The Roles of Neuronal Activity in Peripheral Nerve Myelination

项目摘要 髓鞘形成对动作电位的正常传导和神经的同步传递至关重要 冲动。最近的研究表明，中枢神经系统髓鞘的发育、成熟和维持是 受神经元活动和经验的调节。相比之下，人们对经验和经验的了解很少。 活动调节PNS中的髓鞘发育，也不是经验依赖的神经活动如何影响Re-Re。 周围神经或神经胶质细胞损伤后的体内髓鞘形成。这在一定程度上是由于准确地 改变PNS神经的活动，因为它们通常是感觉和运动纤维的混合物，或者 感觉神经轴突调节不同类型的通道。我们假设感官活动调节 周围神经髓鞘形成、髓鞘维持和再髓鞘形成，并建议解决这一根本问题 以听觉系统为模型的知识鸿沟。小鼠的I型听神经纤维 耳蜗提供了一个理想的平台来分析活动在外周髓鞘形成中的作用，因为：(A)成熟 髓鞘的变化与出生后第一个月的听觉功能成熟相吻合，这表明 活动可能影响雪旺细胞；(B)雪旺细胞消融后神经纤维重新髓鞘形成；(C) 髓鞘功能障碍与听力障碍有关，显示了髓鞘形成在 耳蜗功能，特别是在声音的关键时间特征的传输中，这些特征对于 理解语言；(D)我们可以通过消融毛细胞来操纵初级听觉神经元的活动，通过 使动物接触到明确的听觉体验，或使用遗传工具；(E)我们可以有效地分离和 在结构、细胞和分子水平上检查整个外周AN；和(F)我们可以评估 髓鞘缺陷对完整小鼠耳蜗神经和听神经功能的影响可以在高密度下进行评估。 用标准的电生理技术进行分辨。此外，轴突既有髓鞘也有髓鞘 雪旺细胞(在远端)和少突胶质细胞(在近端)，允许直接比较 活动对同一神经内两种类型的髓鞘细胞的影响。我们将使用鼠标模型来 在三个具体目标中解决这一知识差距。在目标1中，我们将使用头发有缺陷的突变体 细胞机械转导和突触功能以确定一种活动在髓鞘形成过程中的作用 新生儿和青少年时期。在目标2中，我们将测试听觉体验和NRG1/ErbBR的作用 在新生儿和幼年期的髓鞘形成过程中发出信号。最后，在目标3中，我们将测试 声音驱动的神经元活动调节成熟耳蜗髓鞘的重新形成。成功完成 提出的目标将提供有价值的洞察神经活动在三叉神经节髓鞘形成中的作用，并提供更多 准确了解髓鞘功能障碍对听力的影响。

Project Summary Myelination is critical for normal conduction of action potentials and synchronized transmission of neural impulses. Recent studies have demonstrated that CNS myelin development, maturation and maintenance are regulated by neuronal activity and experience. In contrast, very little is known about how experience and activity regulate myelin development in the PNS, nor how experience-dependent neural activity affects re- myelination after peripheral nerve or glial cell injury in vivo. This is in part due to the difficulty in precisely altering activity of PNS nerves, since they are typically a mixture of both sensory and motor fibers, or of sensory axons mediating different types of modalities. We hypothesize that sensory activity regulates peripheral nerve myelination, myelin maintenance and remyelination, and propose to address this fundamental gap in knowledge using the auditory system as a model. Type I auditory nerve (AN) fibers in the mouse cochlea offer an ideal platform to dissect the role of activity on peripheral myelination because: (a) maturation of AN myelin coincides with auditory function maturation during the first postnatal month, suggesting that activity may affect Schwann cells; (b) re-myelination of AN fibers occurs following Schwann cell ablation; (c) AN myelin dysfunction is associated with hearing deficits, demonstrating a critical role for myelination in cochlear function, particularly in the transmission of key temporal features of sound that are important for understanding speech; (d) we can manipulate the activity of primary auditory neurons by ablating hair cells, by exposing animals to defined auditory experiences, or using genetic tools; (e) we can efficiently isolate and examine the entire peripheral AN at the structural, cellular and molecular levels; and (f) we can assess the impact of myelin defects on cochlear and auditory nerve function in the intact mouse can be assessed at high- resolution with standard electrophysiological techniques. Furthermore, AN axons are myelinated by both Schwann cells (in the distal part) and oligodendrocytes (in the proximal part), permitting a direct comparison of the effects of activity on both types of myelinating cells within the same nerve. We will use mouse models to address this gap in knowledge in three specific aims. In Aim 1, we will use mutants that are defective in hair cell mechanotransduction and synaptic function to determine the role of AN activity in myelination during the neonatal and juvenile time periods. In Aim 2, we will test the roles of auditory experience and NRG1/ErbBR signaling in AN myelination during the neonatal and juvenile periods. Finally, in Aim 3, we will test whether sound-driven neuronal activity modulates AN re-myelination in the mature cochlea. Successful completion of the proposed aims will provide valuable insight into the role of neural activity in PNS myelination and a more precise understanding of the impact of myelin dysfunction on hearing.