Physiological and Perceptual Assessment of Hearing in Noise in Nonhuman Primates Following Noise-Induced Cochlear Synaptopathy

项目摘要 噪声中的听力是一项复杂的听觉任务，对于在存在噪声的情况下进行有效沟通至关重要。 竞争的声音几种神经元机制和回路有助于噪声中的听力能力，包括 编码阈上信号的神经元亚群，神经元反应适应，和中间 耳肌和内侧橄榄耳蜗反射（MEMR，MOCR）。许多寻求听力保健的患者报告 在噪音中听力有困难，但听力正常（即“隐性听力损失”）。耳蜗 突触病（SYN;内耳毛细胞带状突触的丧失）是一种内耳病理学，被认为有助于 在没有毛细胞损伤和听力阈值差的情况下， 在标准听力测试组合中容易识别。在啮齿类动物中，SYN破坏突触信号， 改变神经元的适应性，并导致听觉神经纤维的损失，特别是那些具有高声音诱发的神经纤维。 将信号编码为噪声并向MEMR和MOCR提供输入的阈值。由于SYN降级 在支持噪声中听觉的神经元机制中，SYN可能导致伴随的噪声中听觉缺陷。 然而，很少有研究直接评估SYN对噪声或感知信号编码的影响。 噪音中的听觉能力疑似SYN的确证在人类中是有限的， 噪声中的听力能力和同步尚未建立，导致翻译的不确定性。我们 噪声诱导SYN的非人灵长类动物模型是唯一适合于评估SYN对 并在啮齿动物和人类研究之间提供了一个翻译桥梁。互补 生理和心理物理测量将用于评估噪声编码和听力中的信号， 猕猴的噪声能力在噪声暴露之前和之后已知会导致SYN。中央 假设噪声中的信号编码和听觉能力在SYN后会受损， 在具有较大突触损失的受试者中观察到的缺陷。在目标1中，噪声中的信号的编码将是 使用传统的非侵入性临床检测方法进行研究，包括听觉脑干反应 （ABR），畸变产物耳声发射（DPOAE），MEMR和MOCR，测量有和没有 同侧和对侧噪声，以探测支持噪声中听觉的神经元机制。在 目标2，噪声中的心理物理信号检测将在掩蔽条件下进行测量， 这是一种神经元的适应性反应，与噪音中的听觉有关。受试者内比较（暴露前与暴露后） 用耳蜗组织学特征对突触丧失进行回归分析， 耳蜗完整性和听觉功能之间的关系这种多模态的方法，从生理和感知上， 测量非人类灵长类动物在噪声中的听觉能力， 导致SYN的新生物标志物。提高听力障碍鉴别诊断的灵敏度，例如 因为隐性听力损失对于人类听力损失的快速治疗方法至关重要。

PROJECT SUMMARY Hearing in noise is a complex auditory task that is critical for effective communication in the presence of competing sounds. Several neuronal mechanisms and circuits contribute to hearing-in-noise abilities, including neuronal subpopulations that encode suprathreshold signals, neuronal response adaptation, and the middle ear muscle and medial olivocochlear reflexes (MEMR, MOCR). Many patients seeking audiologic care report difficulties hearing in noise, but have normal hearing sensitivity (i.e. `hidden hearing loss'). Cochlear synaptopathy (SYN; the loss of inner hair cell ribbon synapses) is an inner ear pathology thought to contribute to hearing-in-noise deficits, in the absence of hair cell damage and poor hearing thresholds that are more readily identified in the standard audiologic test battery. In rodents, SYN disrupts synaptic signaling, which alters neuronal adaptation and leads to loss of auditory nerve fibers, especially those with high sound-evoked thresholds that encode signals in noise and provide input to the MEMR and MOCR. Since SYN degrades neuronal mechanisms that support hearing-in-noise, SYN may result in concomitant hearing-in-noise deficits. However, few studies have directly assessed the effect of SYN on encoding of signals in noise or perceptual hearing-in-noise abilities. Corroboration of suspected SYN is limited in humans and the relationship between hearing-in-noise abilities and SYN has not been established, leading to translational uncertainty. Our nonhuman primate model of noise-induced SYN is uniquely suited to assess the consequences of SYN on hearing-in-noise and provide a translational bridge between rodent and human research. Complementary physiological and psychophysical measures will be used to assess signal in noise encoding and hearing-in- noise abilities of macaque monkeys before and after noise exposure known to cause SYN. The central hypothesis is that signal encoding and hearing abilities in noise will be impaired following SYN, with greater deficits observed in subjects with greater synapse loss. In Aim 1, encoding of signals in noise will be investigated using variants of traditional noninvasive clinical assays, including auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), MEMRs, and MOCRs, measured with and without ipsilateral and contralateral noise, in order to probe neuronal mechanisms that support in hearing-in-noise. In Aim 2, psychophysical signal detection in noise will be measured under masking conditions that elicit different kinds of neuronal adaptation involved in hearing-in-noise. Within-subject comparisons (pre- vs. post-exposure) and regressions with cochlear histological characterization of synapse loss will assess the relationship between cochlear integrity and auditory function. This multimodal approach to physiologically and perceptually measure hearing-in-noise abilities in nonhuman primates with histologically verified noise-induced SYN could result in novel biomarkers for SYN. Improving the sensitivity of differential diagnosis of hearing disorders such as hidden hearing loss is critically important with the rapid approach of therapeutics for human hearing loss.