RESUMO
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.
Assuntos
Acetamidas/farmacologia , Acetamidas/uso terapêutico , Estimulação Acústica/efeitos adversos , Cóclea/patologia , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Caracteres Sexuais , Sinapses/patologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/fisiologia , Animais , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Células Ciliadas Auditivas , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/terapia , Masculino , Camundongos Endogâmicos CBA , Percepção da Fala , ZumbidoRESUMO
An active process in the inner ear expends energy to enhance the sensitivity and frequency selectivity of hearing. Two mechanisms have been proposed to underlie this process in the mammalian cochlea: receptor potential-based electromotility and Ca(2+)-driven active hair-bundle motility. To link the phenomenology of the cochlear amplifier with these cellular mechanisms, we developed an in vitro cochlear preparation from Meriones unguiculatus that affords optical access to the sensory epithelium while mimicking its in vivo environment. Acoustic and electrical stimulation elicited microphonic potentials and electrically evoked hair-bundle movement, demonstrating intact forward and reverse mechanotransduction. The mechanical responses of hair bundles from inner hair cells revealed a characteristic resonance and a compressive nonlinearity diagnostic of the active process. Blocking transduction with amiloride abolished nonlinear amplification, whereas eliminating all but the Ca(2+) component of the transduction current did not. These results suggest that the Ca(2+) current drives the cochlear active process, and they support the hypothesis that active hair-bundle motility underlies cochlear amplification.