How does neuronal activity regulate central nervous system myelination?

神经元活动如何调节中枢神经系统髓鞘形成？

• 批准号: MR/P006272/1
• 负责人: David Lyons
• 金额: $ 52.48万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP006272%2F1
• 关键词: How; does; neuronal; activity; regulate

Approximately half of the volume of our brain and spinal cord, our central nervous system, is comprised of white matter. White matter is essential for normal brain formation, function and health, and damage to white matter causes the symptoms of many human diseases, such as multiple sclerosis, MS. The "white" in white matter refers to the presence of a fatty substance called myelin, which is made by specialized cells called oligodendrocytes, and which is wrapped around the nerve cables of our brain (called axons). The presence of myelin on axons insulates them and allows our neurons to rapidly transmit electrical impulses over long distances. Myelin also provides nutritional support to axons, essential for their health. Until recently it was though that myelin was a static structure, but in recent years it has become clear that myelin is made throughout our lives, and that it is dynamically regulated by brain activity, perhaps to optimize brain function and repair. Humans make new myelin well into adult life, by the formation of new oligodendrocytes, and, likely, by remodeling of existing myelin. Very interestingly, studies in humans have shown that learning new tasks, e.g. juggling, can stimulate changes in our white matter and investigations in animal models have shown that the learning of new tasks in adulthood requires the formation of new myelin-producing oligodendrocytes. Importantly, the ability of our brain to make new myelin is also key to the regeneration that is observed following the loss of myelin in diseases such as MS. In line with a role for brain function in regulating myelination, own work has shown that the electrical activity of our brain cells stimulates myelin production by oligodendrocytes, and studies by our colleagues have shown that neuronal activity is required for normal myelin regeneration. However, many important questions remain: how do our brain cells tell our oligodendrocytes to promote myelination? Can stimulating brain activity promote regeneration of myelin? We use zebrafish as an animal model to study myelination. Zebrafish produce embryos that are small, transparent, and develop very quickly, and we have made zebrafish where myelin and myelinated axons are fluorescently labelled. These properties of fish together with our tools means that we can directly visualize myelin as it is made, remodelled, and even regenerated over time. To study myelin regeneration (called remyelination), we have recently made a transgenic fish in which we can delete two-thirds of oligodendrocytes in a non-invasive manner, which leads to the loss of myelin (demyelination) from axons. Although the nervous system of both fish and man has the capacity to replace lost myelin through remyelination, this process is imperfect, and ultimately fails in diseases like MS. Therefore it is an important goal of medical research to find ways to promote our endogenous capacity for remyelination. The possibility to directly observe myelination and remyelination in a living animal is a great strength of the system and will be exploited through the work of this proposal. The aim of this proposal is to use zebrafish to directly observe how myelin is made along axons over time in the normal animal, and to assess how this can be regulated by the electrical activity of neurons. We will carry out the first ever (to our knowledge) direct observations of remyelination of single axons over time in a living animal and investigate whether promoting brain function can enhance the regeneration of myelin. This work will provide much needed insight into how our brain builds and regenerates myelin and how brain activity could be manipulated to stimulate myelination in humans in the future.

