The Roles of Neuronal Activity in Peripheral Nerve Myelination

神经元活动在周围神经髓鞘形成中的作用

• 批准号: 10604374
• 负责人: Gabriel Corfas
• 金额: $ 50.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604374
• 关键词: Ablation; Acoustic Nerve; Action Potentials; Acute; Address; Adolescent; Adult; Affect; Age; Animals; Auditory; Auditory Threshold; Auditory system; Axon; Behavior; Cells; Central Nervous System; Cessation of life; Cochlea; Cochlear Nerve; Data; Defect; Demyelinations; Development; Diphtheria Toxin; Disease; Distal; Ear; Electron Microscopy; Electrophysiology (science); Environment; Fiber; Functional disorder; Genes; Genetic; Genetic Recombination; Hair Cells; Hearing; Hearing Tests; Human; Injections; Knockout Mice; Knowledge; Labyrinth; Maintenance; Measures; Mediating; Messenger RNA; Modality; Modeling; Molecular; Morphology; Motor; Mus; Mutant Strains Mice; Myelin; Myelin Basic Proteins; Myelin Sheath; NRG1 gene; Neonatal; Nerve; Nerve Fibers; Neuroglia; Neurons; Oligodendroglia; Peripheral; Peripheral Nerves; Peripheral Nervous System; Process; Publishing; Ranvier' s Nodes; Resolution; Role; SLC17A8 gene; Schwann Cells; Sensory; Signal Transduction; Speech; Synaptic Transmission; Tamoxifen; Techniques; Testing; Time; Transgenes; Transgenic Mice; auditory deprivation; auditory neuropathy; cell injury; cell type; experience; experimental study; hearing impairment; in vivo; insight; mechanotransduction; mouse model; mutant; myelination; neural; normal hearing; novel therapeutics; postnatal; postnatal development; prevent hearing loss; remyelination; repaired; sound; spiral ganglion; synaptic function; tool; transmission process

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.

项目概要 髓鞘形成对于动作电位的正常传导和神经元的同步传输至关重要 冲动。最近的研究表明，中枢神经系统髓磷脂的发育、成熟和维持与 受神经元活动和经验的调节。相比之下，人们对经验和经验如何了解知之甚少。 活动调节 PNS 中的髓磷脂发育，也不影响经验依赖的神经活动如何影响重新 体内周围神经或神经胶质细胞损伤后的髓鞘形成。这部分是由于精确地 改变 PNS 神经的活动，因为它们通常是感觉纤维和运动纤维的混合物，或者 介导不同类型模式的感觉轴突。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，并提出解决这一根本问题 使用听觉系统作为模型的知识差距。小鼠 I 型听觉神经 (AN) 纤维 耳蜗提供了一个理想的平台来剖析活动对周围髓鞘形成的作用，因为：(a) 成熟 AN 髓磷脂的形成与出生后第一个月听觉功能的成熟同时发生，表明 活性可能会影响雪旺细胞； (b) 雪旺细胞消融后发生 AN 纤维的髓鞘再生； (三) 髓鞘质功能障碍与听力缺陷有关，这表明髓鞘质形成在 耳蜗功能，特别是在传输声音的关键时间特征方面，这对于人类来说很重要 理解言语； (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 让动物接触特定的听觉体验，或使用遗传工具； (e) 我们可以有效地隔离和 在结构、细胞和分子水平上检查整个外周 AN； (f) 我们可以评估 髓磷脂缺陷对完整小鼠耳蜗和听觉神经功能的影响可以在高 使用标准电生理学技术解决。此外，AN 轴突由两种物质形成有髓鞘： 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。我们将使用鼠标模型来 通过三个具体目标解决这一知识差距。在目标 1 中，我们将使用头发有缺陷的突变体 细胞力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，我们将测试听觉体验和 NRG1/ErbBR 的作用 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，我们将测试是否 声音驱动的神经元活动调节成熟耳蜗的髓鞘再生。顺利完成 所提出的目标将为了解神经活动在 PNS 髓鞘形成中的作用提供有价值的见解，并提供更多信息 准确了解髓磷脂功能障碍对听力的影响。