The role of myelination in cortical circuit function and motor behavior

髓鞘形成在皮质回路功能和运动行为中的作用

• 批准号: 10307999
• 负责人: Ethan Garrett Hughes
• 金额: $ 39.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307999
• 关键词: Affect; Animals; Area; Axon; Behavior; Behavior Therapy; Behavioral; Biology; Brain; Central Nervous System Diseases; Data; Demyelinations; Effectiveness; Equilibrium; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Health; Impaired cognition; Impairment; Individual; Inflammatory; Injury; Learning; Lesion; Monitor; Motor; Motor Cortex; Movement; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurons; Neurophysiology - biologic function; Neuropsychology; Oligodendroglia; Pattern; Performance; Persons; Pharmacology; Physiology; Population; Recovery; Recovery of Function; Role; Techniques; Thalamic structure; Time; Treatment Efficacy; United States; White Matter Disease; behavioral impairment; blood oxygen level dependent; central nervous system demyelinating disorder; cerebral atrophy; clinically relevant; cognitive function; efficacy testing; gray matter; improved; in vivo; motor behavior; motor disorder; motor impairment; motor learning; mouse model; multiple sclerosis patient; myelination; neural circuit; neuromechanism; neuronal circuitry; neurophysiology; novel; novel strategies; novel therapeutics; physically handicapped; recruit; relating to nervous system; remyelination; repaired; restoration; skills; spatiotemporal; therapeutic candidate; therapeutically effective; white matter

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.

仅在美国，就有近100万人受到多发性硬化症（MS）的影响。 MS是一个 中枢神经系统（CNS）的炎症，脱髓鞘疾病。而MS经典被视为 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，灰质区域有明显的髓磷脂损失，并且 皮质病变负荷增加与皮质萎缩和认知能力下降有关。功能 MS患者的成像显示，原发性运动皮层和整个过程中的过度兴奋性 电机网络。此外，MS患者的功能恢复与异常的归一化有关 皮质活动，表明电动机网络过度兴奋与电动机受损之间存在关系 行为。但是，我们对髓磷脂损失如何影响单神经元或神经的活动的理解 电路，在灰质内非常有限。出色的问题，例如，有什么后果 完整中枢神经系统中神经生理学的脱髓鞘，脱髓鞘损伤如何影响新的收购 技能和可以增强雷余的疗法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可视化髓磷脂，少突胶质细胞及其 完整小鼠大脑中的前体，以及记录和监测神经活动的纵向方法 行为动物。我们还确定了增强髓磷脂修复的新型行为干预措施。在这个 应用，我们建议利用这些技术揭示的动态，以辨别 髓磷脂损失和修复局部电路活动和运动行为。该提议的目标是：1） 评估髓磷脂损失如何影响神经元电路功能，2）阐明雷呈有效性 恢复神经功能和行为的疗法。该建议将证明脱髓鞘的影响 在体内的皮质神经元和电路功能上。这些研究将验证一个体内鼠标模型平台 测试新的治疗候选者对MS的功效，并提供有关临床相关数据 在恢复神经和行为功能的MS中刺激内源性透明的疗法。