Research Project Leaders
Hui Hong
Hearing loss affects ~20% of the global population, leading to significant changes in both the peripheral and central auditory systems. While extensive research has examined how hearing loss leads to hair cell loss and spiral ganglion neuron degeneration, resulting in significant changes in the downstream afferent pathway, its impact on the auditory efferent system, which provides feedback from the brain to the ear, remains less understood. Auditory efferent system is important for adjusting hearing sensitivity, enhancing the signal-to-noise ratio, and protecting the ear from loud sounds. Dysfunctional efferents lead to increased susceptibility to noise. Lateral olivocochlear (LOC) neurons – the most numerous auditory efferent neurons – show enhanced neurotransmitter and neuropeptide expression with hearing loss, potentially altering efferent modulation in the ear. However, how LOC’s physiology and transcriptomics change with hearing loss is unknown. This proposal aims to bridge this knowledge gap by studying the impact of two types of hearing loss on mouse LOC neurons. Aim 1 will examine the effects of noise-induced hearing loss on mature LOCs, while Aim 2 will explore congenital hearing loss on developing LOCs. The central hypothesis is that peripheral auditory activity regulates the interdependent physiology and gene expression of the LOC system across the lifespan, facilitating the development of LOC neurons into adulthood and sustaining their proper function over time. Recently, I discovered a unique infra-slow spontaneous burst firing pattern driven by Ca2+ channels in LOC neurons, a type of activity not previously reported in the central auditory system. The seconds-long bursts might be important for neuropeptide release from LOC terminals onto the dendrites of spiral ganglion neurons. Hence, I predict that enhanced neuropeptide expression in LOC neurons with noise-induced hearing loss is closely associated with altered burst firing pattern, and these changes correspond to altered gene expression in LOC. Cutting-edge Patch-seq technique will be employed to correlate gene expression with electrical properties at the single-cell level. Understanding how hearing loss affects this activity could shed light on altered efferent modulation in the inner ear under pathological conditions, potentially leading to additional auditory disorders like tinnitus and hyperacusis. Moreover, this research will focus on ion channel changes associated with hearing loss, offering insights into potential therapeutic targets for treating hearing loss. With this knowledge, the long-term objective is to understand the precise function of the auditory efferent system in adjusting hearing sensitivity and protecting the ear from acoustic trauma.
Jemma Webber
The mammalian cochlea contains inner hair cells (IHCs), which transmit auditory signals to the brain, and outer hair cells (OHCs), which amplify and refine these signals. Loss of either cell type results in irreversible hearing impairment, as neither can regenerate. Current therapeutic approaches are limited by an incomplete understanding of the signaling pathways governing IHC versus OHC development. The Insm1 mutant mouse model, in which OHCs transdifferentiate into IHCs, provides a unique system for studying IHC formation. In the absence of INSM1, approximately half of all OHCs lose their identity, acquiring the characteristic morphology and molecular markers of an IHC fate. This transdifferentiation occurs in a gradient, with medial OHCs more likely to transition, suggesting the involvement of a graded IHC-inducing morphogen that INSM1 normally represses.
In our organotypic cochlear explants from Insm1 mutants, we observed OHC-to-IHC transdifferentiation mirroring in vivo findings, evidenced by the loss of the OHC marker, BCL11b, and gain of the IHC marker, VGLUT3. Pharmacological modulation of candidate signaling pathways demonstrated that transdifferentiation is dynamic, supporting the hypothesis of morphogen involvement. Enhancing or inhibiting specific candidate signaling pathways either promoted near-complete transdifferentiation or suppressed it. Here, we propose to leverage the Insm1 mutant model to identify the morphogen(s) driving IHC and OHC development, using spatial transcriptomics and genetic models to validate their roles and determine their cellular sources. Additionally, we will investigate how downstream transcriptional effectors are recruited to chromatin in response to morphogens, to activate IHC-specific gene expression programs. These insights will advance our understanding of cochlear development and help to guide strategies for targeted hair cell regeneration to ultimately restore hearing.
Justine Renauld
Ménière’s disease (MD) is characterized by symptoms such as hearing loss and vertigo, but its underlying cause is still unclear. Research on the temporal bones of MD patients has identified a condition known as endolymphatic hydrops, marked by an expansion of the scala media, indicating a disruption in fluid balance within the inner ear. Endolymph, a vital fluid within the membranous labyrinth, is essential for maintaining hearing and balance. However, the mechanisms that regulate this fluid are not yet fully understood. Given the critical role of fluid homeostasis in the inner ear, our research aims to investigate the formation of endolymphatic hydrops and its impact on neuronal dysfunction.
In this research, we will investigate inner ear dysfunction in an animal model of endolymphatic hydrops. We will correlate hearing and balance thresholds with the ionic and protein composition of endolymph and perilymph. We will test if there is degradation of the blood endolymph barrier during development of endolymphatic hydrops. Finally, we will conduct transcriptomic analysis on the hydropic neurons to better understand the cause of neuronal dysfunction during the development of endolymphatic hydrops.
These studies are essential for comprehending potential mechanisms underlying disruptions in inner ear homeostasis and the development of conditions like MD. This understanding will be essential in developing targeted therapies for MD and related conditions.
