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）：在过去的十年中，大量工作已将听觉系统的多动症与耳鸣的重要神经相关。对于某些形式的耳鸣，首先在背侧耳蜗核（DCN）中观察到这种多动症，在该核中，它是由于听觉神经正常输入而触发的。通过更好地理解a）在DCN中，对耳鸣相关的多动性的细胞起源和潜在机制可能会增强对耳鸣的有效治疗的能力。拟议的研究将迈出满足所有三个需求的重大步骤。 AIM 1和2将采用电生理学和药理方法的组合来确定受体介导的可塑性和离子通道改变的相对重要性，而离子通道改变是多动症的潜在机制。 AIM 3将研究其他脑干听觉核对DCN多动症水平的下降途径的影响。我们将专注于两种不同的离心途径，一种来自下丘，另一个来自上橄榄络合物。这些途径对DCN多动症的影响将通过选择性病变，以及对其原产结构的电气和声刺激来研究。 AIM 4将检查噪声暴露对听觉系统脑干水平上听觉中心化学反应的长期后果。 AIM 5将集中在下丘中，作为耳鸣相关多动症的可能发电机位点。我们将使用电生理记录方法来证明由于强烈的噪声暴露而在下丘中发生了多动症。然后将烧毁DCN，以确定IC多动症是否持续还是消失。结果将使我们能够确定IC是耳鸣的独立部位，还是仅从DCN级别获得这种多动症。从这项研究中获得的耳鸣机制的更深入的理解将为转化研究的基础提供抗细胞核治疗的发展。 相关性：通过a）更好地理解在背侧耳蜗核中细胞起源和耳鸣相关多动的基础机制，可以增强为耳鸣开发有效治疗的能力，b）b）b）如何通过从高级听觉中心从降级输入来控制这种活动。拟议的研究将迈出满足两种需求的重大步骤。从这项研究中获得的耳鸣机制的更深入的理解将为转化研究的基础提供抗细胞核治疗的发展。