Effects of Age-related Cochlear Synaptopathy on Speech-in-noise Intelligibility: A Cross-species Approach

项目摘要 与年龄相关的听力损失非常普遍，据估计，70岁以上的人中有60% 听力损失严重到足以干扰交流并影响生活质量的年龄。然而， 越来越多的证据表明，仅凭听力阈值的明显丧失并不能捕捉到真实世界的听力 老年人所经历的困难。到目前为止，听力障碍的一个尚未诊断的原因可能是 内毛细胞与听神经之间的突触随年龄增长而逐渐丧失，称为耳蜗病 突触疗法。耳蜗性突触被认为在复杂的听力条件下会影响语言的可理解性， 然而，它没有被阈值听力图检测到，仍然处于“隐藏”状态。虽然功能上的后果是 耳蜗性突触病变仍不清楚，新出现的证据表明，它与 时序提示在听觉外周的表现。这可能会不同地影响RAPID的编码 语音中的刺激时间精细结构(STF)线索对于在噪声环境下听是至关重要的。 不能确定耳蜗性突触对噪声中语音清晰度降低的影响 在单一物种中完成。在人类中观察到的知觉缺陷不能直接归因于 耳蜗性突触，因为解剖性突触只有在尸检标本中才能得到证实。啮齿动物 模型提供了直接测量耳蜗突触完整性的方法，但其服务潜力有限 作为真实世界环境下人类语音感知的模型。该提案解决了这些翻译问题 将人类和动物模型的研究与非侵入性电生理相结合所面临的挑战 在人类和动物模型中，在几乎相同的条件下测量的反应 翻译桥。目标1中的实验将使用一组行为和电生理方法 人类来测试这一假设，即噪声中语音清晰度随年龄的下降伴随着 改变了STF信号的神经编码。在目标2中，与年龄相关的耳蜗性突触在退化的STF中的作用 处理将在其听力范围对人类语音频率敏感的动物模型中进行研究， 使用STF处理的电生理生物标记物在人类中得到验证。AIM 3将分离出 年龄相关的混杂提示中耳蜗性突触对神经编码的贡献 通过在幼年动物中诱导分级突触和评估相同的电生理和 目标2中使用的免疫组织学标志物。该项目的完成有可能导致单一的 将耳蜗性突触与噪声中语音清晰度缺陷联系起来的生物标记物。该项目将进一步 建立整合的研究渠道，加速临床前研究向早期人类的转化 未来生物标记物或介入疗法的试验。最后，这里获得的数据将为未来的工作奠定基础 将遵循这一翻译方法的研究将探索与年龄相关的耳蜗之间的相互作用 突触、外周阈值敏感性和中枢听觉通路的代偿性可塑性。

Project Summary Age-related hearing loss is exceedingly common, with an estimated 60% of individuals over 70 years of age having hearing loss significant enough to interfere with communication and affect quality of life. However, increasing evidence suggests that the overt loss of hearing thresholds alone fails to capture real-world hearing difficulties experienced by older adults. One hitherto undiagnosed cause of hearing deficits could be the progressive loss of synapses between the inner hair cell and the auditory nerve with age, termed cochlear synaptopathy. Cochlear synaptopathy is thought to affect speech intelligibility under complex listening conditions, yet it goes undetected by the threshold audiogram, remaining ‘hidden’. While the functional consequences of cochlear synaptopathy are still unclear, emerging evidence suggests that it is associated with deficits in representation of timing cues in the auditory periphery. This may differentially affect the encoding of rapid stimulus temporal fine structure (sTFS) cues in speech, which are critical for listening in noisy conditions. Establishing the effects of cochlear synaptopathy on decreased speech-in-noise intelligibility cannot be accomplished in a single species. Perceptual deficits observed in humans cannot be attributed directly to cochlear synaptopathy, because anatomical synaptopathy is only verifiable in post-mortem specimens. Rodent models offer the means to directly measure cochlear synaptic integrity but are limited in their potential to serve as models of human speech perception under real-world settings. This proposal addresses these translational challenges by integrating research in humans and animal models, with non-invasive electrophysiological responses measured under near identical conditions in both humans and animal models acting as the translational bridge. Experiments in Aim 1 will use a battery of behavioral and electrophysiological methods in humans to test the hypothesis that degradations in speech-in-noise intelligibility with age are accompanied by altered neural coding of sTFS cues. In Aim 2, the role of age-related cochlear synaptopathy in degraded sTFS processing will be studied in an animal model whose hearing range is sensitive to human speech frequencies, using the electrophysiological biomarkers of sTFS processing validated in humans. Aim 3 will isolate contributions of cochlear synaptopathy to the neural coding of sTFS cues from possible confounding age-related effects by inducing graded synaptopathy in young animals and evaluating the same electrophysiological and immunohistological markers used in Aim 2. The completion of this project has the potential to result in a single biomarker that links cochlear synaptopathy to deficits in speech-in-noise intelligibility. The project will further establish an integrated research pipeline that can accelerate the translation of pre-clinical studies to early human trials for future biomarkers or interventional therapies. Finally, the data obtained here will form the basis for future studies that will follow this translational approach to explore the interactions between age-related cochlear synaptopathy, peripheral threshold sensitivity, and compensatory plasticity in the central auditory pathway.