Takako Kondo, Ph.D.

Takako Kondo, Ph.D.

Indiana University School of Medicine

Role of T1x3 signaling in inner ear sensory neuron development

The primary goal of this study is to elucidate novel functions of the Y1x3-class homeobox gene 3 (T1x3) in the development of inner ear sensory neurons. The specific aims in this study are: (1) To test whether T1x3 is required for normal development of inner ear sensory neurons, and (2) To test whether T1x3 is sufficient for multipotent progenitor cells in the early embryonic ear to become competent to commit to a glutamatergic neural subtype. The long-term goal of this study is to clearly understand the molecular mechanisms underlying specification of auditory and vestibular neurons.

Manoj Kumar, Ph.D.

Manoj Kumar, Ph.D.

University of Pittsburgh

KCNQ2/3 potassium channel activator mitigates noise-trauma–induced hypersensitivity to sounds
in mice

Noise-induced hearing loss (NIHL) is one of the most common causes of hearing disorders. NIHL reduces the auditory sensory information relayed from the cochlea to the brain, including the primary auditory cortex (A1). To compensate for reduced peripheral sensory input, A1 undergoes homeostatic plasticity. Namely, the sound-evoked activity of A1 excitatory principal neurons (PNs) recovers or even surpasses pre-noise trauma levels and exhibits increased response gain (the slope of neuronal responses against sound levels). This increased gain of A1 PNs after NIHL is associated with highly debilitating hearing disorders, such as tinnitus (perception of phantom sounds), hyperacusis (painful perception of sounds), and hypersensitivity to sounds (increased sensitivity to everyday sounds). Despite the high prevalence of these hearing disorders, treatment options are limited to cognitive behavioral therapy and hearing prosthetics with no FDA-approved pharmacotherapeutic options available. Therefore, to aid in the development of pharmacotherapeutic options, it is imperative to 1) develop animal models of these hearing disorders, 2) identify the brain plasticity underlying these hearing disorders, and 3) test potential pharmacotherapy to rehabilitate hearing and brain plasticity after NIHL. Here, we aim to develop a novel mouse model of hypersensitivity to sounds, identify its underlying A1 plasticity, and test pharmacotherapy to mitigate it after NIHL.

Manoj Kumar, Ph.D.

Manoj Kumar, Ph.D.

University of Pittsburgh
Signaling mechanisms of auditory cortex plasticity after noise-induced hearing loss

Exposure to loud noises is the most common cause of hearing loss, which can also lead to hyperacusis and tinnitus. Despite the high prevalence and adverse consequences of noise-induced hearing loss (NIHL), treatment options are limited to cognitive behavioral therapy and hearing prosthetics. Therefore, to aid in the development of pharmacotherapeutic or rehabilitative treatment options for impaired hearing after NIHL, it is imperative to identify the precise signaling mechanisms underlying the auditory cortex plasticity after NIHL. It is well established that reduced GABAergic signaling contributes to the plasticity of the auditory cortex after the onset of NIHL. However, the role and the timing of plasticity of the different subtypes of GABAergic inhibitory neurons remain unknown. Here, we will employ in vivo two-photon Ca2+ imaging and track the different subtypes of GABAergic inhibitory neurons after NIHL at single-cell resolution in awake mice. Determining the inhibitory circuit mechanisms underlying the plasticity of the auditory cortex after NIHL will reveal novel therapeutic targets for treating and rehabilitating impaired hearing after NIHL. Also, because auditory cortex plasticity is associated with hyperexcitability-related disorders such as tinnitus and hyperacusis, a detailed mechanistic understanding of auditory cortex plasticity will highlight a pathway toward the development of novel treatments for these disorders.

Elliot Kozin, M.D.

Elliot Kozin, M.D.

Massachusetts Eye and Ear, Harvard University
Evaluation of hearing loss and quality of life in patients with mild traumatic brain injury

This project will focus on auditory dysfunction following head injury, and findings will provide information about the pathophysiology of hearing loss after mild traumatic brain injury (TBI). To date, little has been described on this topic. We aim to assess auditory symptoms and their association with quality-of-life metrics in patients with mild TBI using patient-reported outcome measures. We further plan to analyze objective audiometric tests to understand the nature and severity of auditory dysfunction. Findings will be applied to clinical guidelines that address at-risk patients and the need for monitoring via audiometric testing. We anticipate findings will generate important discussion regarding an often-overlooked area of health effects following head injury.

