低强度噪声对耳蜗I型传入神经支配的破坏与机制

Noise exposure is one of the most common causes for sensorineural hearing loss and currently, impact of noise on hearing is mainly evaluated by the hearing threshold shift. However, recent study in mice demonstrated that noise, which causes no permanent threshold shift, can damage the ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) and results in a massive neuron death thereafter. In the preliminary study of our team, similar damage on cochlear afferent innervation has been verify in other species of animals, suggesting that this that such a lesion is universal across different species of mammals. We have also found that the temporal coding ability of the cochlea declined in those animals after such a low-level noise exposure in association with the damage of ribbon synapses and the loss of SGNs. This project will systematically investigate the cross-species generalization of the ribbon synapse damage and SGN death induced by noise causing no threshold shift, and the impact of such noise on human hearing. We will explore the nature of noise induced damage of synaptic ribbon and the relationship with SGN damage and death to understand the potential mechanisms underlying. We will explore the impact of the damage on cochlear function especially ability of temporal encoding, and establish clinical methods for detecting corresponding functional impairments. The outcome of this project will refresh our understanding on noise impact to hearing function as the bases for more reasonable and effective prevention, early diagnosis and potentially the development of medical treatment.

噪声暴露是感音神经性耳聋的主要原因之一,听觉阈值改变是目前评价噪声所致听觉损害的主要依据。然而最近的小鼠研究发现，未引起永久听觉阈移的低强度噪声暴露即可导致耳蜗内毛细胞(IHC)与I型螺旋神经节细胞（SGN）之间的带状体突触损伤并继发SGN死亡。我们的实验在其他动物也观察到了类似耳蜗I型传入神经支配的损伤，提示此损伤有跨物种普遍性。我们还发现伴随带状体突触的损伤和SGN死亡，动物的听觉信息时间编码能力也出现了明显减退。本项目将系统研究噪声所致无阈移带状体突触损伤和SGN死亡的普遍性，探索噪声所致耳蜗带状体损伤的本质及与SGN损伤的关系；明确该损伤对耳蜗功能尤其是时间编码能力的影响及机制；分析其对人听觉功能的影响，初步建立能早期发现相关听觉损伤的临床功能检测指标。本课题将从病理机制及危害效应上更新对噪声致听觉损伤的认识，为噪声性听觉功能损伤的合理预防、早期诊断和有效治疗的提供重要依据。

感音神经性聋（SNHL）是最常见的神经系统功能障碍；噪声暴露是获得性SNHL的重要原因。根据传统观念，听觉阈值的改变（阈移）是临床上判断噪声性听觉损伤的主要根据；是否导致听觉阈值升高也是噪声安全标准的主要制定依据。然而近年小鼠研究显示，以往认为是安全的噪声暴露可以在不引起永久性听觉阈移的情况下造成耳蜗内毛细胞（IHC）和I型螺旋神经节细胞（SGN）之间突触的严重损伤; 如果突触不能重建，失去IHC支配的SGN将发生退行性死亡。由于不累及听觉敏感性，此损伤不会成为临床主诉；而目前临床听觉检查不能探测到没有阈值改变的突触损伤，因此该损伤和其对听觉功能的潜在影响被称为噪声性隐性听力损失（NIHHL）。本项目全面研究了噪声所致突触损伤发生发展的动态过程以及对听觉功能的隐性，在以下几个方面取得了重要进展： （1）通过豚鼠实验证实了噪声隐性突触损伤具有跨物种普遍性； （2）证实IHC-SGN突触在噪声损伤后有一定程度的修复并伴随趣的突触可塑性改变；（3）突触的修复是不完全的，因此损伤可能经多次噪声暴露累积；（4）伴随突触修复，听神经单纤维编码功能出现多项不利改变，提示修复的突触功能上不健康。上述成果明确了NIHHL的概念，提示 “听觉阈值正常”不能作为噪声安全的标签而影响防范。由于导致NIHHL的噪声见于日常生活，其效应随年龄的累积可能是老年性听觉功能障碍的主要原因之一。听觉阈值正常的老年个体通常存在噪声中信号识别和理解快速信号两大困难。通常这两大困难的成因均归为未明的中枢机制。本研究的结果第一次提出了这些功能障碍的外周病理机制。本研究的成果为今后的深入研究奠定了坚实的基础。