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

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...

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Bibliographic Details
Published in:Scientific reports 2020-10, Vol.10 (1), p.18063, Article 18063
Main Authors: Rouse, Stephanie L., Matthews, Ian R., Li, Jiang, Sherr, Elliott H., Chan, Dylan K.
Format: Article
Language:English
Subjects:
631/378/2619/1387
631/378/2619/1592
Acetamides - pharmacology
Acetamides - therapeutic use
Acoustic Stimulation - adverse effects
Animals
Brain injury
Brain stem
Cochlea
Cochlea - pathology
Cognitive ability
Cyclohexylamines - pharmacology
Cyclohexylamines - therapeutic use
Disease Models, Animal
Endoplasmic reticulum
Endoplasmic Reticulum Stress
Evoked Potentials, Auditory, Brain Stem - physiology
Female
Hair cells
Hair Cells, Auditory
Hearing loss
Hearing Loss, Noise-Induced - etiology
Hearing Loss, Noise-Induced - pathology
Hearing Loss, Noise-Induced - prevention & control
Hearing Loss, Noise-Induced - therapy
Hearing protection
Humanities and Social Sciences
Male
Mice, Inbred CBA
multidisciplinary
Neurodegeneration
Noise
Noise reduction
Protein folding
Science
Science (multidisciplinary)
Sex Characteristics
Speech Perception
Stress response
Synapses
Synapses - pathology
Tinnitus
Unfolded Protein Response - drug effects
Unfolded Protein Response - physiology
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-75058-w