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

在本提案中，我将探索哺乳动物皮层中发现的不连续髓鞘模式的原理和机制，以及这种模式在脱髓鞘时的弹性。我还将研究神经元的身份和活动在皮层髓鞘模式的建立、恢复和可塑性中的作用。最近发现的沿兴奋性和抑制性皮质神经元轴突不连续的髓磷脂模式，以及在回路可塑性过程中的髓磷脂重塑，已经确立了皮质髓磷脂及其重塑作为神经元回路功能的潜在调节剂。皮层少突胶质细胞的丢失和因此脱髓鞘发生生理年龄，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神经回路的功能至关重要。然而，建立和维持皮层髓鞘模式的原理和机制尚不清楚。同样，通过引导局部少突胶质前体细胞（OPC）分化和皮层轴突靶向来决定适当的髓鞘形成和再髓鞘形成的神经元细胞类型和功能轴突线索仍然难以捉摸。为了解决这些基本问题，我现在想探讨：1)皮质髓鞘形成是一个有针对性的还是随机的过程；2)轴突特征对皮质髓鞘形成模式和再髓鞘形成效率的影响；3)神经元活动对皮质髓鞘形成选择性、形态可塑性和再髓鞘形成效率的影响。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方面的专业知识。总之，这些工具使我能够通过跟踪皮层脱皮和髓鞘再生，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，这只是刚刚完全出现，但已经使皮质髓鞘成为理解多发性硬化症和相关皮质髓鞘病的认知后遗症的中心主题。因此，拟议的研究将产生的知识将具有深远的基础和生物医学意义。

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.