Neuronal hyperactivity: tinnitus and distress

神经元过度活跃：耳鸣和痛苦

• 批准号: 10064143
• 负责人: Alexander Galazyuk
• 金额: $ 46.58万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064143
• 关键词: Acoustics; Address; Adult; Affect; Agonist; Agreement; Amygdaloid structure; Animal Experimentation; Animal Model; Animals; Auditory; Auditory Perception; Auditory area; Auditory system; Behavioral; Brain; Cochlea; Data; Distress; Down-Regulation; Drug Targeting; Electrophysiology (science); FDA approved; Goals; Hour; Human; Hyperactivity; Immunochemistry; Inferior Colliculus; Injections; Label; Limbic System; Link; Loudness; Marble; Metabotropic Glutamate Receptors; Methods; Microelectrodes; Minor; Mus; Neurons; Operant Conditioning; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Pilot Projects; Play; Property; Reflex action; Research; Residual state; Role; Structure; Symptoms; Testing; Therapeutic; Tinnitus; United States; awake; excitatory neuron; extracellular; human imaging; imaging study; inhibitory neuron; insight; multi-electrode arrays; neural correlate; neurobiotin; neuromechanism; relating to nervous system; response; sound; vocalization

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.

耳鸣是一种幻觉，影响着美国约 17% 的成年人。 目前尚无 FDA 批准用于人体成像研究和动物研究的耳鸣治疗药物。 表明耳鸣与耳蜗损伤后中枢听觉神经元的过度活跃有关。 相关的多动症通常被描述为自发放电增加和神经元增加 这项研究的目的是阐明导致多动症的细胞机制。 确定控制多动症以缓解耳鸣症状的药物疗法。 已经确定了两种可能导致耳鸣相关多动症的机制： 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个问题。 结合细胞内标记和免疫染色研究听觉神经元的内在特性 对于 GABA 能神经元，“残余抑制”，即大声响后耳鸣的短暂抑制。 声音，可以诱发大约80%的耳鸣患者，我们发现了残留的机制。 抑制可能是通过声音诱发的中枢听觉神经元自发放电抑制来解释的， 我们认为代谢型谷氨酸受体 (mGluR) 在这种抑制中发挥着关键作用。 自发放电和神经同步性的升高是耳鸣的神经相关因素，并且抑制它们 我们的初步数据表明，全身应用 II 组 mGluR 应该可以缓解耳鸣。 激动剂 elumegad 可靠地抑制下丘 (IC) 和听觉皮层 (AC) 的自发放电 类似药物对小鼠神经元的声音诱发活动的影响可以忽略不计。 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困扰有关的大脑结构。 此外，Eglumegad 对小鼠进行了系统性抑制耳鸣超过一个小时。 首先，我们希望小鼠像其他动物一样表现出耳鸣相关的多动症。 传统的细胞外和多电极阵列记录将用于评估自发的、 耳鸣阳性和耳鸣中 AC、IC 和杏仁核神经元的声音诱发放电和神经同步 其次，我们发现兴奋性和抑制性神经元受到不同程度的影响。 使用锋利的微电极在清醒小鼠的 IC 中进行细胞内记录。 然后用神经生物素进行细胞内标记，然后进行免疫化学来区分 GABA 能与非 GABA 能 第三，我们勇敢地认为 II 组 mGluR 的激活可以减少神经元的过度活跃。 AC、IC 和杏仁核也可以注射 Eglumegad 来抑制耳鸣和耳鸣相关的困扰。 系统地评估神经元的自发性、声音诱发的放电和神经同步性。 药物注射后，将通过弹珠埋藏和发声测试来评估耳鸣相关的不适。