Neural Mechanism Underlying Sound-Evoked Suppression of Tinnitus:Residual Inhibit

声诱发耳鸣抑制的神经机制：残留抑制

基本信息

批准号：
8968829
负责人：
Alexander Galazyuk
金额：
$ 32.73万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-23 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968829
关键词：
Acoustics Adult Adverse effects Affect Agonist Auditory Auditory area Auditory system Behavioral Binding Blood - brain barrier anatomy Characteristics Clinical Clinical Trials Cochlear nucleus Complex Data Drug Targeting Exhibits Foundations Goals Hyperactive behavior Inferior Colliculus Knowledge Laboratories Lead Link Measures Metabotropic Glutamate Receptors Midbrain structure Mus Neurons Perception Pharmaceutical Preparations Pharmacologic Substance Pilot Projects Play Population Process Quality of life Reducing Agents Reflex action Research Residual state Source Stimulus Structure Techniques Testing Therapeutic Effect Tinnitus United States awake base extracellular improved interest millisecond mouse model nanomolar nervous system disorder neuromechanism prepulse inhibition receptor receptor expression response sound therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Tinnitus, the perception of a sound without an external acoustic source, can be suppressed briefly following the offset of an external sound. This phenomenon, termed "residual inhibition," has been known for almost four decades, although its underlying cellular mechanism remains unknown. The goal of the proposed research is to elucidate the mechanism(s) responsible for residual inhibition to identify a class of drug that can either prolong residual inhibition or suppress tinnitus without the application of any external sounds. Preliminary observations in our laboratory have established the foundation for a theoretical and methodological approach to study residual inhibition. We have found that a loud, long-lasting sound stimulus (typical for sounds that evoke residual inhibition) can suppress spontaneous firing in central auditory neurons for as long as the duration of residual inhibition. Abnormally high spontaneous firing has been linked to behavioral manifestations of tinnitus; therefore, suppression of this firing is a plausible candidate for the underlying mechanism of residual inhibition. Three major hypotheses will be tested in the proposed project. First, we hypothesize that sound stimuli lasting several seconds, which typically trigger seconds of residual inhibition, suppress spontaneous firing in auditory neurons for as long as the residual inhibition lasts. We will measure the duration of suppression of spontaneous firing in auditory neurons in mice with tinnitus in response to sound stimuli of several seconds. Second, we hypothesize that metabotropic glutamate receptors (mGluRs) play a key role in this suppression. We will quantify the suppression in auditory neurons recorded extracellularly before and after iontophoretic application of drugs targeting mGluRs. Third, we hypothesize that there is a link between sound-triggered suppression in auditory neurons and residual inhibition. To test this hypothesis, we will inject the mGluR-targeting drugs that affect suppression systemically to determine whether these drugs also affect residual inhibition. Drugs targeting mGluRs are suitable for treating tinnitus because they bind to mGluRs at nanomolar concentrations, easily penetrate the blood-brain barrier and yet show few clinical side effects.

描述（由申请人提供）：耳鸣，没有外部声音源的声音的感知，可以在外部声音偏移后短暂抑制。这种现象称为“残留抑制”，尽管其潜在的细胞机制仍然未知，但已闻名已有近四十年了。拟议的研究的目的是阐明负责残留抑制的机制，以识别可以在不应用任何外部声音的情况下延长残留抑制或抑制耳鸣的一类药物。我们实验室的初步观察为研究残留抑制的理论和方法学方法奠定了基础。我们发现，只要在残留抑制的持续时间内，响亮而持久的声音刺激（典型的唤起残留抑制的声音）就可以抑制中央听觉神经元的自发性触发。异常高度的自发解雇与耳鸣的行为表现有关。因此，抑制这种射击是残留抑制的基本机制的合理候选者。在拟议的项目中将检验三个主要的假设。首先，我们假设声音刺激持续了几秒钟，通常会触发残留抑制的秒，只要残留抑制持续下去，在听觉神经元中自发发射。我们将测量带有耳鸣的小鼠听觉神经元自发性解散的持续时间，以响应几秒钟的声音刺激。其次，我们假设代谢型谷氨酸受体（MGLURS）在这种抑制中起着关键作用。我们将量化在靶向mglurs的药物施用之前和之后，在细胞外记录的听觉神经元中的抑制。第三，我们假设在听觉神经元中声触发的抑制与残留抑制之间存在联系。为了检验这一假设，我们将注入系统地影响抑制的MGLUR靶向药物，以确定这些药物是否还会影响残留抑制作用。靶向mglurs的药物适合治疗耳鸣，因为它们与纳米尔浓度的mglurs结合，很容易穿透血脑屏障，但几乎没有临床副作用。