Function of Somatosensory Pathways to Cochlear Nucleus

描述（由申请人提供）：到耳蜗核的谷氨酸能体感觉投射（CN）起源于三叉神经和背柱系统，主要终止于CN颗粒细胞结构域（GCD）。刺激这些输入可以长时间改变神经网络背侧和腹侧主要神经元的自发和声音驱动反应。这种长期的双峰性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牙等躯体运动来调节耳鸣。本研究的目的是确定体感投射神经元长期抑制和增强耳鸣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将研究长期突触可塑性作为正常和噪声损伤豚鼠梭状和丛状细胞双峰增强和抑制的机制。我们假设双峰增强将在噪声损伤动物中占主导地位，具有生理相关（自发率和同步性增加）和耳鸣的行为证据，使用间隙检测耳鸣筛查方法（Aim 1b）。目的2将检验耳鸣动物双峰增强的优势（初步数据）是耳聋后CN中特异性Vglut2阳性体感觉末梢上调的结果。在Aim 2a中，通道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。Aim 2b将利用Vglut2缺陷小鼠来验证Vglut2+/-小鼠对耳鸣诱导具有抗性的假设。小鼠将在窄带噪声过度暴露前后使用间隙检测进行耳鸣测试。初步数据表明，与匹配的野生型相比，Vglut2+/-小鼠耳鸣的证据明显减少，支持了这一假设。Aim 2c将探索成纤维细胞生长因子FGF22作为突触后信号参与耳聋后体感苔藓纤维突触前上调。我们的研究强烈暗示了躯体感觉系统不仅参与了耳鸣的调节，而且还参与了耳鸣的产生。不足为奇的是，超过一半的耳鸣患者（约2000万）可以通过躯体运动调节耳鸣，或将其发病归因于体感觉损伤。研究耳蜗损伤后体感-听觉整合的潜在机制将使我们能够阐明导致耳鸣的变化，从而为成功的干预提供见解。

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.