ROLE OF MACROPHAGES IN NOISE-INDUCED COCHLEAR SYNAPTOPATHY AND NEUROPATHY

 描述(申请人提供)：噪声暴露会导致永久性阈值漂移(伴随毛细胞丢失)和暂时性阈值漂移(没有明显毛细胞丢失)，也会导致突触元素和耳蜗神经末梢的快速和永久性丢失。这种损伤也会导致螺旋神经节(SG)细胞体退化，但这种情况会发生在几个月到几年的时间里。神经元存活是人工耳蜗术成功与否的关键因素，因此了解人工耳蜗术后促进神经元存活的机制具有重要意义。我们最近发现，毛细胞丢失足以将巨噬细胞重新聚集到螺旋神经节，并且巨噬细胞和传入神经元之间的信号传导中断(通过基因缺失Fractalkine受体CX3CR1)，导致巨噬细胞聚集到螺旋神经节，也导致传入神经元存活率降低。在这里，我们建议研究在噪声性听力损失后Fractalkine信号的作用。我们假设：1)Fractalkine调节巨噬细胞重新聚集到噪声损伤的耳蜗区，2)Fractalkine促进噪声损伤后传入突触和神经元的存活。目的1研究Fractalkine信号在永久性阈值漂移引起的神经病变中的作用。具体的实验将评估在短(周)和长(月)生存期内，Fractalkine信号的遗传干扰对巨噬细胞渗透、螺旋神经节细胞病理和听觉功能的影响。目标2将测试假设，即巨噬细胞在噪声暴露后也发挥关键作用，导致暂时性阈值漂移(TTS)。我们将描述巨噬细胞向内毛细胞传入神经纤维突触迁移的特征，并确定Fractalkine信号的中断是否会影响噪声诱导的耳蜗突触和神经病的严重程度或恢复。为了达到这两个目的，我们将通过ABR监测耳蜗功能的变化，并收集耳蜗组织进行巨噬细胞、毛细胞和传入神经元的组织学分析，以及内毛细胞-耳蜗神经末梢突触的数量和形态。

 DESCRIPTION (provided by applicant): Noise exposures that cause both permanent threshold shift (with accompanying hair cell loss) and temporary threshold shifts (no evident hair cell loss) also result in rapid and permanent loss of synaptic elements and cochlear nerve terminals. Such injury also leads to degeneration of spiral ganglion (SG) cell bodies, but this occurs over a period of months to years. Neuronal survival is a key determinant of the success of cochlear implants, so it is of great interest to understand the mechanisms that promote neuronal survival after cochlear insults. We have recently discovered that hair cell loss is sufficient to recruit macrophages into the spiral ganglion, and that disruption of signaling between macrophages and afferent neurons (by genetic deletion of fractalkine receptor CX3CR1), leads to reduced macrophage recruitment into the spiral ganglion, and also results in diminished survival of afferent neurons. Here we propose to investigate the role of fractalkine signaling after noise induced hearing loss. We hypothesize that: 1) fractalkine regulates macrophage recruitment into the noise-damaged cochlea, and 2) fractalkine promotes the survival of afferent synapses and neurons after noise injury. Aim 1 will examine the role of fractalkine signaling in neuropathy caused by permanent threshold shift. Specific experiments will assess the effects of genetic disruption of fractalkine signaling on macrophage infiltration, spiral ganglion cell pathology, and auditory function over short (weeks) and long (months) survival periods. Aim 2 will test the hypothesis that macrophages also serve a critical role after noise exposure that causes temporary threshold shift (TTS). We will characterize any migration of macrophages towards inner hair cell-afferent nerve fiber synapse, and determine whether disruption of fractalkine signaling can influence the severity of, or recovery from, noise-induced cochlear synaptopathy and neuropathy. For both aims, we will monitor changes in cochlear function via ABRs, and cochleae will be collected for histological analysis of macrophages, hair cells and afferent neurons, as well as inner hair cell- cochlear nerve terminal synapse number and morphology.