Central auditory plasticity as a basis of tinnitus

中枢听觉可塑性是耳鸣的基础

• 批准号: 7742160
• 负责人: James A Kaltenbach
• 金额: $ 38.86万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742160
• 关键词: Ablation; Acetylcholine; Acoustic Nerve; Acoustic Stimulation; Acute; Affect; Amino Acids; Amygdaloid structure; Animals; Area; Auditory; Auditory system; Brain; Brain Stem; Cell Nucleus; Cells; Chemicals; Chemistry; Choline O-Acetyltransferase; Cholinergic Antagonists; Cochlear nucleus; Complex; Contralateral; Control Animal; Development; Drug usage; Electric Stimulation; Etiology; Excision; Fusiform Cell; Generations; Glutamates; Glycine; Hamsters; Hyperactive behavior; Inferior Colliculus; Ion Channel; Ions; Ipsilateral; Label; Lateral; Lesion; Maintenance; Maps; Measures; Mediating; Methods; Microelectrodes; Neurons; Neurotransmitters; Noise; Pathway interactions; Population; Property; Relative (related person); Research; Role; Site; Structure; Structure of tractus olivocochlearis; Synaptic Receptors; Techniques; Testing; Time; Tinnitus; Translational Research; Tropicamide; Work; auditory nuclei; base; cell type; dorsal cochlear nucleus; effective therapy; enzyme activity; gamma-Aminobutyric Acid; prevent; receptor; receptor sensitivity; relating to nervous system; response; sound

DESCRIPTION (provided by applicant): Much work over the past decade has implicated hyperactivity in the auditory system as an important neural correlate of tinnitus. For some forms of tinnitus, this hyperactivity is first observed in the dorsal cochlear nucleus (DCN), where it is triggered by loss of normal input from the auditory nerve. The ability to develop effective treatments for tinnitus is likely to be enhanced by a better understanding of a) the cellular origins and underlying mechanisms of tinnitus-related hyperactivity in the DCN b) how this activity is controlled by descending inputs from higher order auditory centers, and c) how DCN hyperactivity influences the emergence of hyperactivity at higher levels of the auditory system. The proposed research will take major steps toward the fulfillment of all three needs. Aims 1 and 2 will apply a combination of electrophysiological and pharmacological approaches to determine the relative importance of receptor-mediated plasticity and ion channel alterations as underlying mechanisms of hyperactivity. Aim 3 will investigate the influence of descending pathways from other brainstem auditory nuclei on the level of hyperactivity in the DCN. We will focus on two different centrifugal pathways, one from the inferior colliculus and the other from the superior olivary complex. The influence of these pathways on DCN hyperactivity will be investigated by selective lesioning, as well as by electrical and acoustic stimulation of their structures of origin. Aim 4 will examine the long-term consequences of noise exposure on the chemistry of auditory centers at brainstem levels of the auditory system. Aim 5 will focus on the inferior colliculus as a possible generator site of tinnitus related hyperactivity. We will use electrophysiological recording methods to demonstrate that hyperactivity develops in the inferior colliculus as a result of intense noise exposure. The DCN will then be ablated to determine whether IC hyperactivity persists or disappears. The results will enable us to establish whether the IC is an independent site of tinnitus generation or instead, simply receives this hyperactivity from the DCN level. The deeper understanding of tinnitus mechanisms to be obtained from this study will provide a basis for translational research oriented toward the development of anti-tinnitus therapies. Relevance: The ability to develop effective treatments for tinnitus is likely to be enhanced by a) a better understanding of the cellular origins and underlying mechanisms of tinnitus- related hyperactivity in the dorsal cochlear nucleus, and b) how this activity might be controlled by descending inputs from higher order auditory centers. The proposed research will take major steps toward the fulfillment of both needs. The deeper understanding of tinnitus mechanisms to be obtained from this study will provide a basis for translational research oriented toward the development of anti-tinnitus therapies.

描述（由申请人提供）：过去十年的许多工作都表明听觉系统的过度活跃是耳鸣的重要神经相关因素。对于某些形式的耳鸣，这种过度活跃首先在耳蜗背核 (DCN) 中观察到，这是由听觉神经正常输入丧失引发的。通过更好地了解 a) DCN 中耳鸣相关多动的细胞起源和潜在机制 b) 这种活动如何通过来自更高阶听觉中枢的降序输入来控制，可能会增强开发有效耳鸣治疗方法的能力， c) DCN 多动如何影响听觉系统高层多动的出现。拟议的研究将采取重大步骤来满足所有这三个需求。目标 1 和 2 将结合电生理学和药理学方法来确定受体介导的可塑性和离子通道改变作为多动症潜在机制的相对重要性。目标 3 将研究其他脑干听觉核团的下行通路对 DCN 过度活跃水平的影响。我们将重点关注两种不同的离心路径，一种来自下丘，另一种来自上橄榄复合体。这些通路对 DCN 过度活跃的影响将通过选择性损伤以及对其起源结构的电和声刺激来研究。目标 4 将检查噪声暴露对听觉系统脑干水平听觉中枢化学的长期影响。目标 5 将重点关注下丘作为耳鸣相关多动症的可能发生部位。我们将使用电生理记录方法来证明由于强烈的噪音暴露而导致下丘过度活跃。然后将消融 DCN，以确定 IC 过度活跃是否持续存在或消失。结果将使我们能够确定 IC 是否是耳鸣产生的独立部位，或者只是从 DCN 水平接收这种过度活动。从这项研究中获得的对耳鸣机制的更深入了解将为面向抗耳鸣疗法开发的转化研究提供基础。 相关性：通过a）更好地了解耳蜗背核耳鸣相关过度活跃的细胞起源和潜在机制，以及b）如何通过下降来控制这种活动，可能会增强开发耳鸣有效治疗方法的能力。来自更高阶听觉中心的输入。拟议的研究将为满足这两种需求采取重大步骤。从这项研究中获得的对耳鸣机制的更深入了解将为面向抗耳鸣疗法开发的转化研究提供基础。