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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

基本信息

批准号：
10375469
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
项目类别：
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/10375469
关键词：
Ablation Acoustic Nerve Action Potentials Acute Address Adolescent Adult Affect Age Animals Auditory Auditory Threshold Auditory system Axon Behavior Cells 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 Neuraxis Neuroglia Neurons Oligodendroglia Peripheral Peripheral Nerves Peripheral Nervous System Process Publishing Ranvier&apos 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 normal hearing novel therapeutics postnatal postnatal development prevent hearing loss relating to nervous system remyelination repaired sound spiral ganglion synaptic function tool transmission process

项目摘要

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.

项目总结