Neuronal hyperactivity: tinnitus and distress

耳鸣是一种幽灵般的声音感觉，在美国约有17%的成年人受到影响。确实有 目前还没有FDA批准的治疗耳鸣的药物。人体成像研究和动物研究 提示耳鸣与耳蜗性损伤后中枢听觉神经元的过度活动有关。耳鸣- 相关的多动症通常被描述为自发放电增加和神经增加。 同步性。本研究的目的是阐明多动的细胞机制(S)，并 确定控制多动症以缓解耳鸣症状的药物疗法。最新研究 已经确定了可能导致耳鸣相关多动的两种可能机制：向下- GABA能抑制的调节和受影响神经元内在特性的变化。鲜为人知 关于这两种机制对多动的相对贡献。我们将通过以下方式解决这个问题 结合细胞内标记和免疫染色研究听神经元的内在特性 对于GABA能神经元。“残留抑制”，是指耳鸣出现后的短暂抑制。 大约80%的耳鸣患者可以诱发出声音。我们发现残留物的机制 抑制可能是通过声音诱发对中枢听神经元自发放电的抑制来解释的， 而代谢型谷氨酸受体(MGluRs)在这种抑制中起着关键作用。我们建议 自发放电和神经同步性升高是耳鸣及其抑制的神经相关因素 应该能缓解耳鸣。我们的初步数据表明，II组mGluR的系统性应用 激动剂Eglumegad可靠地抑制下丘(IC)和听觉皮质(AC)的自发放电 在小鼠体内停留约两个小时。这种药物对声音诱发活动的影响可以忽略不计。类似药物 在杏仁核观察到了影响，这是一个很可能与耳鸣相关的痛苦有关的大脑结构。 此外，Eglumegad应用系统地抑制了小鼠的耳鸣超过一个小时。三 假说将会得到检验。首先，我们假设小鼠和其他动物一样表现出与耳鸣相关的多动。 模特们。将使用常规的细胞外和多电极阵列记录来评估自发， 耳鸣阳性患者AC、IC和杏仁核神经元的声诱发放电和神经同步性 控制小鼠。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。使用锐利微电极的细胞内记录将在清醒小鼠的IC中进行 然后用神经生物素细胞内标记，然后免疫化学区分GABA能和非GABA能 GABA能神经元。第三，我们假设激活第二组mGluRs可以减少脑内多动。 AC、IC和杏仁核，也抑制耳鸣和耳鸣相关的痛苦。Eglumegad将被注射 从系统上讲。在此之前，将在神经元中评估自发的、声音诱发的放电和神经同步 注射毒品后。与耳鸣有关的痛苦将通过大理石埋藏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.