CENTRAL MECHANISMS RELATED TO TINNITUS

与耳鸣相关的中枢机制

• 批准号: 6603753
• 负责人: James A Kaltenbach
• 金额: $ 36.08万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603753
• 关键词: audiometry; auditory nuclei; autoradiography; behavior test; disease /disorder model; ear hair cell; glutamate receptor; glutamates; hamsters; high performance liquid chromatography; loudness; microdialysis; microelectrodes; model design /development; nerve threshold; neural information processing; neural plasticity; neurochemistry; neurophysiology; neurotransmitter receptor; noise biological effect; tinnitus

The main objective of this study is to further develop our animal model of tinnitus with the goal of defining physiological and chemical correlates of this hearing disorder at the level of the cochlear nucleus. This project builds on our recent studies showing that intense sound exposure at levels sufficient to induce tinnitus in humans leads to increases in spontaneous neural activity (hyperactivity) in the dorsal cochlear nucleus. The specific aims of this project are as follows: 1) Two-choice behavioral tests will be employed to characterize the pitch and loudness of sound-induced tinnitus in hamsters. The relationship of these measures to altered activity in the cochlear nucleus will be investigated by quantifying the magnitude and spatial distribution patterns of hyperactivity in the same animals. 2) The laminar distribution of the hyperactive cells will be determined by marking sites where activity is highest with horseraddish peroxidase,HRP. Further clarification of the cellular substrates underlying hyperactivity will be sought by immunolabeling hyperactive cells with antibodies to the c-fos gene product in cochlear nucleus sections. 3) The cochlear nuclei will then be analyzed chemically to determine whether increases in spontaneous activity are correlated with chemical changes. The concentrations of selected neurotransmitter candidates, neurotransmitter-associated enzymes, and neurotransmitter receptors will be assayed using high performance liquid chromatography and autoradiography. Changes in these elements will be mapped along the tonotopic axis. Chemically altered areas will be identified and correlated with regions showing hyperactivity. 4) The possible role of cochlear outer hair cell loss as a trigger of hyperactivity and tinnitus will be investigated by testing whether animals treated with cisplatin, an agent known to induce tinnitus in humans and to cause selective outer hair cell loss in humans and animals, show evidence of behavioral tinnitus and hyperactivity in the cochlear nucleus. Findings from these experiments are expected to contribute to an understanding of central mechanisms of tinnitus and pave the way toward the development of anti-tinnitus therapies.

这项研究的主要目的是进一步开发耳鸣动物模型，目的是在耳蜗核水平上确定这种听力障碍的生理和化学相关性。 该项目建立在我们最近的研究基础上，该研究表明，足以诱发人类耳鸣的强烈声音暴露会导致耳蜗背核的自发神经活动（多动）增加。该项目的具体目标如下： 1）采用二选一行为测试来表征仓鼠声音引起的耳鸣的音高和响度。 这些措施与耳蜗核活动改变的关系将通过量化同一动物多动的幅度和空间分布模式来研究。 2) 过度活跃细胞的层状分布将通过用辣根过氧化物酶 (HRP) 标记活性最高的位点来确定。 通过在耳蜗核切片中用 c-fos 基因产物的抗体对过度活跃的细胞进行免疫标记，可以进一步阐明过度活跃的细胞底物。 3) 然后对耳蜗核进行化学分析，以确定自发活动的增加是否与化学变化相关。 将使用高效液相色谱和放射自显影来测定选定的神经递质候选物、神经递质相关酶和神经递质受体的浓度。 这些元素的变化将沿着主题轴映射。 化学改变的区域将被识别并与表现出过度活跃的区域相关联。 4) 将通过测试是否用顺铂治疗动物来研究耳蜗外毛细胞损失作为多动症和耳鸣触发因素的可能作用，顺铂是一种已知会诱发人类耳鸣并导致人类和动物选择性外毛细胞损失的药物，显示行为性耳鸣和耳蜗核过度活跃的证据。 这些实验的结果预计将有助于了解耳鸣的核心机制，并为抗耳鸣疗法的发展铺平道路。