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

描述(申请人提供)：耳鸣，没有外部声源的声音的感觉，可以在外部声音的偏移后被短暂地抑制。这种现象被称为“残留抑制”，尽管其潜在的细胞机制仍不清楚，但人们已经知道近40年了。这项研究的目的是阐明残余抑制的机制(S)，以确定一类可以延长残余抑制或在不施加任何外部声音的情况下抑制耳鸣的药物。我们实验室的初步观察为研究残留抑制的理论和方法奠定了基础。我们发现，响亮、持续的声音刺激(典型的是引起残留抑制的声音)可以在残留抑制的持续时间内抑制中枢听神经元的自发放电。异常高的自发放电与耳鸣的行为表现有关；因此，抑制这种放电可能是残留抑制的潜在机制。三个主要假设将在拟议的项目中得到检验。首先，我们假设持续几秒的声音刺激通常会触发几秒钟的残留抑制，只要残留抑制持续，就会抑制听神经元的自发放电。我们将测量耳鸣小鼠听觉神经元对几秒声音刺激的自发放电抑制的持续时间。其次，我们假设代谢型谷氨酸受体(MGluRs)在这种抑制中起关键作用。我们将量化细胞外记录的以mGluRs为靶点的药物在离子导入应用前后对听神经元的抑制。第三，我们假设在听觉神经元的声音触发抑制和残留抑制之间存在联系。为了验证这一假设，我们将系统地注射影响抑制的mGluR靶向药物，以确定这些药物是否也影响残留抑制。靶向mGluRs的药物适合于治疗耳鸣，因为它们以纳摩尔浓度与mGluRs结合，容易穿透血脑屏障，但几乎没有临床副作用。 公共卫生相关性：拟议的研究将提高我们对耳鸣的主要机制的了解，并为开发治疗耳鸣的治疗药物提供基础。

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. PUBLIC HEALTH RELEVANCE: The proposed study will improve our knowledge of the central mechanisms responsible for tinnitus and provide a foundation for the development of therapeutic drugs to treat tinnitus.