Functional development of hair cells and neurons in the inner ear

项目总结 内耳毛细胞是听觉系统的主要感受器。他们把机械的 与声波相关的信息，转化为机电(外部毛细胞)和电化学(内部 毛细胞)信号，导致初始信号的放大和传入神经元纤维的激活， 分别进行了分析。虽然毛细胞和神经纤维在小鼠出生前就已经出现，但 毛细胞、神经元和突触一直持续到听力开始，出生后12天。这一过程被认为是 保持活力，并受毛细胞活动的调节。特别是，最近的研究表明，缺乏毛细胞 由于缺乏功能性突触或机械感觉缺陷，传递会导致神经元改变 成熟和规范。新疗法的成功结果，包括基因疗法，旨在恢复 毛细胞出生后的功能，可能取决于听觉回路的恢复，包括成熟和功能 毛细胞突触和神经纤维。在这里，我们建议评估感觉转导的中断或丢失 在几个小鼠模型中影响毛细胞功能、突触成熟和螺旋神经节规范。 此外，我们将确定内耳基因疗法是否能够逆转这些观察到的变化。 确定最佳恢复听功能的条件。我们将结合最先进的技术 解决这些重要问题的技术，包括高分辨率成像、电生理学、单一 细胞RNA测序和RNA转录本的定位。

Project summary Hair cells of the inner ear are the primary receptors of the auditory system. They transduce mechanical information, associated with sound waves, into electro-mechanical (outer hair cells) and electro-chemical (Inner hair cells) signals, which lead to amplification of the initial signal and activation of afferent neuronal fibers, respectively. While hair cells and neuronal fibers appear before birth in mice, development and maturation of the hair cells, neurons and synapses proceeds until hearing onset, ~postnatal day 12. This process is believed to be dynamic and modulated by hair cell activity. In particular, recent work has shown that lack of hair cell transmission, due to absence of functional synapses or defective mechanosensation, leads to altered neuronal maturation and specification. Successful outcomes for new therapies, including gene therapy, aimed at restoring hair cell function after birth, may depend on restoration of auditory circuits, including mature and functional hair cell synapses and neuronal fibers. Here we propose to assess how disruption or loss of sensory transduction in several mouse models affects hair cell function, synaptic maturation and spiral ganglion specification. Furthermore, we will determine if inner ear gene therapy is capable of reversing any of these observed changes and identify the conditions for optimal recovery of auditory function. We will combine state-of-the-art technologies to address these important questions, including high-resolution imaging, electrophysiology, single cell RNA sequencing and localization of RNA transcripts.