Experimental study of the cochlear amplifier

项目摘要/摘要 耳蜗产生的声音，耳声发射(OAEs)，已经被常规测量为非 用于诊断人类听力损失和研究实验性耳聋机制的侵入性工具 动物。然而，耳声发射产生和抑制的潜在机械机制仍不清楚。 最近在低相干干涉测量方面的技术突破使我们能够测量内部的振动 活体耳蜗和基因工程小鼠模型中的耳蜗区划分使研究成为可能 耳蜗微力学的分子机制。这项研究的目的是确定细胞 失真产物(DP)耳声发射(DPOAE)的起源和亚细胞机制 最常用的OAE，通过使用定制的扫描进行一系列新颖的活体实验 外差低相干干涉仪。我们最重要的假设是，在哺乳动物中，非线性 外毛细胞的机械电转导产生电DPS，而躯体运动将其转化 变成机械DPS和DPOAE。DPOAE抑制是由于抑制了原声诱发的 行波，DPOAE抑制调谐曲线(STC)与耳蜗相关但又不同 机械调谐。这一中心假设将通过进行以下实验来检验。实验 人们将通过测量网状板(RL)的振动来确定DPS的细胞起源。 健康耳蜗外毛细胞的顶端和基底膜(BM)以DP频率出现。 显示RL DPS大于BM DPS的数据将是第一次在体内证明DPOAE是 由外毛细胞产生。实验二将确定外毛细胞的体细胞运动性 通过测量RL和BM对双频电流电刺激的反应，在体内产生DPS 在α-tectorin蛋白突变(TectaC1509G/C1509G)小鼠中。因为这些小鼠有功能的躯体 盖层变形导致的运动和无效的发束运动和机电传导 膜，数据显示缺乏电诱发的RL和BM DPS将表明躯体运动 在体内不产生DP。第三个实验将研究DPOAE抑制的力学机制 并确定DPOAE STC与耳蜗机调谐之间的关系。DPOAE的STC At 2f1-f2将被测量并与BM f2和RL f2的STC以及 BM和RL.拟议的实验将证明DPOAE的起源，并揭示机械 抑制DPOAE的机制。DPOAE STC与耳蜗机调谐关系的研究结果 可以通过获得关于耳蜗的准确信息而潜在地使患者和基础科学研究受益 通过客观和非侵入性的DPOAE测量进行主动处理。

Project Summary/Abstract The cochlea-generated sounds, otoacoustic emissions (OAEs), have been routinely measured as a non- invasive tool for diagnosing hearing loss in humans and for studying cochlear mechanisms in experimental animals. However, underlying mechanical mechanisms of OAE generation and suppression remain unclear. Recent technological breakthroughs in low-coherence interferometry allow us to measure vibrations inside the cochlear partition in living cochleae and genetically engineered mouse models make it possible to study molecular mechanisms of cochlear micromechanics. The objective of this study is to determine the cellular origin and sub-cellular mechanisms responsible for generation of distortion product (DP) OAE (DPOAE), the most commonly used OAE, by conducting a series of novel in vivo experiments using a custom-built scanning heterodyne low-coherence interferometer. Our overarching hypothesis is that, in mammals, nonlinear mechanoelectrical transduction of outer hair cells generates electrical DPs and somatic motility converts them into mechanical DPs and DPOAEs. DPOAE suppression results from suppression of the primary tone-induced traveling waves, and the DPOAE suppression tuning curve (STC) is related to but different from cochlear mechanical tuning. This central hypothesis will be tested by conducting the following experiments. Experiment One will determine the cellular origin of DPs by measuring vibrations from the reticular lamina (RL) at the apical ends of outer hair cells and from the basilar membrane (BM) at DP frequencies in healthy cochleae. Data showing that RL DPs are larger than BM DPs will be the first in vivo demonstration that DPOAEs are generated by outer hair cells. Experiment Two will determine whether or not somatic motility of outer hair cells generates DPs in vivo by measuring RL and BM responses to electrical stimulation with two-frequency currents in alpha-tectorin protein mutant (TectaC1509G/C1509G) mice. Since these mice have functional somatic motility and ineffective hair-bundle motility and mechanoelectrical transduction due to the deformed tectorial membrane, data showing the lack of electrically evoked RL and BM DPs will indicate that somatic motility does not generate DP in vivo. The third experiment will study the mechanical mechanism of DPOAE suppression and determine the relationship between the DPOAE STC and cochlear mechanical tuning. The STC of DPOAE at 2f1-f2 will be measured and compared to the STCs of the BM f2 and RL f2 and iso-response curves of the BM and RL. The proposed experiments will demonstrate the origin of DPOAEs and reveal mechanical mechanisms of DPOAE suppression. Results on the relation of the DPOAE STC to cochlear mechanical tuning can potentially benefit patients and basic science research by gaining precise information on the cochlear active process through objective and noninvasive DPOAE measurement.