PDF(Pubmed)
Abstract：
Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique α9α10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function α9L9\'T nAChR into α9-knockout mice. Continued progress with \"efferent gene therapy\" will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged α9 or α10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis.
摘要：
对哺乳动物耳蜗的传出反馈包括胆碱能内侧橄榄耳蜗神经元（MOC），其释放ACh以超极化并分流驱动外毛细胞（OHC）电动性的电压变化。通过脑干连接，MOCs以频率和强度依赖的方式被声音激活，从而减少了由OHC电运动提供的耳蜗振动的放大。在其他角色中，这种传出反馈保护耳蜗免受声学损伤。病变研究,以及各种遗传小鼠模型，支持外传保护免受声学创伤的假设。毛细胞中独特的含α9α10的烟碱乙酰胆碱受体（nAChR）的基因敲除和功能获得敲入表明，声学保护与胆碱能抑制OHC的功效相关。通过将功能获得α9L9\'TnAChR病毒转导到α9敲除小鼠中，可以复制这种保护作用。“传出基因疗法”的持续进展将需要一种可靠的方法来可视化耳蜗毛细胞中nAChR的表达。为此,使用CRISPR技术产生表达HA标记的α9或α10nAChR的小鼠。这一进展将有助于继续研究毛细胞nAChR作为预防听力损失的治疗靶标，并有可能改善相关的病变，例如过度听觉。