Kelvin Y. Kwan, Ph.D.

Kelvin Y. Kwan, Ph.D.

Rutgers University
Identification of Transcription Factors for Hair Cell Regeneration

In mammals, when hair cells die from ototoxic drugs or loud noises, they are not replaced. Kwan’s efforts are focused on identifying transcription factors that promote repopulation and replacement of lost sensory hair cells. Transcription factors are DNA binding proteins that play crucial roles in global gene regulation. By repurposing transcription factors that are normally expressed during hair cell development, he plans to promote regeneration by controlled cell division to repopulate lost hair cells before differentiating nascent cells into hair cells.

Research area: hair cell regeneration

Long-term goal of research: To use a cocktail of small molecules that activates expression of transcription factors or their associated signaling pathways in order to promote functional auditory hair cell regeneration and alleviate hearing loss.

Kristy J. Lawton, Ph.D.

Kristy J. Lawton, Ph.D.

Washington State University Vancouver
Characterizing noise-induced synaptic loss in the zebrafish lateral line

Recent findings indicate that noise levels thought to be safe for auditory sensory hair cells may actually damage hearing at the level of peripheral auditory synapses. Little is known about this type of damage, which is usually not detectable using traditional audiograms and so has been dubbed “hidden hearing loss.” This project will study noise-induced hearing loss using zebrafish, where the auditory sensory cells are easily accessible and highly similar to those in humans, in order to uncover mechanisms of synaptic damage due to noise exposure. It will use a combination of techniques including immunohistochemistry and calcium imaging to directly examine the timing and extent of noise damage on peripheral auditory synapses.

Snezana Levic, Ph.D.

Snezana Levic, Ph.D.

University of California Davis

Mechanism of hair cell development and regeneration

Hair cells (HCs) convert sound signals into electrical impulses in the cochlea with remarkable precision and sensitivity. Our long-term goals are to stimulate HC regeneration in human inner ears in a controlled fashion, and to enable the functional innervation of the regenerated HC's by spiral ganglion neurons (SGNs). To do this, the functional mechanisms of the development of HCs must be understood. In the developing systems, there is temporal overlap between ion channel development, spontaneous activity and activity-dependent development. Therefore, APs could serve both intrinsic (ion channel expression) and extrinsic (neuronal refinement) development roles. We have identified differential patterning of APs in the developing cochlear axis that reflects differences in expression of ionic conductances. We will test the prediction that the activity of HCs influenced that of its neighbors, including the preservation of the synaptic transmission between auditory nerve and HCs. The proposed study will increase our understanding of the activity dependent development in the auditory system.

Ben-Zheng Li, Ph.D.

Ben-Zheng Li, Ph.D.

University of Colorado

Alterations in the sound localization pathway resulting in hearing deficits: an optogenetic approach

Sound localization is a key function of the brain that enables individuals to detect and focus on specific sound sources in complex acoustic environments. When spatial hearing is impaired, such as in individuals with central hearing loss, it significantly diminishes the ability to communicate effectively in noisy environments, leading to a reduced quality of life. This research aims to advance our understanding of the neural mechanisms underlying sound localization, focusing on how the brain processes very small differences in the timing of sounds reaching each ear (interaural time differences, or ITDs). These differences are processed by a nucleus of the auditory brainstem called the medial superior olive (MSO), which integrates excitatory and inhibitory inputs from both left and right ears with exceptional temporal precision, allowing for the detection of microsecond-level differences in the time of arrival of sounds. By developing a computational model of this process and validating it through optogenetic manipulation of inhibitory inputs in animal models, this project will provide new insights into how alterations in inhibition and myelination affect sound localization. Ultimately, the goal of this research is to contribute to the development of innovative therapeutic strategies aimed at restoring spatial hearing in individuals with hearing impairments, including those with autism and age-related deficits.

