Neuronal hyperactivity: tinnitus and distress

耳鸣是一种幻音，影响了美国约17%的成年人。有 目前没有FDA批准的药物用于耳鸣治疗。人类成像研究和动物研究 提示耳鸣与耳蜗损伤后中枢听觉神经元的过度活跃有关。锡- 相关的多动性通常被描述为自发放电的升高和神经活动的增加。 同步性本研究的目的是阐明多动症的细胞机制， 确定控制多动症的药物治疗，以缓解耳鸣症状。最近的研究 已经确定了两种可能的机制，可能是负责耳鸣相关的多动症：下降- GABA能抑制的调节和受影响神经元内在特性的变化。知之甚少 关于这两种机制对多动症的相对贡献。我们将通过以下方式解决这一问题： 结合细胞内标记和免疫染色研究听觉神经元的内在特性 对GABA能神经元的作用。“残留抑制”，短暂的抑制耳鸣后，介绍大声 耳鸣的症状有哪些？耳鸣的症状有哪些？我们发现， 抑制很可能是由中央听觉神经元中的自发放电的声音诱发抑制来解释的， 代谢型谷氨酸受体（mGluRs）在这种抑制中起关键作用。我们建议 提高自发放电和神经同步性是耳鸣的神经相关性， 应该能缓解耳鸣我们的初步数据表明，系统应用II组mGluR 受体激动剂Eglumegad可靠地抑制下丘（IC）和听皮层（AC）的自发放电 在小鼠的神经元中大约两个小时。这种药物对声音诱发的活动的影响微乎其微。类似药物 在杏仁核中观察到了影响，杏仁核是一种可能与耳鸣相关的痛苦有关的大脑结构。 此外，Eglumegad在小鼠中全身性应用耳鸣抑制超过1小时。三 将对假设进行检验。首先，我们假设老鼠像其他动物一样表现出耳鸣相关的多动症 模型常规细胞外和多电极阵列记录将用于评估自发性， 耳鸣患者AC、IC和杏仁核神经元的声诱发放电和神经同步性， 对照小鼠。其次，我们假设兴奋性和抑制性神经元受到不同的影响， 多动症。将在清醒小鼠的IC中使用尖锐微电极进行细胞内记录 然后用神经生物素进行细胞内标记，然后用免疫化学法区分GABA能与非GABA能。 GABA能神经元。第三，我们假设II组mGluRs的激活可以减少大脑中的多动性。 AC，IC和杏仁核，也抑制耳鸣和耳鸣相关的痛苦。将注射艾谷美加 系统地。自发的，声音诱发的放电和神经同步将在神经元中进行评估， 注射药物后。耳鸣相关的痛苦将通过大理石掩埋和发声测试进行评估。

Tinnitus is a phantom sound perception that affects about 17% of adults in the United States. There are currently no FDA-approved drugs for tinnitus treatment. Both human imaging studies and animal research suggest that tinnitus is linked to hyperactivity in central auditory neurons following cochlear insult. Tinnitus- related hyperactivity has commonly been described as an elevated spontaneous firing and increased neural synchrony. The goal of this study is to elucidate the cellular mechanism(s) responsible for hyperactivity and to identify pharmacological therapy for controlling hyperactivity to relieve tinnitus symptoms. Recent research has identified two possible mechanisms that may be responsible for tinnitus-related hyperactivity: down- regulation of GABAergic inhibition and changes in the intrinsic properties of affected neurons. Little is known about the relative contributions of these two mechanisms to the hyperactivity. We will address this question by studying intrinsic properties of auditory neurons in conjunction with intracellular labeling and immunostaining for GABAergic neurons. “Residual inhibition”, the brief suppression of tinnitus after presentation of loud sounds, can be induced in about 80% of tinnitus patients. We discovered that the mechanism of residual inhibition is likely explained by sound-evoked suppression of spontaneous firing in central auditory neurons, and that metabotropic glutamate receptors (mGluRs) play a critical role in this suppression. We propose that elevated spontaneous firing and neural synchrony are neural correlates of tinnitus and that their suppression should bring relief from tinnitus. Our preliminary data indicate that systemic application of the group II mGluR agonist Eglumegad reliably suppresses spontaneous firing in inferior colliculus (IC) and auditory cortex (AC) neurons in mice for about two hours. Sound-evoked activity is negligibly affected by this drug. Similar drug effects were observed in the amygdala, a brain structure likely to be involved in tinnitus-related distress. Furthermore, Eglumegad applied systemically suppressed tinnitus in mice for more than one hour. Three hypotheses will be tested. First, we hypothesize that mice show tinnitus-related hyperactivity like other animal models. Conventional extracellular and multi-electrode array recordings will be used to assess spontaneous, sound-evoked firing and neural synchrony in neurons of the AC, IC, and amygdala in tinnitus positive and control mice. Second, we hypothesize that excitatory and inhibitory neurons are differentially affected by hyperactivity. Intracellular recordings using sharp microelectrodes will be conducted in the IC of awake mice followed by intracellular labeling with neurobiotin and then immunochemistry to distinguish GABAergic vs non- GABAergic neurons. Third, we hypothesize that activation of group II mGluRs can reduce hyperactivity in the AC, IC, and amygdala and also suppress tinnitus and tinnitus-related distress. Eglumegad will be injected systemically. Spontaneous, sound-evoked firing and neural synchrony will be assessed in neurons before and after drug injection. Tinnitus-related distress will be evaluated by marble-burying and vocalization tests.