Differential Pathologies Resulting from Sound Exposure: Tinnitus vs Hearing Loss

描述（由申请人提供）：耳鸣是一种没有外部来源的声音感知，是一种复杂的感知现象，影响美国17%的成年人的生活质量。尽管耳鸣的普遍性和发病率，但其病理生理机制尚不清楚，也没有普遍认可的医学治疗方法。耳鸣最常见的原因之一是暴露在大声的声音中。在人类和实验动物中，声音暴露通常会导致听力丧失，但只是偶尔会引起耳鸣。我对这种声音暴露的抵抗力知之甚少。我的最终目标是确定耳鸣动物模型中耳鸣抵抗的机制，以开发有效的人类耳鸣保护。确定耳鸣抵抗机制的第一步是发现在耳鸣阳性和耳鸣阴性动物中差异表达的神经关联。先前的研究已经确定了几种与耳鸣有关的神经相关物质。异常高的自发活动经常与耳鸣有关。然而，尽管一些研究表明多动与耳鸣的行为证据呈正相关，但其他研究表明，当所有动物对声音暴露都表现出多动时，并非所有暴露的动物都表现出耳鸣的证据。该项目将确定多动症或其特殊特征是否可以作为区分一般听力损失和耳鸣的生物标志物。我将使用我们实验室开发的耳鸣小鼠模型。将对三组小鼠进行研究：(1)有耳鸣行为症状的暴露在声音中的小鼠，(2)没有耳鸣的暴露在声音中的小鼠，以及(3)没有暴露在声音中的小鼠。目的1将确定多动症是否与耳鸣或/和听力损失有关。听觉脑干、中脑和皮层神经元的过度活跃将通过测量它们在细胞外记录时的自发和声诱发放电率来评估。比较这三组小鼠的放电活动和过度活跃神经元的相对数量将检验我们的假设是否正确。目的2将确定听觉神经元过度活跃的细胞机制。对三组动物的过度活跃神经元进行细胞内记录。我将测量和比较它们的静息膜电位、输入电阻、尖峰阈值和放电特性。这个研究项目的结果可能区分耳鸣和听力损失基于特定的特征多动。建议的学习将帮助我掌握两个重要的技能

DESCRIPTION (provided by applicant): Tinnitus, the perception of a sound without an external source, is a complex perceptual phenomenon affecting the quality of life in 17% of the adult population in the United States. Despite its ubiquity and morbidity, the pathophysiology of tinnitus is poorly understood, and there is no universal medically recognized treatment. One of the most common causes of tinnitus is exposure to loud sounds. In humans and laboratory animals sound exposure typically leads to hearing loss, but only occasionally to tinnitus. Little i known about such resistance to sound exposure. My ultimate goal is to determine the mechanisms responsible for tinnitus resistance in tinnitus animal models to develop effective tinnitus protection in humans. The first step in identifying the mechanism(s) responsible for tinnitus resistance would be to discover a neural correlate that is differentially expressed in tinnitus positive and tinnitus negative animals. Previous research has identified several neural correlates that have tested positive for tinnitus. Abnormally high spontaneous activity has frequently been linked to tinnitus. However, while some studies demonstrate that hyperactivity positively correlates with behavioral evidence of tinnitus, others show that when all animals develop hyperactivity to sound exposure, not all exposed animals show evidence of tinnitus. This project will determine whether hyperactivity or its particular features can be used as a biomarker to separate general hearing loss from tinnitus. I will use a tinnitus mouse model that has been developed in our laboratory. Three groups of mice will be studied: (1) sound exposed mice that develop behavioral signs of tinnitus, (2) exposed mice that do not develop tinnitus, and (3) unexposed mice. Aim 1 will determine whether hyperactivity is linked to tinnitus or/and to hearing loss. Hyperactivity in neurons of the auditory brain stem, midbrain and cortex will be assessed by measuring their spontaneous and sound-evoked firing rates during extracellular recording. Comparison of firing activity and the relative number of hyperactive neurons between these three groups of mice will test whether our hypothesis is correct. Aim 2 will determine the cellular mechanism underlying hyperactivity in auditory neurons. Intracellular recordings will be completed on hyperactive neurons in the three groups of animals. I will measure and compare their resting membrane potentials, input resistances, spike thresholds, and firing properties. The results of this research project may differentiate tinnitus from hearing loss based on particular characteristics of hyperactivity. The proposed study will help me to master skills in two important electrophysiological techniques. Aim 1 will provide training for single unit extracellular recordin from neurons of the major auditory centers in awake animals. Aim 2 will allow me to acquire expertise with intracellular recording techniques using sharp glass microelectrodes. My current expertise in a behavioral tinnitus model combined with this training in electrophysiology will help me to become a capable auditory scientist.