Effect of Noise Induced Hearing Loss on AVCN Principal Neurons

描述(申请人提供)：超过1000万美国人患有噪声性听力损失(NIHL)。在某些“正常”的工作和生活环境中，短期和长期的噪声暴露是一种主要危险。噪声暴露根据强度和持续时间的不同，可能导致暂时性或永久性的听阈值漂移(TTS，PTS)。最近的研究表明，在一种年龄相关性听力损失的小鼠中，耳蜗前腹核(AVCN)内的终球突触的突触效能下降。此外，在突触后丛状神经元中存在对高频刺激的缠绕作用的功能性减少。这些变化可能是由于传入听神经纤维的活动减少所致。另一方面，噪音侮辱会在听神经中产生反复出现的短期多动。过度兴奋可能对内球突触及其突触后靶点产生不利影响。由于AVCN为声音定位和语音识别的高级听觉中枢提供了重要的线索，因此了解噪声性听力损失在第一个中继性突触的功能后果是至关重要的。因此，我们提出了两个具体目标。在第一个目标中，我们将明确地检验这一假设，即在噪声暴露后，终末突触的有效性立即受损；然而，在适度的侮辱下，有效性恢复，导致仅出现TTS，而在伴有PTS的NIHL中，有效性永久降低。我们将利用近交系CBA小鼠噪声暴露结果的低个体变异性。使用改良的全耳蜗核切片制备方法，我们将利用噪声过度暴露后的电生理记录来探讨突触传递的几个方面。在第二个目标中，我们将验证这样的假设，即噪声导致的听力损失影响突触后丛状神经元的低阈值K+电导(LLT)，这种效应反过来降低了这些神经元的时间编码能力。我们将表征诱导NIHL后丛生细胞的LLT，并通过在切片上用真实的泊松分布的棘波串激活听神经纤维来测试丛生细胞的精细时间编码。该项目的数据将补充和加强现有的关于噪声性听力损失的外周效应的丰富信息。最后，我们想探讨NIHL后用药物或设备干预能否保持中枢听觉通路的完整性，因为中枢神经系统的功能完整性是成功的听力损失干预的重要组成部分。

DESCRIPTION (provided by applicant): More than 10 million Americans suffer from noise induced hearing loss (NIHL). Short and long term noise exposure is a major hazard in certain "normal" working and living environments. Noise exposure, depending on intensity and duration, can result in temporary or permanent auditory threshold shift (TTS, PTS). Recent studies have shown that synaptic efficacy deteriorates at the endbulb synapse in the anterior ventral cochlear nucleus (AVCN) in a strain of mice with age-related hearing loss. Furthermore, there is a functional reduction of entrainment to high frequency stimulation in postsynaptic bushy neurons. These changes are likely due to diminished activity in the afferent auditory nerve fibers. Noise insults, on the other hand, generate recurring short term hyperactivity in the auditory nerve. The excessive excitation could have detrimental effect on the endbulb synapse and its postsynaptic target. Because the AVCN provides vital cues to higher auditory centers for sound localization and speech recognition, it is essential to understand the functional consequences of noise induced hearing loss at this first relay synapse. Thus, we propose 2 specific aims. In the first aim, we will explicitly test the hypothesis that synaptic efficacy at the endbulb terminal is impaired immediately following noise exposure; however, the efficacy recovers with moderate insults resulting in only TTS, whereas the efficacy becomes permanently reduced in NIHL with PTS. We will take advantage of the low individual variability in noise exposure outcome in inbred CBA mice. Using a modified whole cochlear nucleus slice preparation, we will probe several aspects of synaptic transmission with electrophysiological recordings after noise overexposure. In the second aim, we will test the hypothesis that noise induced hearing loss affects the low threshold K+ conductance (lLT) in the postsynaptic bushy neurons; this effect in turn reduces the temporal coding capability in these neurons. We will characterize the lLT from bushy cells after inducing NIHL, and test the fine temporal coding of the bushy cell by activating the auditory nerve fiber with a realistic Poisson distributed spike train in the slice. Data from this project will complement and enhance the existing wealth of information regarding the peripheral effect of noise induced hearing loss. Ultimately we would like to address whether the integrity of the central auditory pathway can be preserved with drug or device intervention after NIHL, because CNS functional integrity is an essential component of successful post hearing loss intervention.