How does neuronal activity regulate central nervous system myelination?

我们的大脑和脊髓，即我们的中枢神经系统，大约有一半的体积是由白质组成的。白质对正常的大脑形成、功能和健康至关重要，白质的损伤会导致许多人类疾病的症状，如多发性硬化症（ms）。白质中的“白色”指的是一种叫做髓磷脂的脂肪物质的存在，髓磷脂是由被称为少突胶质细胞的特殊细胞产生的，它包裹在我们大脑的神经电缆（被称为轴突）周围。轴突上髓磷脂的存在使轴突与外界隔绝，使我们的神经元能够远距离快速传输电脉冲。髓磷脂还为轴突提供营养支持，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，人们已经清楚地认识到髓磷脂是在我们的一生中产生的，它受到大脑活动的动态调节，可能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，很可能通过重塑现有的髓磷脂，在成年后很好地制造出新的髓磷脂。非常有趣的是，对人类的研究表明，学习新的任务，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，成年后学习新的任务需要形成新的产生髓磷脂的少突胶质细胞。重要的是，我们的大脑制造新髓磷脂的能力也是在诸如ms等疾病中髓磷脂丢失后观察到的再生的关键。与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，我们的脑细胞的电活动刺激少突胶质细胞产生髓磷脂，我们的同事的研究表明，正常的髓磷脂再生需要神经元活动。然而，许多重要的问题仍然存在：我们的脑细胞如何告诉我们的少突胶质细胞促进髓鞘形成？刺激大脑活动能促进髓磷脂再生吗？我们用斑马鱼作为动物模型来研究髓鞘形成。斑马鱼的胚胎很小，透明，发育非常快，我们培育出的斑马鱼的髓鞘和髓鞘轴突都有荧光标记。鱼类的这些特性加上我们的工具，意味着我们可以直接看到髓磷脂的形成、重塑，甚至随着时间的推移而再生。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的方式删除三分之二的少突胶质细胞，从而导致轴突髓鞘的损失（脱髓鞘）。尽管鱼和人的神经系统都有能力通过髓鞘再生来替代丢失的髓磷脂，但这一过程并不完善，在ms等疾病中最终会失败。因此，寻找促进我们内源性髓鞘再生能力的方法是医学研究的重要目标。直接观察活体动物髓鞘形成和再髓鞘形成的可能性是该系统的一大优势，将通过本提案的工作加以利用。这项提议的目的是利用斑马鱼直接观察正常动物的轴突是如何随着时间的推移产生髓磷脂的，并评估这是如何通过神经元的电活动来调节的。我们将首次（据我们所知）在活体动物中对单个轴突的髓鞘再生进行长期的直接观察，并研究促进脑功能是否可以增强髓鞘再生。这项工作将为我们的大脑如何构建和再生髓鞘，以及未来如何操纵大脑活动来刺激人类的髓鞘形成提供急需的见解。

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.