How does Adaptive Myelination Re-shape Neural Circuits During Learning?

在脊椎动物的大脑和脊髓中，被称为“少突胶质细胞”的细胞在“轴突”周围构建了一层脂肪绝缘层——轴突是“神经元”的长丝状延伸，是可电兴奋的细胞。这种被称为“髓磷脂”的绝缘层，极大地加速了神经细胞发出的电信号，并为神经元及其轴突提供能量支持。最近有研究表明，少突胶质细胞及其产生的髓磷脂也有助于大脑适应新的经历，有助于学习和记忆的形成。髓磷脂究竟是如何影响学习的，目前还没有得到很好的理解。我们的假设是，少突胶质细胞可以感知被特定行为激活的神经元，从而导致这些活跃神经元上髓磷脂的形成或重塑。我们预测，这一过程将微调电信号，改变活跃神经元的连通性，从而导致负责新行为的新神经元回路的发展。在这个项目中，我们将训练老鼠学习一项新的运动技能（在一个有不规则间距的轮子上跑步），并观察激活神经元上的髓磷脂如何随着学习而变化。然后，我们将使用许多不同的基因操作来破坏可能使少突胶质细胞感知神经元活动的途径，并确定这些小鼠是否保持学习运动技能的能力。我们还将破坏在技能学习过程中形成的新髓磷脂的形成和维持，以了解这一过程如何改变神经元连接。我们的实验将有助于阐明支撑大脑基本功能之一——适应能力——的一般机制，并可能为在健康衰老过程中如何更好地保持认知能力，或帮助疾病或损伤后大脑功能的恢复提供见解。

In the vertebrate brain and spinal cord, cells called "oligodendrocytes" construct a fatty insulating layer around "axons" - long filamentous extensions of "neurons", the electrically excitable cells. This insulation, called "myelin", greatly speeds up the electrical signals sent by nerve cells as well as providing energetic support to neurons and their axons.Recently it has been demonstrated that oligodendrocytes and the myelin that they make also help the brain to adapt to new experiences, contributing to learning and memory formation. How exactly myelin influences learning is still not well understood. Our hypothesis is that oligodendrocytes can sense the neurons that are activated by specific behaviours, resulting in the formation or remodelling of myelin on those active neurons. We predict that this process will fine-tune electrical signals and alter the connectivity of the active neurons leading to the development of new neuronal circuits responsible for new behaviours. In this project we will train mice to learn a new motor skill (running on a wheel with irregularly spaced rungs) and observe how the myelin on activated neurons changes with learning. We will then use a number of different genetic manipulations to disrupt pathways that may enable oligodendrocytes to sense neuronal activity and determine if these mice maintain the ability to learn motor skills. We will also disrupt the formation and maintenance of new myelin that is formed during skill learning to ask how this process changes neuronal connectivity. Our experiments will help illuminate the general mechanisms underpinning one of the fundamental functions of the brain - the ability to adapt - and may provide insights into how better to maintain cognitive ability during healthy aging, or to aid recovery of brain function following disease or injury.