The role of myelination in cortical circuit function and motor behavior

仅在美国就有近100万人受到多发性硬化症(MS)的影响。MS是一种 中枢神经系统(CNS)的炎性脱髓鞘疾病。而多发性硬化症被经典地视为 一种白质疾病，白质病变的数量与身体残疾或 认知障碍。最近的证据表明，灰质区域有显著的髓鞘丢失和 皮质损伤负荷的增加与皮质萎缩和认知功能下降的增加有关。功能性 多发性硬化症患者的影像显示，初级运动皮质和整个大脑皮质的超兴奋性增加。 汽车网络。此外，MS患者的功能恢复与异常的正常化有关 皮质活动，提示运动网络过度兴奋和运动受损之间的关系 行为。然而，我们对髓鞘丢失如何影响单个神经元或神经活动的理解 回路，在灰质内是极其有限的。悬而未决的问题，如， 脱髓鞘对完整中枢神经生理的影响，脱髓鞘损伤如何影响新神经元的获得 技能，以及可以增强髓鞘再生的疗法是否可以恢复神经和行为功能 未知。最近，我们开发了新的方法来显示髓鞘、少突胶质细胞和它们的 在完整的小鼠大脑中的前体，以及记录和监测神经活动的纵向方法 表现得像动物一样。我们还确定了增强髓鞘修复的新的行为干预措施。在这 应用程序，我们建议利用这些技术揭示的动态来辨别 髓鞘丢失和修复对局部电路活动和运动行为的影响。这项建议的目标是：1) 评估髓鞘丢失对神经元回路功能的影响；2)阐明髓鞘再生的有效性 恢复神经功能和行为的疗法。这项建议将证明脱髓鞘的效果。 关于活体皮质神经元和回路功能的研究。这些研究将验证体内小鼠模型平台 测试治疗多发性硬化症的新候选药物的疗效，并提供与临床相关的数据 刺激多发性硬化症内源性再髓鞘形成的治疗方法对恢复神经和行为功能的作用。

Nearly 1 million people in the United States alone are affected by Multiple Sclerosis (MS). MS is an inflammatory, demyelinating disease of the central nervous system (CNS). While MS is classically regarded as a disease of the white matter, the number of white matter lesions does not correlate with physical disability or cognitive impairment. Recent evidence indicates that gray matter areas have significant myelin loss and increased cortical lesion load is associated with increased cortical atrophy and cognitive decline. Functional imaging of patients with MS reveals increased hyperexcitability within primary motor cortex and throughout the motor network. Moreover, functional recovery in MS patients is associated with normalization of aberrant cortical activity, suggesting a relationship between motor network hyperexcitability and impaired motor behavior. However, our understanding of how myelin loss influences the activity of single neurons, or neural circuits, within grey matter is extremely limited. Outstanding questions such as, what are the consequences of demyelination on neural physiology in the intact CNS, how demyelinating injuries affect the acquisition of new skills, and can therapies that can enhance remyelination can restore neural and behavioral function remain unknown. Recently, we have developed new approaches to visualize myelin, oligodendrocytes, and their precursors in the intact mouse brain, as well as longitudinal approaches to record and monitor neural activity in behaving animals. We have also identified novel behavioral interventions that enhance myelin repair. In this application, we propose to capitalize on the dynamics revealed by these techniques to discern the effects of myelin loss and repair on local circuit activity and motor behavior. The objectives of this proposal are: 1) evaluate how myelin loss affects neuronal circuit function and 2) to elucidate the effectiveness of remyelination therapies on restoring neural function and behavior. This proposal will demonstrate the effects of demyelination on cortical neuronal and circuit function in vivo. These studies will validate an in vivo mouse model platform to test efficacy of new therapeutic candidates for MS, and provide clinically relevant data regarding the efficacy of therapies that stimulate endogenous remyelination in MS on restoring neural and behavioral function.