The Roles of Neuronal Activity in Peripheral Nerve Myelination

项目摘要 髓鞘形成对于动作电位的正常传导和神经传导的同步化是至关重要的。 冲动最近的研究表明，中枢神经系统髓鞘的发育、成熟和维持是神经系统的重要组成部分。 由神经元活动和经验调节。相比之下，很少有人知道经验和 活动调节PNS中髓鞘的发育，也不知道经验依赖性神经活动如何影响再神经元的发育。 在体内外周神经或胶质细胞损伤后的髓鞘形成。这部分是因为很难准确地 改变PNS神经的活性，因为它们通常是感觉和运动纤维的混合物，或者是感觉和运动纤维的混合物。 感觉轴突介导不同类型的方式。我们假设感觉活动调节 周围神经髓鞘形成，髓鞘维持和髓鞘再生，并提出解决这一基本问题， 以听觉系统为模型的知识差距。小鼠的I型听神经（AN）纤维 耳蜗提供了一个理想的平台来剖析活动对外周髓鞘形成的作用，因为：（a）成熟 出生后第一个月，AN髓鞘的形成与听觉功能的成熟相一致，这表明， 活动可影响雪旺细胞;（B）在雪旺细胞消融后发生AN纤维的髓鞘再形成;（c） AN髓鞘功能障碍与听力缺陷相关，表明髓鞘形成在听力障碍中起关键作用。 耳蜗功能，特别是在声音的关键时间特征的传输中， 理解语言;（d）我们可以通过消融毛细胞， 使动物暴露于确定的听觉体验，或使用遗传工具;（e）我们可以有效地分离， 在结构、细胞和分子水平上检查整个外周AN;以及（f）我们可以评估 髓鞘缺陷对完整小鼠耳蜗和听觉神经功能的影响可以在高- 分辨率与标准电生理技术。此外，AN轴突是由两个神经元共同髓鞘化的。 雪旺细胞（在远端部分）和少突胶质细胞（在近端部分），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。我们将使用小鼠模型， 在三个具体目标中解决这一知识差距。在目标1中，我们将使用毛发有缺陷的突变体 细胞机械转导和突触功能，以确定AN活性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，我们将测试听觉经验和NRG 1/ErbBR的作用 在新生儿和青少年时期AN髓鞘形成中的信号传导。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中的AN髓鞘再生。成功完成 提出的目标将为神经活动在PNS髓鞘形成中的作用提供有价值的见解， 准确理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.