Mass Eye and Ear

Auditory-limbic circuit dynamics as therapeutic targets in hyperacusis

Our research addresses a critical gap in understanding the neural basis of hyperacusis by focusing on the emotional dimensions of sound hypersensitivity. Previous work has established that cochlear damage leads to hyperexcitability throughout the central auditory pathway, but our approach uniquely focuses on the circuit-specific mechanisms that link auditory processing to emotional responses.

Specifically, we investigate how noise-induced hearing loss affects two parallel pathways to the lateral amygdala: the cortico-amygdalar (CAmy) and thalamo-amygdalar (TAmy) projections. This pathway- specific investigation represents a novel approach to understanding hyperacusis, as it targets the precise neural circuits that may mediate both the perceptual and emotional components of this disorder.

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.

University at Buffalo

FOXG1 gene mutation-caused hyperacusis—a novel model to study hyperacusis

Hyperacusis is a common symptom in children with neurological disorders such as autism spectrum disorder, Williams syndrome, Rett syndrome, and FOXG1 syndrome (FS). The cause of hyperacusis in these neurological disorders has not been fully discovered. FOXG1 mutation is a recently defined, rare and devastating neurodevelopmental disorder. MRI studies show a spectrum of structural brain anomalies, including cortical atrophy, hypogenesis of the corpus callosum, and delayed myelination in children with FS. However, the impact of the FOXG1 mutation on the central auditory system and hyperacusis is largely unknown. Children with FS show signs of hyperacusis, including becoming startled, upset, and even experiencing seizures from loud sounds. The mouse model of FOXG1 mutation provides a novel model to study neurological dysfunction in the central auditory system resulting in hyperacusis. In this project, we will use a mouse model developed by colleagues at University at Buffalo that replicates gene mutations in FS children to study hyperacusis. In our preliminary studies, we found that the mutant mice showed a lack of habituation in the startle tests and an aversive reaction to loud sounds in the open field test. We also found that the cortical neurons showed reduced neural activities and prolonged responses to sound stimuli, suggesting hypoexcitability and a lack of adaptation to sound stimuli. The results point toward a novel neurological model of hyperacusis compared with the current “central gain” theory. Our findings will provide mechanistic insights into the role of the FOXG1 gene on hyperacusis and shed light on detecting potential therapeutic targets to alleviate hyperacusis caused by FS and other neurological disorders.

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.