Geng-Lin Li, Ph.D.

Geng-Lin Li, Ph.D.

Oregon Health & Science University

Auditory signal coding at the hair cell ribbon synapses

The sense of hearing starts at hair cells, which connect to afferent fibers via ribbon synapses. Across these synapses, auditory signals contained in graded potentials on hair cells are transformed into all-or-none spikes on afferent fibers. Therefore, these synapses face the tremendous challenge of continuous coding of auditory signals over a remarkable dynamic range. It is not well understood how these specialized synapses achieve their extraordinary ability to release transmitters continuously. This has greatly impaired our ability to treat hearing loss. The long-term objective of this study is to investigate mechanisms of synaptic transmission and strategies for auditory signal coding at this very first chemical synapse along the auditory pathway. In two years, the specific aims are: 1) To study multivesicular release and its mechanisms; 2) To determine how the release of vesicles is transformed to spikes on afferent fibers; 3) To investigate short-term plasticity and how it helps the coding of auditory signals.

Yan Li, Ph.D.

Yan Li, Ph.D.

New York University School of Medicine

Mouse models of human syndromic hearing loss linked to mutant MYH9 alleles

Mutations within the nonmuscle myosin heavy chain type IIA (MYH9) have been linked to human hearing loss. The study will examine the biological role of MYH9 in hearing and the role of its mutant alleles MYH9R702C in hearing loss with the goal of developing and characterizing transgenic mouse models that express the mutant alleles MYH9R702C which is linked to syndromic hereditary hearing loss in humans. Characterizing these mice models will lead to elucidation of the role of MYH9 in hearing and help to development of therapeutic strategies for circumventing hearing loss due to MYH9 mutation.

Harrison W. Lin, M.D.

Harrison W. Lin, M.D.

University of California, Irvine
Objective and subjective suprathreshold measures of auditory neurodegeneration

Recent research on animals convincingly demonstrates that degeneration of the auditory nerve, called auditory neurodegeneration, will result from a brief, moderate noise exposure. These animals suffered from severe, permanent deterioration of the function and microscopic appearance of the auditory nerve from a seemingly short, innocuous noise exposure. Interestingly, the animal’s ability to recognize the presence of sound fully recovered to normal threshold levels following the trauma.

However, when presented with sound levels above their ability to hear (“suprathreshold” levels), the strength of the electric signals from the auditory nerve was reduced by as much as 50 percent in some frequencies. Because standard hearing tests (audiograms) of these noise-exposed animals were indistinguishable from unexposed animals, the phenomenon of auditory neurodegeneration may result in a “hidden hearing loss,” and moreover, play a key role in the development of tinnitus, hyperacusis, and other auditory processing abnormalities.

Many military personnel who are subject to severe noise trauma and blast injuries subsequently develop chronic, oftentimes debilitating, tinnitus, and it is thought that this auditory neurodegeneration phenomenon is at least partially responsible for these symptoms. But auditory neurodegeneration in humans has not been established, and its perceptual consequences, including tinnitus, remain unknown. This project aims to establish the missing link between animal and human studies on auditory neurodegeneration and to provide quantitative and qualitative assessment of perceptual consequences of neurodegeneration.

Patricia A. Loomis, Ph.D.

Patricia A. Loomis, Ph.D.

Rosalind Franklin University of Medicine and Science

Splicing regulation of pre-mRNA generated from the deafness-associated Espin gene

The goal of this proposal is to determine how Espin gene expression is controlled at the level of RNA processing. Loss of function mutational analysis will identify RNA sequences on the Espin pre-mRNA that are essential for alternative splicing reactions. Proteins that bind the regulatory RNA sequences will be identified by UV-cross- linking, Western blotting and immunoprecipitation. Correlation of the in vitro analysis with in vivo activity will be accomplished through modulating by RNAi and overexpression the levels of these proteins in HeLa cells transfected with Espin mini-gene constructs containing genomic sequence corresponding to the alternatively spliced exon and flanking introns.

Sean Eric Low, Ph.D.

Sean Eric Low, Ph.D.

