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.

耳鸣是一种幻影声音，影响了美国约17％的成年人。有 目前尚无通过FDA批准的耳鸣治疗药物。人类成像研究和动物研究 表明耳鸣与耳蜗损伤后中央听觉神经元的多动症有关。耳鸣- 相关的多动症通常被描述为高高的赞助和神经增加 同步。这项研究的目的是阐明负责多动症和对的细胞机制 确定药物治疗以控制多动症以减轻耳鸣症状。最近的研究 已经确定了可能导致耳鸣相关的多动症的两种可能机制： 调节GABA能抑制作用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症的相对贡献。我们将通过 研究听觉神经元与细胞内标记和免疫染色的内在特性 用于GABA能神经元。 “残留抑制”，响亮后，短暂抑制耳鸣 声音，大约80％的耳鸣患者可以诱导。我们发现残留的机制 在中央听觉神经元中，声音诱发的发起射击，抑制作用可能可以解释 代谢型谷氨酸受体（MGLURS）在这种抑制中起着关键作用。我们提出了这一点 提高的发射和神经同步是耳鸣的神经元相关性，并且它们的抑制作用 应该带来耳鸣。我们的初步数据表明II组的全身应用 激动剂Eglutegad可靠地抑制在下丘（IC）和听觉皮层（AC）中赞助的 小鼠的神经元大约两个小时。声音诱发的活动受此药物的影响可忽略不计。类似的药物 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困扰涉及的大脑结构。 此外，Eglumegad在小鼠中系统地施加了一小时以上的小鼠耳鸣。三 假设将进行检验。首先，我们假设小鼠像其他动物一样表现出与耳鸣相关的多动症 型号。常规的细胞外和多电极阵列记录将用于评估赞助， 在耳鸣阳性和 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。使用尖锐的微电极的细胞内记录将在清醒小鼠的IC中进行 然后用神经生物素和免疫化学进行细胞内标记，以区分Gabaergic与非 - GABA能神经元。第三，我们假设II组mglurs的激活可以减少动力的多动症 AC，IC和杏仁核，还抑制耳鸣和耳鸣相关的困扰。 Eglumegad将被注入 全身。自发，诱发的触发和神经同步将在神经元中进行评估 药物注射后。耳鸣相关的困扰将通过大理石燃烧和发声测试评估。