Myelin remodeling in vivo: A longitudinal study of targeted myelination and neuronal control of sparse myelination in mouse cortex

体内髓鞘重塑：小鼠皮质中靶向髓鞘形成和稀疏髓鞘形成的神经元控制的纵向研究

• 批准号: 426715780
• 负责人: Dr. Nicolas Snaidero, Ph.D.
• 金额: --
• 依托单位: Hertie-Institut für klinische Hirnforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426715780?language=en
• 关键词: Myelin; remodeling; vivo; longitudinal; study

In this proposal, I will explore the principles and mechanisms underlying the discontinuous myelin pattern found in the mammalian cortex and the resilience of this pattern upon demyelination. I will also investigate the role of neuronal identity and activity in the establishment, resilience and plasticity of cortical myelin patterns. Recent discoveries of discontinuous myelin patterns along axons of excitatory and inhibitory cortical neurons, as well as of myelin remodelling during circuit plasticity, have established cortical myelin and its remodelling as a potential regulator of neuronal circuit function. Cortical oligodendrocyte loss and hence demyelination occurs physiologically with age but also in several brain diseases. Hence, the efficiency and quality of remyelination is critical for maintaining axonal and circuit function. Still, the principles and mechanisms of establishing and maintaining cortical myelin patterns are not understood. Similarly, the neuronal cell type and functional axonal cues that determine proper functional myelination and remyelination by guiding local oligodendrocyte precursor cell (OPC) differentiation and axon targeting in the cortex remain elusive. To address these fundamental questions, I now want to explore: 1) whether cortical myelination is a targeted or random process; 2) the effects of axonal signatures on cortical myelination patterns and the efficiency of remyelination; 3) the role of neuronal activity on cortical myelination selectivity, morphological plasticity and remyelination efficiency. For this, I will take advantage of my expertise in longitudinal two-photon imaging, virus- and transgene-based labelling and manipulations, correlated ultrastructural analysis and a newly developed 2-photon laser ablation-based cortical demyelination model. Together these tools allow me to address the points raised above with unique single-cell precision by following cortical de- and remyelination over time. Given the physiological and pathological significance of cortical myelination that is only fully emerging, but already makes cortical myelin a central topic in understanding the cognitive sequels of MS and related cortical myelinopathies. Thus the knowledge that will result from the proposed study will have profound basic and biomedical implications.

在这篇论文中，我将探讨哺乳动物大脑皮层中髓鞘不连续模式的原理和机制，以及这种模式在脱髓鞘后的恢复力。我也将探讨神经元的身份和活动的作用，在建立，弹性和可塑性的皮质髓鞘模式。最近发现的不连续髓鞘模式沿着兴奋性和抑制性皮层神经元的轴突，以及髓鞘重塑电路可塑性，建立了皮层髓鞘和其重塑作为一个潜在的调节神经元电路功能。皮质少突胶质细胞的损失，因此脱髓鞘发生生理随着年龄的增长，但也在一些脑部疾病。因此，髓鞘再生的效率和质量对于维持轴突和回路功能至关重要。然而，建立和维持皮质髓鞘模式的原理和机制尚不清楚。类似地，通过引导局部少突胶质细胞前体细胞（OPC）分化和皮质中的轴突靶向来确定适当的功能性髓鞘形成和髓鞘再生的神经元细胞类型和功能性轴突线索仍然难以捉摸。为了解决这些基本问题，我现在想探索：1）皮层髓鞘形成是一个有针对性的还是随机的过程; 2）轴突标记对皮层髓鞘形成模式和髓鞘再生效率的影响; 3）神经元活动对皮层髓鞘形成选择性，形态可塑性和髓鞘再生效率的作用。为此，我将利用我在纵向双光子成像，基于病毒和转基因的标记和操作，相关的超微结构分析和新开发的基于双光子激光消融的皮质脱髓鞘模型的专业知识。这些工具使我能够通过跟踪皮层脱髓鞘和髓鞘再生的时间变化，以独特的单细胞精度来解决上述问题。考虑到皮质髓鞘形成的生理和病理意义，皮质髓鞘形成才刚刚完全出现，但已经使皮质髓鞘成为理解MS和相关皮质髓鞘病的认知后遗症的中心主题。因此，从拟议的研究中获得的知识将具有深刻的基础和生物医学意义。