Effect of selective inner hair cell loss on functional hearing

描述(申请人提供)：虽然外毛细胞(OHC)在放大内耳的机械能方面发挥了主要作用，但将信息传递到大脑的是内毛细胞(IHC)，它接触了90-95%的听觉传入纤维。到目前为止，选择性IHC缺失对听觉知觉的影响还不是很清楚，尽管它们对简单和复杂的信号(如语音)进行编码都很重要。本项目的总体目标是描述和量化选择性IHC缺失对听力敏感度、噪声中的听力和时间处理的影响。重要的是，在龙猫身上，抗癌药物卡铂选择性地损伤IHC和I型听神经纤维。这项建议的目的是使用栗鼠模型来识别作为IHC丧失的函数而发生的特定听觉缺陷。目前正在使用针对耳蜗死区的临床测试来确定耳蜗区中可能不再存在IHC的区域。然而，部分IHC丧失的程度和功能性听力障碍之间的关系在很大程度上是未知的。临床上，IHC病理可能在听神经病(AN)或听觉不同步(AD)中发挥作用1。为了确定哪些功能缺陷与IHC丧失有关，将训练栗鼠执行五项听觉任务，这些任务测量听觉感知的不同方面：(1a)安静时的纯音阈值来确定听力敏感度，(1b)在宽带噪声存在下的纯音阈值来评估噪声性能中的信号，以及(1c)以带通噪声测量的音阈值来确定频率分辨率和离频听力。(2a)宽带噪声中的间隙检测，以评估时间敏锐度和阈值与持续时间函数的关系，以确定时间总和。将在卡铂治疗前后评估听力行为测试，听力表现的变化将与IHC丧失的程度相关。此外，在卡铂治疗前后将获得OHC的客观测量，即失真产物耳声发射(DPOAE)。我推测，在IHC损伤后，基本功能，如安静状态下的音调检测，将显示出很小的变化。然而，随着IHC丢失的程度，在背景噪声、间隙检测和时间求和下的性能将受到损害。我还假设，这些类型的障碍可能会严重影响处理复杂声音(如语音)的能力。 与公共卫生相关：选择性IHC丧失对听力的影响仍然知之甚少，尽管它们扮演着关键角色，因为这些细胞与90%以上的传入听神经纤维突触，将声音信息传递到大脑。该项目的总体目标是确定在用抗癌药物卡铂治疗的龙猫中，当IHC及其传入连接受损时，听觉敏感度、噪声中的听力和时间处理是如何改变的。

DESCRIPTION (provided by applicant): Although outer hair cells (OHC) play a major role in amplifying mechanical energy in the inner ear, it is the inner hair cells (IHC), which contact 90-95% of the auditory afferent fibers that relay information to the brain. To date, the effects of selective IHC loss on auditory perception are not well understood despite their importance coding both simple and complex signals such as speech. The overall goal of this project is to characterize and quantify the effects of selective IHC loss on hearing sensitivity, hearing in noise, and temporal processing. Importantly, in the chinchilla, carboplatin, an anticancer drug, selective damages IHC and type-I auditory nerve fibers. The purpose of this proposal is to use the chinchilla model to identify specific auditory deficits that occur as a function of IHC loss. Clinical tests, for cochlear dead regions, are currently in use to determine areas of the cochlea where IHC presumably no longer exist. However, the relationship between the extent of partial IHC loss and functional hearing deficits is largely unknown. Clinically, it has been suggested that IHC pathology could play a role in Auditory Neuropathy (AN) or Auditory Dyssynchrony (AD) 1. To determine what functional deficits are associated with IHC loss, chinchillas will be trained to perform five auditory tasks that measure different aspects of auditory perception: (1a) Pure-tone thresholds in quiet to determine hearing sensitivity, (1b) pure-tone thresholds in the presence of broadband noise to assess signal in noise peformance and (1c) tone thresholds measured in bandpass noise to determine frequency resolution and off frequency hearing ability, (2a) gap detection in broadband noise to assess temporal acuity and threshold versus duration functions to determine temporal summation. Behavioral test of hearing will be assessed before and after carboplatin treatment and changes in hearing performance will be correlated with the degree of IHC loss. In addition, objective measures of OHC, distortion product otoacoustic emissions (DPOAE), will be obtained before and after carboplatin treatment. I hypothesize that basic function such as detection of tones in quiet will show little change after IHC damage. However, performance under background noise, gap detection, and temporal summation will be impaired in relation to the extent of IHC loss. I also hypothesize that these types of impairments could severely impact the ability to process complex sounds such as speech. PUBLIC HEALTH RELEVANCE: The consequences of selective IHC loss on hearing remain poorly understood despite their critical role as these cells synapse with over 90% of afferent auditory nerve fibers that transmit acoustic information to the brain. The overall goal of this project is to determine how auditory sensitivity, hearing in noise and temporal processing is altered when IHC and their afferent connections are damaged in chinchillas treated with the anticancer drug, carboplatin.