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

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 但降低了声音的可辨别性，特别是在嘈杂的环境中， 由于中枢听觉神经系统兴奋/抑制的变化， 电路.在先前的工作中，项目1表明，几个阈上电生理指标， 可以预测动物在阈值正常时的突触损失，项目3表明， 这些指标与具有挑战性的听力中的单词识别表现相关 正常听力阈值的受试者之间的环境，与 隐藏在听力图后面的听力障碍中的CND。 在接下来的5年里，所有中心项目都将重点转移到CND的研究上， 门槛提高了。根据P50机制的意图， 项目1的动物研究是为了支持人体研究。为此，我们制定了一套 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：1）阐明细胞发电机的总和潜力，生物标志物 与人类受试者的单词分数最相关，2）验证小说的实用性 电生理测量，矩形波振幅响应后的包络 调制，在存在外毛细胞损伤的情况下检测CND，以及3）确定 是否不同的CND诱发病变都选择性地靶向耳蜗神经元， 阈值和低自发率。对于目标2，我们开发了一种新的 中枢听觉活动过度的电生理学测定（其也将用于人类 受试者）和一组行为测定来检测响度感知的变化， 出现幻音。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 增益控制调整，以及耳鸣和听觉过敏的禁用感知异常。

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.