Integrated stress response inhibition provides sex-dependent protection against noise-induced cochlear synaptopathy

Stephanie L Rouse,Jiang Li,Dylan K Chan,Elliott H Sherr,Ian R Matthews

doi:10.1038/s41598-020-75058-w

Stephanie L Rouse, Jiang Li + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-75058-w

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Journal: Scientific Reports	Publication Date: Oct 22, 2020
Citations: 13	License type: open-access

Affiliation: University of California, San Francisco

Abstract

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.

Highlights

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications
The physiologic manifestation of cochlear synaptopathy is reduction in the amplitude of wave I of the suprathreshold auditory brainstem response (ABR), which serves as an indicator of the function of spiral ganglion neurons (SGNs) stimulated by ribbon synapses onto I HCs15
While there was no difference in ABR thresholds between male and female mice (Fig. 1A), growth of wave-I amplitude with increasing stimulus presentation level and average suprathreshold wave-I peak amplitudes were significantly higher in female mice between 8 and 40 kHz (Fig. 1B,C)

Summary

Introduction

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate noise exposure that does not cause permanent shifts in hearing thresholds can result in permanent loss of synapses between cochlear inner hair cells (IHCs) and spiral ganglion neurons (SGNs), associated with permanent reduced amplitude of wave I of the suprathreshold auditory brainstem response (ABR)[1]. These anatomic and physiologic findings are thought to correlate behaviorally with tinnitus and impaired speech perception in complex acoustic environments, both hallmarks of human auditory functional d isability[2]. ISRIB has been shown to rescue synaptic plasticity in a mouse model of Down syndrome, restore cell-specific synaptic function in a mouse model of repetitive traumatic brain injury, reverse trauma-induced hippocampal-dependent learning and memory deficits, and improve memory in wild-type and memory-impaired mice[5,12,13,14]

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