Are there different mechanisms of oligodendrocyte recruitment when new myelin is made during nervous system plasticity and regeneration?

在神经系统可塑性和再生过程中产生新髓磷脂时，少突胶质细胞募集是否存在不同的机制？

• 批准号: BB/V017012/1
• 负责人: Tim Czopka
• 金额: $ 58.14万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV017012%2F1
• 关键词: there; different; mechanisms; oligodendrocyte; recruitment

Our central nervous system (CNS), which comprises brain and spinal cord, consists of myriads of cells that constantly interact and influence each other. Nerve cells (neurons) are the main information processing unit in the CNS, which form a network that is interconnected via long cell processes called axons.Neurons and their axons are not alone in the brain, but their function critically depends on the presence of surrounding support cells, for which the umbrella term 'glial cells' is used. One specific type of such glial cells are oligodendrocytes. Oligodendrocytes form an insulating substance around axons which is called myelin, and which is in fact the 'white' in the white matter of our brain.Myelin formation by oligodendrocytes is absolutely crucial for nervous system function. It insulates and feeds axons, and in doing so enables rapid information processing between neurons.New myelin can dynamically be formed in the healthy CNS almost lifelong and is of importance for structural changes within our CNS that underlie learning. Damage of myelin has devastating neurological consequences and is a hallmark of demyelinating diseases such as Multiple Sclerosis (MS). Damaged myelin can get repaired in an endogenous regenerative process called remyelination. Both, myelination in the healthy CNS and remyelination in the diseased CNS are carried out by oligodendrocytes. For a long time, oligodendrocytes have been considered a homogenous cell population. However, recent research results revealed that oligodendrocytes are diverse and have different properties and functions.Therefore, it is an important open question if new myelin formed in the healthy and diseased CNS is made by the same or by different oligodendrocytes and how this is controlled. It is important to gain knowledge of the regulatory principles that underlie these processes in order device strategies of how to specifically target oligodendrocytes when these processes naturally fail to occur.In this proposal, we use a unique approach with which to address the question of how new myelin is made in the healthy and in the damaged CNS. We will use small tropical zebrafish as model organisms because young zebrafish are optically transparent, allowing us to investigate all oligodendrocytes in the CNS of a living animal in real time without the need of any surgical intervention. Being able to easily see how different oligodendrocytes master myelin formation in the healthy CNS, as well as remyelination in the damaged CNS, will allow us to unambiguously answer whether oligodendrocytes with similar or different properties are involved. Furthermore, because we will also analyse genetic information of the oligodendrocytes that we investigate, we will gain knowledge on how this is controlled by our genes. Together, our work will lead to the discovery of potentially new pathways which govern myelin formation in the healthy and damaged brain; and may therefore permit the development of new strategies to specifically manipulate these processes where they fail to occur naturally.

我们的中枢神经系统（CNS）包括大脑和脊髓，由无数细胞组成，这些细胞不断相互作用和影响。神经细胞（神经元）是中枢神经系统中主要的信息处理单元，它们形成一个通过称为轴突的长细胞过程相互连接的网络。神经元及其轴突在大脑中并不孤单，但它们的功能关键取决于周围支持细胞的存在，其中使用了总括术语“胶质细胞”。这种神经胶质细胞的一种特定类型是少突胶质细胞。少突胶质细胞在轴突周围形成一种绝缘物质，称为髓鞘，实际上是我们大脑白色物质中的“白色”。少突胶质细胞形成的髓鞘对神经系统功能至关重要。它隔离和喂养轴突，从而使神经元之间的快速信息处理成为可能。新的髓磷脂可以在健康的中枢神经系统中动态地形成，几乎终身，对我们中枢神经系统内的结构变化至关重要，而这些结构变化是学习的基础。髓磷脂的损伤具有破坏性的神经学后果，并且是脱髓鞘疾病如多发性硬化症（MS）的标志。受损的髓鞘可以在称为髓鞘再生的内源性再生过程中得到修复。健康CNS中的髓鞘形成和患病CNS中的髓鞘再生都是由少突胶质细胞进行的。长期以来，少突胶质细胞被认为是一个同质的细胞群体。然而，最近的研究结果表明，少突胶质细胞是多样性的，具有不同的性质和功能。因此，在健康和患病的CNS中形成的新髓鞘是由相同还是由不同的少突胶质细胞产生的，以及如何控制这是一个重要的未决问题。重要的是要获得的监管原则，这些过程的基础上，为了设备策略，如何具体针对少突胶质细胞时，这些过程自然无法发生。在这个建议中，我们使用一个独特的方法来解决这个问题，新的髓鞘是如何在健康和受损的中枢神经系统。我们将使用小型热带斑马鱼作为模式生物，因为年幼的斑马鱼是光学透明的，使我们能够在真实的时间内研究活体动物CNS中的所有少突胶质细胞，而不需要任何手术干预。能够很容易地看到不同的少突胶质细胞如何在健康的CNS中控制髓鞘形成，以及在受损的CNS中的髓鞘再生，将使我们能够明确地回答是否涉及具有相似或不同性质的少突胶质细胞。此外，因为我们还将分析我们研究的少突胶质细胞的遗传信息，我们将获得关于这是如何由我们的基因控制的知识。总之，我们的工作将导致发现潜在的新途径，这些途径控制健康和受损大脑中的髓鞘形成;因此，可能允许开发新的策略来专门操纵这些过程，而这些过程不能自然发生。

项目成果

Myelination-independent functions of oligodendrocyte precursor cells in health and disease.

少突胶质细胞前体细胞在健康和疾病中的髓鞘形成独立功能。

• DOI: 10.1038/s41593-023-01423-3
• 发表时间: 2023
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Xiao Y