Mechanisms guiding axon selection for myelination in vivo

 描述(申请人提供)：这个项目的长期目标是了解少突胶质细胞，即中枢神经系统的神经胶质细胞，如何用专门的富含蛋白质脂的髓鞘膜包裹特定的轴突。在髓鞘轴突中，少突胶质细胞延伸出许多膜突起，而不是螺旋包裹轴突。然而，并不是所有的轴突都有髓鞘。基于大脑活动可以修饰髓鞘的观察，我们假设轴突的活动依赖信号会影响选择哪些轴突进行髓鞘形成。该项目使用斑马鱼作为模型系统，将活体细胞成像与遗传和药物操作相结合，以研究引导特定轴突上髓鞘形成的机制，以响应神经元活动。特殊目的1将通过直接观察体内具有不同电活动的可识别轴突的包膜和髓鞘作用来检验这一假说，即神经元活动为轴突的髓鞘形成提供了竞争优势。特殊目的2将使用遗传学和药理学方法以及活体成像来验证神经元活动通过激活PI3K-Akt-mTor信号通路促进选定轴突上的髓鞘生长的假说。具体目标3将检验一种假说，即活动介导的信号转导促进稳定和翻译 编码髓鞘蛋白并识别新的活性调节转录本的mRNAs。这些目标的完成将极大地扩展我们对少突胶质细胞选择轴突进行髓鞘形成的细胞机制以及促进活性调节的髓鞘膜生长的关键分子的理解。该项目的结果有可能为学习、记忆和精神疾病提供重要的新见解，并为设计治疗策略提供基础，以促进因疾病或损伤而受损的大脑的髓鞘形成。

 DESCRIPTION (provided by applicant): The long term goal of this project is to understand how oligodendrocytes, which are glial cells of the central nervous system, ensheath specific axons with specialized, proteolipid-rich myelin membrane. To myelinate axons, oligodendrocytes extend numerous membrane processes than spirally wrap axons. However, not all axons are myelinated. Based on observations that brain activity can modify myelin, we hypothesize that activity-dependent signals from axons influence which axons are selected for myelination. Using zebrafish as a model system, this project combines in vivo live cell imaging with genetic and pharmacological manipulations to investigate mechanisms that guide formation of myelin on specific axons in response to neuronal activity. Specific Aim 1 will test the hypothesis that neuronal activity provides axons with a competitive advantage for myelination through direct observation of ensheathment and myelination of identifiable axons that have different electrical activities in vivo. Specific Aim 2 will use genetic and pharmacological approaches and live imaging to test the hypothesis that neuronal activity promotes myelin sheath growth on select axons by activating the PI3K-Akt-mTor signaling pathway. Specific Aim 3 will test a hypothesis that activity-mediated signaling promotes the stability and translation of mRNAs that encode myelin proteins and identify new activity- regulated transcripts. Completion of these aims will substantially extend our understanding of the cellular mechanisms by which oligodendrocytes choose axons for myelination and key molecules that promote activity- regulated myelin membrane growth. The results of this project have the potential for important new insights to learning, memory and psychiatric disease and to provide a foundation for designing therapeutic strategies to promote myelination of brains damaged by disease or injury.