Cochlear synaptopathy, neural pathophysiology and suprathreshold processing in animal models of sensorineural hearing loss

感音神经性听力损失动物模型中的耳蜗突触病、神经病理生理学和阈上处理

• 批准号: 10641749
• 负责人: Sharon G Kujawa
• 金额: $ 57.84万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641749
• 关键词: Acceleration; Acoustic Nerve; Action Potentials; Acute; Affect; Aging; Aminoglycosides; Amplifiers; Animal Experiments; Animal Model; Animals; Auditory; Auditory Perception; Behavioral; Behavioral Assay; Biological Assay; Biological Markers; Cell physiology; Cells; Chronic; Clinical Trials; Cochlea; Cochlear Nerve; Diagnosis; Diagnostic; Disinhibition; Electrophysiology (science); Environment; Etiology; Exposure to; Fiber; Functional disorder; Gene Expression; Hair Cells; Hearing; Hearing Tests; Hearing problem; Histologic; Histopathology; Human; Hyperactivity; Hyperacusis; Hypersensitivity; Injury; Inner Hair Cells; Labyrinth; Lesion; Light; Linear Regressions; Link; Loudness; Loudness Perception; Measures; Modeling; Mus; Nerve Degeneration; Nerve Fibers; Neurons; Noise; Ouabain; Outcome; Outer Hair Cells; Pattern; Peptide Initiation Factors; Performance; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Prevalence; Process; Protocols documentation; Psychophysics; Regression Analysis; Resolution; Role; Sensorineural Hearing Loss; Sensory; Specialized Center; Speech Discrimination; Stimulus; Synapses; Synaptic Potentials; Testing; Therapeutic; Tinnitus; Work; auditory pathway; behavior measurement; behavior prediction; behavioral outcome; cell injury; cochlear synaptopathy; design; diagnostic tool; diagnostic value; hearing impairment; hearing range; human subject; improved; mouse model; neural; neural patterning; normal hearing; novel; novel strategies; ototoxicity; postsynaptic; public health relevance; receptor; repaired; response; round window; sound; speech in noise

Project 1 Summary - Abstract Animal studies of acquired sensorineural hearing loss (SNHL) have shown that loss of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) often occurs before permanent hair cell damage. This primary cochlear nerve degeneration (CND) has little effect on thresholds, but decreases discriminability of sounds, especially in noisy environments, and may trigger tinnitus and hyperacusis due to changes in excitation/inhibition in central auditory circuits. In prior work, Project 1 showed that several suprathreshold electrophysiological metrics can predict synaptic loss in animals when thresholds are normal, and Project 3 showed that these metrics correlate with word-identification performance in challenging listening environments among subjects with normal audiometric thresholds, consistent with a role for CND in hearing impairment that hides behind the audiogram. Over the next 5 years, all Center Projects shift focus to the study of CND in cases where thresholds are elevated. Consistent with the intent of the P50 mechanism, the primary role of Project 1 animal work is in support of the human studies. To that end, we have developed a set of animal models with complementary patterns of neural and hair cell damage. In Aim 1 we use these models to: 1) clarify the cellular generators of the summating potential, the biomarker best correlated with word scores in human subjects, 2) validate the utility of a novel electrophysiologic metric, the envelope following response to rectangular-wave amplitude modulation, in detecting CND in the presence of outer hair cell damage, and 3) determine whether the different CND-eliciting lesions all selectively target cochlear neurons with high thresholds and low spontaneous rates. For Aim 2, we have developed a novel electrophysiological assay of central auditory hyperactivity (that will also be used in human subjects) and a set of behavioral assays to detect changes in loudness perception and the presence of phantom sounds. By applying these assays to animals with different lesion patterns, we can test key hypotheses about the interactions between peripheral CND, central gain control adjustments, and the disabling perceptual anomalies of tinnitus and hyperacusis.

项目 1 摘要 - 摘要 获得性感音神经性听力损失 (SNHL) 的动物研究表明， 听觉神经纤维 (ANF) 和内毛细胞 (IHC) 之间的突触通常发生在 永久性毛细胞损伤。这种原发性耳蜗神经变性（CND）影响不大 在阈值上，但会降低声音的辨别能力，尤其是在嘈杂的环境中，并且 由于中枢听觉兴奋/抑制的变化，可能会引发耳鸣和听力过敏 电路。在之前的工作中，项目 1 显示了几个超阈值电生理指标 当阈值正常时可以预测动物的突触损失，项目 3 表明 这些指标与挑战性听力中的单词识别表现相关 具有正常听力阈值的受试者之间的环境，与角色一致 隐藏在听力图后面的听力障碍中的 CND。 在接下来的 5 年内，所有中心项目都将重点转向 CND 的研究，以应对以下情况： 门槛提高了。与 P50 机制的意图一致， 项目 1 动物工作支持人类研究。为此，我们开发了一套 具有神经和毛细胞损伤互补模式的动物模型。在目标 1 中，我们使用 这些模型的目的是：1）阐明细胞总和电位、生物标志物的生成器 与人类受试者的单词分数最相关，2）验证小说的实用性 电生理指标，对矩形波振幅的响应的包络 调节，在存在外毛细胞损伤的情况下检测 CND，以及 3) 确定 不同的 CND 诱发病变是否都选择性地靶向具有高 阈值和低自发率。对于目标 2，我们开发了一部小说 中枢听觉亢进的电生理测定（也将用于人类 受试者）和一组行为测定来检测响度感知的变化和 幻音的存在。通过将这些测定应用于具有不同病变的动物 模式，我们可以测试关于外周 CND、中枢神经元之间相互作用的关键假设 增益控制调整，以及耳鸣和听觉过敏的禁用感知异常。