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

Johns Hopkins University School of Medicine

Emergence of tonotopically organized spontaneous activity in the brain after genetic disruption of MET channel

Secondary disorders develop alongside hearing loss, such as the perception of phantom sounds (tinnitus) and a hypersensitivity to sound (hyperacusis). These disorders have no curative treatment, in part due to our poor understanding of the underlying neurobiology. Using experimental models of hearing loss, I recently discovered that sound-independent (SI) patterns of neural activity emerge in the brain’s auditory centers that resemble those elicited by sound in hearing mice. This finding indicates that the brain can self- generate neural patterns that resemble sound processing, independent of the inner ear. To understand the relevance of SI activity to human disorders like tinnitus, I’ll expand these findings to more translationally relevant models of hearing loss (loud noise exposure and age-related hearing loss), as well as determine the area of the brain that generates these patterns. The results of these studies may help to develop new approaches to treat tinnitus, hyperacusis, and related disorders.

The University of Texas at Dallas

Serotonin signaling of auditory efferent neurons in noise-induced hyperacusis and tinnitus (NIHT)

A single exposure to loud noise can cause lasting changes in hearing. Tinnitus (the phantom perception of sounds such as ringing or buzzing) and hyperacusis (an increased sensitivity to everyday sounds resulting in discomfort or pain) can develop following exposure to loud sounds. Both conditions can have a profound impact on quality of life, affecting communication, concentration, sleep, mood and social interactions. Depression and other mood disorders also occur at unusually high rates in people with tinnitus and/or hyperacusis, suggesting that hearing and mental health may be biologically connected.

Serotonin is a chemical messenger in the brain best known for its role in mood, but it also regulates the activity of nerve cells throughout the brain, including those involved in hearing. Altered serotonin signaling is associated with depression and is targeted by antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs). SSRIs increase serotonin signaling by blocking the serotonin transporter (SERT), a protein that normally removes serotonin from the spaces between neurons, known as synapses. By blocking SERT, SSRIs increase the amount of serotonin available to signal nerve cells.

A specialized group of nerve cells called medial olivocochlear (MOC) efferent neurons act as a volume control for the auditory system. When activated, MOC neurons reduce the ear’s sensitivity to sound, helping protect the auditory system from the effects of intense noise. Our previous work has shown that serotonin can increase MOC activity. However, it is not yet known if differences in serotonin signaling change an individual’s vulnerability to noise-related hearing problems.

We propose that altered serotonin signaling provides a mechanistic link between mood and auditory disorders. We hypothesize that serotonin influences the ear’s protective mechanisms, and, consequently, vulnerability to tinnitus and hyperacusis following exposure to loud sounds. Using mice with genetically altered SERT function, we will directly test this possibility. We will determine whether long- term disruption of serotonin signaling during development alters MOC activity, vulnerability to noise-induced hyperacusis and tinnitus, and measures of depression-like behaviors. By manipulating both serotonin signaling and noise exposure, we can test whether serotonin plays a causal role rather than simply being associated with hearing or mood disorders.

This research offers a new approach for understanding the neurobiological connection between auditory and mental health disorders. Our findings could help explain why some individuals are particularly vulnerable to noise-induced hearing problems, identify an underexplored protective pathway in the auditory system, and provide a foundation for investigating whether medications that alter serotonin signaling, including SSRIs, could eventually have utility in preventing or treating these disabling conditions.

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.

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.