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

 描述(申请人提供)：多发性硬化症(MS)是一种衰弱的脱髓鞘疾病，影响全球数百万人的生活质量。这些缺陷很大程度上被认为是由于髓鞘的慢性丢失造成的，髓鞘是一种脂质致密结构，对中枢神经系统的正常功能非常重要。治疗多发性硬化症的药物降低了髓鞘损伤的可能性，但不能刺激髓鞘修复。运动还可以减少多发性硬化症患者的残疾，但造成这种效果的潜在生物学原因尚不清楚。此外，目前尚不清楚运动是否会影响髓鞘修复或少突胶质细胞的成熟，少突胶质细胞是中枢神经系统的髓鞘细胞。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，与脑白质大小的增加有关，白质是大量髓鞘的大脑区域。不幸的是，目前还不清楚运动是否影响髓鞘本身，或者更确切地说，是影响白质元素。有趣的是，最近对啮齿类动物的研究发现，运动可以刺激大脑记忆区域--海马体中新神经元的产生。这让我们想知道，运动是否也能刺激少突胶质细胞制造新的髓鞘。因此，我们已经开始测试运动影响少突胶质细胞变化以促进髓鞘修复的假设。通过给健康的年轻成年雌性啮齿动物提供几周的跑轮，我们观察到与久坐不动的啮齿动物相比，跑步啮齿动物大脑中成熟的少突胶质细胞数量增加。在另一项实验中，我们让小鼠暴露于铜酮，这是一种会导致髓鞘损伤的化学物质。我们发现，与久坐不动的铜氮酮治疗的小鼠相比，运动的铜吡酮治疗的小鼠有更多的髓鞘。我们还发现，这些小鼠的胰岛素生长因子B受体水平较低，这表明它可能起到保护髓鞘的作用。我们目前的建议旨在更全面地评估运动对关键的少突胶质细胞反应，如细胞分裂和成熟的影响，以及对髓鞘本身修复的影响，无论是在铜酮介导的髓鞘损伤期间，还是在铜酮去除后不久，当显著的髓鞘修复发生时。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。我们还将使用带有未成熟少突胶质细胞的转基因小鼠，这些少突胶质细胞可以在不同的时间点被诱导成荧光细胞，使我们能够精确地监测运动和久坐小鼠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对运动有助于改善髓鞘修复的细胞信号的研究奠定基础。如果成功，我们的发现可能会导致更好地理解运动在多发性硬化症治疗中的作用，并开发新的髓鞘修复治疗靶点。

 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.