我们的大脑和脊髓（我们的中枢神经系统）大约一半的体积是由白质组成的。白质对于正常的大脑形成、功能和健康至关重要，白质受损会导致许多人类疾病的症状，例如多发性硬化症、多发性硬化症。白质中的“白色”是指存在一种称为髓磷脂的脂肪物质，它是由称为少突胶质细胞的特殊细胞制成的，包裹在我们大脑的神经电缆（称为轴突）周围。轴突上髓磷脂的存在使轴突绝缘，并使我们的神经元能够长距离快速传输电脉冲。髓磷脂还为轴突提供营养支持，这对轴突的健康至关重要。直到最近，人们还认为髓磷脂是一种静态结构，但近年来人们已经清楚，髓磷脂是在我们的一生中产生的，并且它受到大脑活动的动态调节，也许是为了优化大脑功能和修复。人类通过形成新的少突胶质细胞，并可能通过重塑现有的髓磷脂，在成年后很好地制造新的髓磷脂。非常有趣的是，对人类的研究表明，学习新任务，例如杂耍可以刺激我们白质的变化，对动物模型的研究表明，成年期学习新任务需要形成新的产生髓磷脂的少突胶质细胞。重要的是，我们的大脑产生新髓磷脂的能力也是再生的关键，在多发性硬化症等疾病中髓磷脂丧失后可以观察到这一点。与大脑功能在调节髓鞘形成中的作用一致，我们自己的工作表明，我们脑细胞的电活动会刺激少突胶质细胞产生髓磷脂，而我们同事的研究表明，神经元活动是正常髓磷脂再生所必需的。然而，许多重要的问题仍然存在：我们的脑细胞如何告诉少突胶质细胞促进髓鞘形成？刺激大脑活动可以促进髓磷脂的再生吗？我们使用斑马鱼作为动物模型来研究髓鞘形成。斑马鱼产生的胚胎小、透明且发育非常快，我们已经培育出髓磷脂和有髓轴突被荧光标记的斑马鱼。鱼的这些特性与我们的工具一起意味着我们可以直接可视化髓磷脂随着时间的推移而产生、重塑甚至再生。为了研究髓鞘再生（称为髓鞘再生），我们最近制作了一种转基因鱼，我们可以以非侵入性方式删除三分之二的少突胶质细胞，从而导致轴突髓鞘丧失（脱髓鞘）。尽管鱼类和人类的神经系统都有能力通过髓鞘再生来替代失去的髓鞘质，但这一过程并不完美，最终会导致多发性硬化症等疾病的失败。因此，寻找促进内源性髓鞘再生能力的方法是医学研究的一个重要目标。直接观察活体动物髓鞘形成和髓鞘再生的可能性是该系统的一大优势，并将通过本提案的工作加以利用。该提案的目的是利用斑马鱼直接观察正常动物中髓磷脂是如何随着时间的推移沿着轴突形成的，并评估如何通过神经元的电活动来调节髓磷脂。我们将首次（据我们所知）直接观察活体动物中单个轴突随时间的髓鞘再生，并研究促进大脑功能是否可以增强髓磷脂的再生。这项工作将为我们的大脑如何构建和再生髓磷脂以及如何操纵大脑活动来刺激未来人类的髓鞘形成提供急需的见解。

项目成果

Forward Genetic Screen Using Zebrafish to Identify New Genes Involved in Myelination.

使用斑马鱼进行正向遗传筛选来识别参与髓鞘形成的新基因。

• DOI: http://dx.10.1007/978-1-4939-9072-6_11
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Kegel L

Revisiting remyelination: Towards a consensus on the regeneration of CNS myelin.

重新审视髓鞘再生：就中枢神经系统髓鞘再生达成共识。

• DOI: 10.1016/j.semcdb.2020.09.009
• 发表时间: 2020-10-17
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: R. Franklin;J. Frisén;D. Lyons
• 通讯作者: D. Lyons

Myelination of Neuronal Cell Bodies when Myelin Supply Exceeds Axonal Demand.

当髓鞘质供应超过轴突需求时，神经元细胞体的髓鞘化。

• DOI: http://dx.10.1016/j.cub.2018.02.068
• 发表时间: 2018
• 期刊: CB
• 作者: Almeida RG

Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.

少突胶质细胞神经成束蛋白独立调节中枢神经系统中的髓磷脂靶向和鞘生长。

• DOI: http://dx.10.1016/j.devcel.2019.10.016
• 发表时间: 2019
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Klingseisen A

Glia as architects of central nervous system formation and function.

神经胶质细胞是中枢神经系统形成和功能的建筑师。

• DOI: http://dx.10.1126/science.aat0473
• 发表时间: 2018
• 期刊: Science (New York, N.Y.)
• 作者: Allen NJ