Function of Somatosensory Pathways to Cochlear Nucleus

描述(申请人提供)：谷氨酸能躯体感觉投射到耳蜗核(CN)起源于三叉神经和背柱系统，主要终止于CN颗粒细胞域(GCD)。刺激这些输入改变了背侧和腹侧CN主神经元的自发和声音驱动的反应。这种长期的双峰改变在单侧耳聋后得到加强，这可以解释为什么患者能够通过咬合下巴等躯体动作来调整他们的耳鸣。本研究的目的是确定躯体感觉投射神经元长期抑制和增强CN反应的生理和分子机制，以及它们对耳鸣的产生和调节的影响。目的1a将在正常和噪声损伤的豚鼠中检测长期突触可塑性作为双峰增强和抑制梭形和丛状细胞的机制。我们假设双模式增强将在噪声损伤的动物中占主导地位，并使用间隙检测耳鸣筛查方法(目标1b)与耳鸣的生理相关性(自发性和同步性增加)和行为证据相关联。目的2将验证一个假设，即耳鸣动物的双峰增强优势(初步数据)是耳聋后CN中特定的Vher2阳性躯体感觉终末上调的结果。在目标2a中，轨迹追踪和免疫细胞化学研究将确定小鼠体内上调输入的确切来源和结束。目的2b将利用Vher2基因缺陷小鼠来验证Vher2+/-小鼠将抵抗耳鸣诱导的假说。在窄带噪声过度暴露前后，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，Vher2+/-小鼠表现出明显较少的耳鸣证据，支持这一假说。目的2c将探讨成纤维细胞生长因子FGF22作为突触后信号对耳聋后体感苔藓纤维突触前上调至CN的影响。我们的研究表明，躯体感觉系统不仅与耳鸣的调节有关，而且还与耳鸣的发生有关。毫不奇怪，超过一半的耳鸣患者(约2000万)可以通过躯体动作来调节耳鸣，或者将耳鸣的发生归因于躯体感觉损伤。研究耳聋后躯体感觉-听觉整合的潜在机制将使我们能够阐明导致耳鸣的变化，从而为成功的干预提供洞察力。

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.