Function of Somatosensory Pathways to Cochlear Nucleus

耳蜗核体感通路的功能

• 批准号: 8420418
• 负责人: SUSAN E SHORE
• 金额: $ 47.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420418
• 关键词: Abbreviations; Acoustic Nerve; Affect; Animals; Auditory; Axon; Behavioral; Brain; Cavia; Cell Nucleus; Cells; Cochlear nucleus; Confocal Microscopy; Data; Dependence; Detection; Disease; Dorsal; Endocannabinoids; FGFR2 gene; Face; Fiber; Fibroblast Growth Factor; Financial compensation; Generations; Glutamates; Hearing; In Situ Hybridization; Injection of therapeutic agent; Injury; Jaw; Label; Lead; Loudness; Methods; Molecular; Molecular Genetics; Mus; N-Methylaspartate; Neurons; Noise; Outcome; Pathway interactions; Patients; Pattern; Physiological; Resistance; Signal Transduction; Synapses; Synaptic plasticity; System; Testing; Time; Tinnitus; Touch sensation; Trigeminal System; Unilateral Hearing Loss; Up-Regulation; Wild Type Mouse; behavior test; deafness; dorsal column; genetic manipulation; granule cell; insight; mossy fiber; mouse model; novel; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; screening; somatosensory; sound; successful intervention; time interval; Abbreviations; Acoustic Nerve; Affect; Animals; Auditory; Axon; Behavioral; Brain; Cavia; Cell Nucleus; Cells; Cochlear nucleus; Confocal Microscopy; Data; Dependence; Detection; Disease; Dorsal; Endocannabinoids; FGFR2 gene; Face; Fiber; Fibroblast Growth Factor; Financial compensation; Generations; Glutamates; Hearing; In Situ Hybridization; Injection of therapeutic agent; Injury; Jaw; Label; Lead; Loudness; Methods; Molecular; Molecular Genetics; Mus; N-Methylaspartate; Neurons; Noise; Outcome; Pathway interactions; Patients; Pattern; Physiological; Resistance; Signal Transduction; Synapses; Synaptic plasticity; System; Testing; Time; Tinnitus; Touch sensation; Trigeminal System; Unilateral Hearing Loss; Up-Regulation; Wild Type Mouse; behavior test; deafness; dorsal column; genetic manipulation; granule cell; insight; mossy fiber; mouse model; novel; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; screening; somatosensory; sound; successful intervention; time interval

DESCRIPTION (provided by applicant): Glutamatergic somatosensory projections to the cochlear nucleus (CN) originate in trigeminal and dorsal column systems and terminate primarily in the CN granule cell domain (GCD). Stimulating these inputs alters spontaneous and sound-driven responses in principal neurons of the dorsal and ventral CN for extended periods of time. This long-term bimodal alteration is enhanced after unilateral deafness and could explain why patients are able to modulate their tinnitus by somatic maneuvers such as jaw clenching. The aims of this proposal are to determine the physiological and molecular mechanisms underlying long-term suppression and enhancement of CN responses by somatosensory projection neurons and their implications for tinnitus generation and modulation. Aim 1a will examine long-term synaptic plasticity as a mechanism underlying bimodal enhancement and suppression in fusiform and bushy cells in normal and noise-damaged guinea pigs. We hypothesize that bimodal enhancement will predominate in noise-damaged animals with physiological correlates (increased spontaneous rates and synchrony) and behavioral evidence of tinnitus using the gap-detection tinnitus screening method (Aim 1b). Aim 2 will examine the hypothesis that the predominance of bimodal enhancement in animals with tinnitus (preliminary data) is a result of up-regulation of specific Vglut2- positive somatosensory endings in the CN after deafness. In Aim 2a, tract-tracing and immunocytochemical studies will determine the precise origins and endings of the upregulated inputs in mouse. Aim 2b will utilize Vglut2-deficient mice to test the hypothesis that Vglut2+/- mice will be resistant to tinnitus induction. Mice will be tested for tinnitus using gap-detection before and after narrow-band noise overexposure. Preliminary data indicate that compared to matched wild-types, the Vglut2+/- mice show significantly less evidence of tinnitus, supporting this hypothesis. Aim 2c will then explore the involvement of the fibroblast growth factor, FGF22, as a postsynaptic signal for presynaptic upregulation of somatosensory mossy fibers to the CN after deafness. Our studies strongly implicate the somatosensory system, not only in the modulation, but also in the generation of tinnitus. Not surprisingly, more than half of tinnitus patients (~20 million) can modulate their tinnitus with somatic maneuvers, or attribute its onset to a somatosensory injury. Investigating underlying mechanisms in somatosensory-auditory integration after cochlear damage will allow us to elucidate the changes that contribute to tinnitus, and thus provide insights leading to successful interventions.

描述（由申请人提供）：针对人工耳蜗核（CN）的谷氨酸能体验投影起源于三叉神经和背柱系统，并主要终止于CN颗粒细胞结构域（GCD）。刺激这些输入会改变背侧和腹CN的主要神经元的自发和声音驱动反应。这种长期的双峰变化在单方面的耳聋后增强了，可以解释为什么患者能够通过诸如颌骨紧握的躯体操纵来调节其耳鸣。该提案的目的是确定长期抑制和增强体感受投射神经元对CN反应的生理和分子机制及其对耳鸣产生和调节的影响。 AIM 1A将检查长期的突触可塑性，作为在正常和噪声损害的豚鼠中梭形和浓密细胞中双峰增强和抑制的一种机制。我们假设双峰增强将在具有生理相关性的噪声损伤动物中占主导地位（自发速率和同步率提高）和使用间隙检测耳鸣筛选方法（AIM 1B）的耳鸣的行为证据。 AIM 2将研究以下假设：耳鸣（初步数据）的动物双峰增强的占主导地位，是聋哑后CN的特定vglut2-阳性体感末积上调的结果。在AIM 2A中，痕迹追踪和免疫细胞化学研究将确定小鼠中上调输入的确切起源和结局。 AIM 2B将利用VGLUT2缺陷的小鼠测试VGLUT2 +/-小鼠对耳鸣诱导具有抗性的假设。在窄带噪声过度暴露之前和之后，将使用间隙检测对小鼠进行耳鸣测试。初步数据表明，与匹配的野生型相比，vglut2 +/-小鼠显示出耳鸣的证据明显较少，支持这一假设。然后，AIM 2C将探索成纤维细胞生长因子FGF22的参与，作为耳聋后体感苔藓纤维的突触前上调的突触后信号。我们的研究强烈暗示了体感系统，不仅在调制中，而且在耳鸣的产生中。毫不奇怪，超过一半的耳鸣患者（约2000万）可以通过体细胞操纵来调节其耳鸣，或者将其发作归因于体感损伤。研究人工耳蜗损害后的体感审计整合中的潜在机制将使我们能够阐明有助于耳鸣的变化，从而提供有关成功干预措施的见解。