Function of Somatosensory Pathways to Cochlear Nucleus

描述（由申请人提供）：谷氨酸能体感投射至耳蜗核（CN）起源于三叉神经和背柱系统，主要终止于CN颗粒细胞区（GCD）。刺激这些输入改变自发和声音驱动的反应，在主神经元的背侧和腹侧CN延长的时间。这种长期的双峰变化在单侧耳聋后增强，可以解释为什么患者能够通过诸如咬紧牙关的躯体动作来调节耳鸣。这项建议的目的是确定生理和分子机制的长期抑制和增强CN反应的躯体感觉投射神经元和耳鸣的产生和调制的影响。目的1a将研究正常和噪声损伤豚鼠的梭形和丛状细胞的长时程突触可塑性作为双峰增强和抑制的机制。我们假设，双峰增强将占主导地位的噪声损伤的动物与生理相关性（增加自发率和同步性）和耳鸣的行为证据，使用间隙检测耳鸣筛查方法（目的1b）。目的2将检验以下假设：耳鸣动物中双峰增强的优势（初步数据）是耳聋后CN中特定VEGF 2阳性体感末梢上调的结果。在目标2a中，追踪和免疫细胞化学研究将确定小鼠中上调输入的精确起源和结束。目的2b将利用VEGF 2缺陷小鼠来测试VEGF 2 +/-小鼠将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，将使用间隙检测测试小鼠的耳鸣。初步数据表明，与匹配的野生型相比，VEGF 2 +/-小鼠显示出明显较少的耳鸣证据，支持这一假设。目的2c，然后将探讨成纤维细胞生长因子，FGF 22的参与，作为突触后信号的突触前上调的体感苔藓纤维的CN耳聋后。我们的研究强烈暗示了躯体感觉系统，不仅在调制，而且在耳鸣的产生。毫不奇怪，超过一半的耳鸣患者（约2000万）可以通过躯体操作来调节耳鸣，或将其发作归因于体感损伤。调查耳蜗损伤后体感听觉整合的潜在机制将使我们能够阐明导致耳鸣的变化，从而提供成功干预的见解。 公共卫生相关性：体感（触觉）系统将连接发送到大脑中的第一个听觉站-耳蜗核。由于许多患者可以通过触摸他们的脸或咬紧下巴来调节耳鸣的响度和音高，这意味着这些输入也可能首先产生耳鸣。在这里，我们研究的生理和分子机制的耳蜗核活动的躯体感觉调制在动物和没有耳鸣，并研究这些机制可能会导致耳鸣。我们希望这些研究的结果将导致新的治疗方法，并最终为世界各地数百万患有这种经常使人衰弱的疾病的人提供救济。

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. PUBLIC HEALTH RELEVANCE: The somatosensory (touch) system sends connections to the first auditory station in the brain, the cochlear nucleus. Since many patients can modulate the loudness and pitch of their tinnitus by touching their face or clenching their jaw, this implies tht these inputs may also produce the tinnitus in the first place. Here we examine the physiological and molecular mechanisms underlying somatosensory modulations of cochlear nucleus activity in animals with and without tinnitus, and examine how these mechanisms might lead to tinnitus. We hope that findings from these studies will lead to novel treatments and ultimately provide relief to millions of people across the world suffering from this often-debilitating disorder.