Differential Pathologies Resulting from Sound Exposure: Tinnitus vs Hearing Loss

声音暴露引起的不同病理：耳鸣与听力损失

• 批准号: 8649522
• 负责人: Ryan James Longenecker
• 金额: $ 2.65万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649522
• 关键词: Acoustics; Adult; Affect; Animal Model; Animals; Auditory; Auditory area; Behavioral; Biological Markers; Brain Stem; CBA/CaJ Mouse; Characteristics; Cochlear nucleus; Complex; Down-Regulation; Electrophysiology (science); Exercise; Exposure to; Functional disorder; Glass; Goals; Hearing; Human; Hyperactive behavior; Inferior Colliculus; Laboratories; Laboratory Animals; Link; Measurement; Measures; Membrane Potentials; Methodology; Microelectrodes; Midbrain structure; Modeling; Morbidity - disease rate; Mus; Neurons; Noise; Outcome; Pathology; Pattern; Perception; Physiologic pulse; Population; Property; Quality of life; Reflex action; Relative (related person); Research; Research Project Grants; Resistance; Rest; Scientist; Source; Techniques; Testing; Tinnitus; Training; United States; Work; awake; base; comparison group; extracellular; hearing impairment; in vivo; mouse model; otoacoustic emission; prepulse inhibition; public health relevance; relating to nervous system; response; skills; sound

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.

描述(申请人提供)：耳鸣，没有外部来源的声音的感觉，是一种复杂的感知现象，在美国17%的成年人中影响生活质量。尽管耳鸣普遍存在，发病率也很高，但其病理生理学机制仍知之甚少，也没有普遍的医学公认的治疗方法。耳鸣最常见的原因之一是暴露在嘈杂的声音中。在人类和实验动物中，暴露在声音中通常会导致听力损失，但只是偶尔会出现耳鸣。我对这种对声音暴露的抵抗力知之甚少。我的最终目标是在耳鸣动物模型中确定耳鸣抵抗的机制，以开发对人类有效的耳鸣保护。确定耳鸣抵抗机制(S)的第一步将是发现一种神经关联，这种关联在耳鸣阳性和耳鸣阴性动物中差异表达。之前的研究已经确定了几个神经相关因素，这些因素被检测出耳鸣呈阳性。异常高的自发活动经常被认为与耳鸣有关。然而，虽然一些研究表明多动症与耳鸣的行为证据呈正相关，但另一些研究表明，当所有动物对声音暴露产生多动症时，并不是所有暴露在声音中的动物都表现出耳鸣的证据。该项目将确定是否可以将多动症或其特殊特征用作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)暴露在声音中的小鼠出现耳鸣的行为迹象，(2)暴露在声音中的小鼠不会出现耳鸣，以及(3)未暴露的小鼠。目标1将确定多动症是否与耳鸣或/和听力损失有关。听觉脑干、中脑和皮质神经元的过度活动将通过在细胞外记录期间测量它们的自发和声音诱发的放电率来评估。对这三组小鼠的放电活动和过度活跃神经元的相对数量进行比较，将检验我们的假设是否正确。目的2将确定听觉神经元多动的细胞机制。细胞内的记录将在三组动物的过度活跃的神经元上完成。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。这一研究项目的结果可能会根据多动症的特殊特征来区分耳鸣和听力损失。拟议中的研究将帮助我掌握两个重要的技能 电生理技术。Aim 1将为清醒动物主要听觉中枢神经元的单个细胞外记录提供训练。Aim 2将使我获得使用锐利玻璃微电极的细胞内记录技术的专业知识。我目前在行为耳鸣模型方面的专业知识与电生理学方面的培训相结合，将会有所帮助。 让我成为一名有能力的听觉科学家。