Rockefeller University
Ascertaining the contribution of Piezo proteins to Mechano-transduction in Zebrafish hair cells

The proteins that mediate the transformation of mechanical forces into electrical signals within the sensory cells that convey the senses of hearing and balance have yet to be identified. This lack of knowledge has undoubtedly hindered the identification of therapeutic compounds capable of alleviating the complications that arise from disorders in hearing and balance, such as deafness and vertigo. Recently, a member of the novel piezo protein family has been shown to contribute to cutaneous mechano-sensation, raising the possibility that related family members may contribute to hearing and balance. Dr. Low will utilize the simple vertebrate commonly known as zebrafish, to address this possibility.

Research area: Fundamental Auditory Research

Long term goal of research: To identify therapeutic agents that can restore normal hearing and balance in individuals who have either lost these senses, or suffer from conditions caused by abnormal activity in the sensory cells that mediate them.

Sean Low Ph.D. received a B.S. in Cellular and Molecular Biology in 2001, and a Ph.D. in Neuroscience in 2008 from the University of Michigan. Desiring to focus on sensory transduction, Low sought out a postdoctoral position in the Saint-Amant lab at the University of Montréal from 2009 – 2011, where he examined the role of a Piezo protein in cutaneous mechano-transduction. These studies evolved into an interest in mechano-transduction processes in general, and a second postdoctoral position with Dr. Hudspeth at The Rockefeller University beginning in 2011.

Anat Lubetzky, Ph.D.

Anat Lubetzky, Ph.D.

New York University
A balancing act in hearing and vestibular loss: assessing auditory contribution to multisensory integration for postural control in an immersive virtual environment

Humans are surrounded by sensory information and need to select the most reliable ones in order to maintain balance and disregard input that might make us fall. This is called “weighting” and “reweighting” of sensory inputs. This project uses a virtual reality, head-mounted display (HMD) application to test balance with varying sensory cues, including visual, somatosensory, and auditory. With this application, an individual’s ability to weight and reweight visual and auditory information based on their head and eye movement and their postural sway can be identified. This method has been successfully used in prior studies to test responses to visual changes. The novelty of this project includes: the addition of auditory cues scaled to well-established visual cues; the measurement of head movement via the HMD; and the portability, simplicity, and affordability of the HMD system, which increases the likelihood of future clinical translation of this assessment. In this current pilot study, 12 individuals with unilateral sensorineural hearing loss will be compared with 12 individuals with unilateral peripheral vestibular hypofunction and with 24 healthy controls. Wearing the HMD, they will go through a series of postural tasks with several combinations of visual and auditory cues of two intensity levels while standing on either a stable floor (all somatosensory cues available) or a compliant foam (to reduce somatosensory input). Their postural sway and head movement responses to the stimuli will be calculated, and gaze patterns among the groups will be compared, along with exploring whether changes in eye position can explain changes in head movement.

Hao Luo, M.D., Ph.D.

Hao Luo, M.D., Ph.D.

Wayne State University
Cochlear electrical stimulation-induced tinnitus suppression and related neural activity change in the rat inferior colliculus

Tinnitus is a prevalent public health problem that affects millions of people and imposes a significant economic burden on society. Cochlear electrical stimulation (CES) is one promising treatment for managing tinnitus. However, little is known about the underlying mechanisms of CES-induced tinnitus suppression. In addition, electrode insertion during surgery can cause acute tissue trauma and cell losses, initiating programmed cell death within the damaged tissue of the cochlea. Recently, we demonstrated that cochlear stimulation suppressed tinnitus-like behaviors in rats, which is accompanied with tinnitus-related neural activity changes. We therefore suggest that CES-induced tinnitus suppression would be more robust when hearing is protected from implant trauma by intra-cochlear application of AM-111, a novel enzyme inhibitor.

Ngoc-Nhi Luu, M.D., Dr. Med

Ngoc-Nhi Luu, M.D., Dr. Med

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.

Ross Maddox, Ph.D.

Ross Maddox, Ph.D.

