Peripheral auditory signaling regulates the cochlear efferent system

Creighton University, Omaha NE

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Abstract

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.