The Effects of Voluntary Exercise on Oligodendroglia and Myelin in Developing and Cuprizone-Treated Mice.

 描述（由申请人提供）：多发性硬化症（MS）是一种使人衰弱的脱髓鞘疾病，影响全球数百万人的生活质量。这些缺陷大部分被认为是由于髓磷脂的慢性丢失，髓磷脂是一种对中枢神经系统正常功能很重要的脂质致密结构。治疗MS的药物降低了髓鞘损伤的可能性，但不刺激髓鞘修复。运动也可以减轻MS患者的残疾，但这种影响的潜在生物学原因尚不清楚。此外，运动是否影响髓鞘修复或少突胶质细胞（中枢神经系统的髓鞘形成细胞）的成熟尚不清楚。然而，一些对健康成年人的研究表明，训练复杂的运动技能（如杂耍）或增加运动水平，与白色物质的大小增加有关，大脑区域有大量髓鞘。不幸的是，目前尚不清楚运动是否影响髓鞘本身或其他白色物质元素。有趣的是，最近对啮齿动物的研究发现，运动可以刺激海马体中新神经元的产生，海马体是大脑中的记忆区域。这让我们想知道运动是否也能刺激少突胶质细胞产生新的髓鞘。因此，我们已经开始测试这一假设，即运动影响少突胶质细胞的变化，增强髓鞘修复。通过向健康的年轻成年雌性啮齿动物提供跑步轮数周，我们观察到与久坐的啮齿动物相比，跑步啮齿动物大脑中成熟少突胶质细胞的数量增加。在另一个实验中，我们将小鼠暴露于铜腙，一种导致髓鞘损伤的化学物质。我们发现，与用cuprizone治疗的久坐小鼠相比，用cuprizone治疗的运动小鼠有更多的髓鞘。我们还发现这些小鼠的胰岛素生长因子B受体水平较低，这表明它可能在保护髓磷脂中起作用。我们目前的建议是为了更充分地评估运动对关键的少突胶质细胞反应，如细胞分裂和成熟，以及对髓鞘本身的修复的影响，无论是在cuprizone介导的髓鞘损伤和cuprizone去除后不久，当显着的髓鞘修复发生。我们将使用全脑成像技术来评估髓鞘，结合传统的组织学和基因表达分析来评估少突胶质细胞和髓鞘。我们还将使用具有未成熟少突胶质细胞的转基因小鼠，这些细胞可以在不同的时间点被诱导成为荧光细胞，使我们能够精确地监测运动和久坐小鼠中少突胶质细胞分化和髓鞘修复的时间动态。总之，这些研究将使我们能够确定运动如何以及何时影响髓鞘修复。我们希望这些研究将为未来研究使运动有助于改善髓鞘修复的细胞信号奠定基础。如果成功的话，我们的研究结果可能会导致更好地理解MS治疗中的运动和髓鞘修复新治疗靶点的开发。

 DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is a debilitating demyelinating disorder that impacts the quality of life of millions of people worldwide. These defects are largel thought to be due to a chronic loss of myelin, a lipid dense structure important for normal functioning of the central nervous system. Drugs that treat MS decrease the likelihood of myelin damage, but do not stimulate myelin repair. Exercise can also lessen disability in MS patients, yet the underlying biological cause for this effect is not well understood. Additionally, it is unknown whether exercise influences either myelin repair or the maturation of oligodendroglia, the myelinating cells of the central nervous system. However, some studies in healthy adults indicate that training intricate motor skills (such as juggling) or increasing levels of exercise, correlate with increases in the size of white matter, brain areas that are heavily myelinated. Unfortunately, it is not yet clear whether exercise is influencing the myelin itself or rather othe white matter elements. Intriguingly, recent studies in rodents have found that exercise can stimulate the production of new neurons in the hippocampus, a memory area in the brain. This made us wonder whether exercise could also stimulate oligodendroglia to make new myelin. We have therefore begun to test the hypothesis that exercise influences changes in oligodendroglia that enhance myelin repair. By providing running wheels to healthy young adult female rodents for several weeks, we observed increased numbers of mature oligodendrocytes in the brains of running rodents compared to sedentary rodents. In another experiment, we exposed mice to cuprizone, a chemical that causes myelin damage. We found that cuprizone-treated mice that exercised had more myelin compared to cuprizone-treated sedentary mice. We also found that these mice had less Insulin growth factor B receptor levels, which suggests that it could play a role in protecting myelin. Our current proposal is designed to more fully evaluate the effect of exercise both on critical oligodendroglial responses such as cell division and maturation, and on the repair of myelin itself, both during cuprizone-mediated myelin damage and shortly after the removal of cuprizone, when significant myelin repair takes place. We will use whole brain imaging techniques to assess myelin, coupled with traditional histological and gene expression analyses to evaluate oligodendrocytes and myelin. We will also use transgenic mice with immature oligodendroglia that can be induced at different time points to become fluorescent, enabling us to precisely monitor the temporal dynamics of oligodendroglial differentiation and myelin repair in the exercising and sedentary mice. Together, these studies will enable us to determine how and when exercise influences myelin repair. We hope that these studies will build the foundation for future studies on the cellular signals that enable exercise to contribute o improved myelin repair. If successful, our findings could lead to a better understanding of exercise in MS treatment and the development of novel therapeutic targets for myelin repair.