University of Washington
Relating behavior to brain in an audio-visual scene

Every day, listeners are presented with a barrage of sensory information in multiple sensory modalities. This can be overwhelming, but it also can allow for redundant information to be combined across the senses. This binding is well documented, but not well understood. Behavioral tests and brain imaging (magneto- and electroencephalography) will be used to study the brain activity associated with combing visual and auditory information. Particular interests include how congruent timing in auditory and visual stimuli allows them to be combined into a single sensory object, and what benefits this has for the listener. Using magneto- and electroencephalography will allow us to examine the brain’s response to our stimuli at a fine time-scale to determine what parts of the brain are involved in binding auditory and visual stimuli together. Listening to speech in noisy conditions can be difficult for normal-hearing listeners, but it is even harder for impaired listeners, such as hearing aid users, cochlear implant users, and those with central auditory processing disorders (CAPD). In this first phase, we will work with normal hearing listeners, to establish a baseline and understand how an individual's brain activity is related to their perception.

Research area: Central Auditory Processing Disorder; Fundamental auditory research,

Long-term goal of research: This proposal is the beginning of a line of research investigating the specific behavioral effects of audio-visual binding and its processing in the brain. Behavioral tests with brain imaging will be used to investigate the importance of combining information across the visual and auditory senses, and establish relationships in brain activity and behavior, an effort that could inspire new audio-logical therapies.

Beula Magimairaj, Ph.D.

Beula Magimairaj, Ph.D.

University of Central Arkansas
Moving the science forward through interdisciplinary collaborative research integrating Hearing, Language, and Cognitive Science

Clinicians and researchers lack a consensual theoretical and clinical framework for conceptualizing Central Auditory Processing Disorder (CAPD) because professionals in different disciplines characterize it differently. Children diagnosed with CAPD may have deficits in attention, language, and memory, which often go unrecognized. There is a lack of a valid and reliable assessment tool that can characterize auditory processing, attention, language, and memory on the front-end. This project is an interdisciplinary effort to lay the foundation for such an assessment. Our goal is to develop an assessment that includes sensitive measures that can help build an initial profile of a child’s source(s) of difficulties that may be manifested as auditory processing deficits. During this 1-year project, computer-based behavioral tasks that integrate theoretical and methodological advances from the CAPD literature, and hearing, language, and cognitive science, will be developed. Tasks will be piloted on sixty typically developing children (7-11 years) who have no history of auditory processing/cognitive disorders for feasibility testing. Developing an assessment that will validly characterize the abilities of affected children is a multi-stage enterprise and this project is a critical first step.

Anna Majewska, Ph.D.

Anna Majewska, Ph.D.

University of Rochester

Cortical synaptic plasticity in a mouse model of moderate sensorineural hearing loss

The development of cortical networks is exquisitely sensitive to patterned activity elicited through sensory stimulation. Although much is known about somatosensory and visual cortical development, very little is known about the development of auditory cortex network connectivity. Changes in hearing that occur as a result of defects in sensation at the cochlea likely affect the development of higher brain areas which process auditory information. Our research will explore changes in the neural networks that process auditory stimuli in the cortex in a mouse model where prestin, a protein crucial for outer hair cell electromotile function is absent during development. We will address this question by looking at synaptic sites which link individual neurons into networks and compare their density, distribution and dynamic remodeling in control and prestin-null mice. We hypothesize that changes in both static and dynamic synaptic structure will be present in the auditory cortex of prestin-null mice, suggesting that cortical auditory networks are altered by degraded hearing during development. This work will shed light on synaptic mechanisms and possible treatments of developmentally acquired hearing loss.

Ani Manichaikul, Ph.D.

Ani Manichaikul, Ph.D.

University of Virginia
Susceptibility to chronic otitis media: translating gene to function

Each year in the United States, over $5 billion is spent on healthcare for inflammation of the middle ear (ME) known as Otitis Media (OM) in children. Some children develop chronic middle ear infections known as chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our goal is to find genetic factors that increase risk for COME/ROM in children. The discovery of causal variants would increase knowledge of novel genes and pathways involved in COME/ROM pathogenesis.

Research area: Otitis Media; Genetics

Long-term goal of research: To improve the clinical prevention of chronic infections; therefore decreasing pediatric antibiotic use, surgery, and deafness.

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