Synaptopathy, Neural Pathophysiology and Suprathreshold Processing in Gerbils with Normal or Elevated Thresholds

阈值正常或升高的沙鼠的突触病、神经病理生理学和阈上处理

• 批准号: 10222643
• 负责人: Sharon G Kujawa
• 金额: $ 50.14万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-02 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222643
• 关键词: Address; Affect; Aging; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Auditory; Behavioral; Binaural; Biological Assay; Brain; Brain Stem; Caliber; Cisplatin; Clinical; Cochlea; Communication; Complex; Diagnosis; Diagnostic; Discrimination; Dose; Ear; Electrocochleographies; Electrophysiology (science); Elements; Etiology; Exposure to; External auditory canal; Fiber; Frequencies; Functional disorder; Future; Gentamicins; Gerbils; Hair Cells; Hearing; Hearing Tests; Hearing problem; High-Frequency Hearing Loss; Histologic; Histopathology; Human; Hyperacusis; Impairment; Inbred Mouse; Individual; Injury; Inner Hair Cells; Interruption; Knowledge; Labyrinth; Lead; Loudness; Masks; Measurement; Measures; Medial; Methods; Modeling; Monitor; Nature; Nerve; Nerve Fibers; Neurons; Neuropathy; Neurophysiology - biologic function; Noise; Outcome; Pathology; Pattern; Performance; Peripheral; Pharmaceutical Preparations; Platinum; Population; Prevalence; Prevention; Process; Psychophysics; Public Health; Reflex action; Risk; Sensorineural Hearing Loss; Sensory; Sensory Hair; Series; Severities; Speech; Structure; Synapses; Techniques; Temporal bone structure; Test Result; Testing; Text; Tinnitus; Training; Translating; Treatment Efficacy; Work; age related; awake; base; cell injury; clinical application; clinical diagnostics; cochlear synaptopathy; density; design; ear muscle; exposed human population; functional decline; hearing impairment; hidden hearing loss; human model; human subject; improved; insight; middle ear; neuron loss; otoacoustic emission; ototoxicity; pressure; public health relevance; relating to nervous system; response; sound; speech in noise

Project 1 Summary – Abstract In common causes of human hearing loss like aging and noise exposure, permanent threshold losses are associated with permanent cochlear injury, often hair cell damage or loss. Recently, work in animal models has revealed what may be a more common consequence of these and other causes of acquired sensorineural hearing loss. This work has shown that synapses between inner hair cells (IHCs) and cochlear neurons are most vulnerable, with their loss interrupting sensory-to-neural communication long before loss of the hair cells themselves, and long before sensitivity losses appear on the threshold audiogram. The silencing of affected neurons that results is a likely contributor to a variety of auditory perceptual abnormalities, including speech-in- noise difficulties, tinnitus and hyperacusis that can occur with or without threshold sensitivity loss. As these findings are translated to the study of human hearing loss, animal models will continue to provide a powerful approach to test hypotheses, to characterize structural and functional consequences of carefully- titrated manipulations and to evaluate the sensitivity of the assessments to the underlying histopathology. Here, animal models of sensorineural hearing loss etiologies common in humans; exposure to noise, to aminoglycoside antibiotics and to platinum-containing chemotherapeutics, will be created. The models will address the mixed (sensory + neural) pathology that will likely be present in many of the humans and human temporal bones evaluated in the other Projects. The human test battery will be applied (Aim 2) and its diagnostic power assessed by directly measuring the underlying cochlear histopathology (Aim 1). Structure- function correlations will be probed further using detailed electrophysiologic assays that might be streamlined for future clinical use (Aim 3). Work will be performed in gerbil, a species with good low frequency hearing and can be trained to perform auditory tasks. By correlating performance on these complex listening tasks with electrophysiology in the same subjects and with explicit measurement of the underlying synaptopathy, the contribution of cochlear neuropathy to the perceptual declines can be quantitatively evaluated and results can be directly compared to those obtained in human subjects. An improved understanding of the extent to which synaptic mechanisms are damaged in common forms of human sensorineural hearing loss will have broad implications for efforts to identify drugs or other treatments with the potential to target these mechanisms for prevention or rescue. Practically, this knowledge will inform clinical diagnostics, the monitoring of new treatments for efficacy or the monitoring of individuals at risk of hearing compromise from drug and noise exposure. It also may help explain auditory performance differences among individuals with the same audiometric configurations, even for those with normal thresholds.

项目1摘要-摘要