research area: Hearing loss, Ototoxicity
Long-term goal of research: To develop and apply practicable intervention strategies to prevent hearing loss induced by drugs that are toxic to the inner ear.