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

• 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
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-75058-w

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.