Central mechanisms related to tinnitus

与耳鸣相关的中枢机制

基本信息

批准号：
7714261
负责人：
James A Kaltenbach
金额：
$ 2.23万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7714261
关键词：
Acoustics Animal Model Animals Attenuated Carbachol Cells Characteristics Cisplatin Class Clinic Control Animal Development Disease Drug usage Elements Elevation Family Financial compensation Fusiform Cell Gene Expression Generations Genes Glutamates Goals Hair Cells Hamsters Hyperactive behavior Injection of therapeutic agent Injury Inner Hair Cells Ion Channel Kynurenic Acid Label MK801 Membrane Methods Modeling Molecular Morphology N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Neurons Neurotransmitter Receptor Neurotransmitters Nicotinic Receptors Noise Noise Induced Tinnitus Otolaryngology Outer Hair Cells Pathway interactions Patients Polymerase Chain Reaction Principal Investigator Process Rate Role Signal Transduction Source Strychnine System Testing Tinnitus Transcriptional Activation Up-Regulation Visit Work base cell injury cell type design dorsal cochlear nucleus excitotoxicity expectation genetic regulatory protein granule cell in vivo insight light microscopy neurobiotin nociceptin receptor programs protective effect receptor relating to nervous system response sound

项目摘要

Tinnitus remains one of the major reasons for patient visits to the otolaryngology clinic, but effective pharmacological therapies have yet to be developed for this disorder. The recent development of animal models of experimentally induced tinnitus offers promising new avenues for understanding the mechanisms of tinnitus and for the development of effective treatments. In this project we will seek further insights into the mechanisms underlying tinnitus using noise-induced hyperactivity in the dorsal cochlear nucleus as a model of tinnitus producing signals. First, we will investigate the roles of outer hair cell loss and excitotoxicity as triggers of hyperactivity in the DON. The goal will be to test the hypothesis that noise-induced hyperactivity consists of two components, one of which correlates strongly with the amount of outer hair cell loss, the other of which involves excitotoxic injury via NMDA receptors. Second, we will use quantitative PCR and related methods to identify the molecular correlates of noise-induced hyperactivity. We will test the prediction that hyperactivity is associated with changes in gene expression for one or more of the key neurotransmitter receptors, ion channel conductance channels, or regulatory proteins that control the level of excitability of DCN neurons. Third, pharmacological studies will be conducted in the DCN to dissect out the principal circuit elements involved in the generation of hyperactivity. These studies will determine whether the fusiform cells are the major generators of hyperactivity and whether that hyperactivity can be modulated by activating the granule cell-cartwheel cell pathway. Fourth, further insight into the identity of hyperactive cells will be sought by juxtacellular labeling of cells from which recordings of spontaneous activity have been obtained. Cells displaying hyperactivity will be distinguished from those with normal activity based on their morphological characteristics. And fifth, we will examine the role of changes in ion channel conductances as a possible mechanism contributing to the generation of hyperactivity. This role will be tested by determining whether neurons in the DCN of exposed animals show altered sensitivity to agents that block selected ion channels. Our focus will be on channels which have a strong influence on the level of spontaneous activity and which have been found in other systems to be up- or down-regulated following loss of afferent input.

耳鸣仍然是患者访问耳鼻喉科诊所的主要原因之一，但有效的药理疗法尚未针对这种疾病开发。实验诱导的耳鸣的动物模型的最新发展为理解耳鸣的机理和有效治疗的发展提供了有希望的新途径。在这个项目中，我们将寻求对耳鸣核中噪声诱导的多动症的基础机制的进一步见解，作为耳蜗核作为耳鸣信号的模型。首先，我们将研究外部细胞损失和兴奋性毒性的作用，因为DON中的多动症触发因素。目的是检验以下假设：噪声诱导的多动症由两个组成部分组成，其中一个与外毛细胞损失的量密切相关，另一种是通过NMDA受体进行兴奋的毒性损伤。其次，我们将使用定量PCR和相关方法来识别噪声诱导的多动症的分子相关性。我们将测试一个预测，即多动症与一个或多个关键神经递质受体，离子通道电导通道或控制DCN神经元兴奋性水平的调节蛋白的基因表达变化有关。第三，将在DCN中进行药理学研究，以剖析与活动过度产生有关的主要电路元素。这些研究将确定梭形细胞是否是多动症的主要发生器，以及该多动症是否可以通过激活颗粒细胞卡车细胞途径来调节。第四，通过将自发活性记录的细胞并列标记来寻求对多动细胞身份的进一步见解。表现出多动症的细胞将与具有正常活性的细胞根据其形态特征区分开。第五，我们将研究离子通道电导中变化的作用，这是导致多动症产生的可能机制。通过确定暴露动物DCN中的神经元是否显示出对阻断选定离子通道的药物的敏感性的改变，将测试该作用。我们的重点将放在对自发活动水平产生强大影响的通道上，并且在其他系统中发现这些渠道会在丢失传入输入后被上调或下调。