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

基本信息

  • 批准号:
    10307999
  • 负责人:
  • 金额:
    $ 39.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 中枢神经系统(CNS)的炎性脱髓鞘疾病。虽然MS被经典地认为是 白色物质疾病,白色物质病变的数量与身体残疾无关,或 认知障碍最近的证据表明,灰质区域有明显的髓鞘丢失, 增加的皮质损伤负荷与增加的皮质萎缩和认知衰退有关。功能 MS患者的成像显示初级运动皮层和整个 运动网络此外,MS患者的功能恢复与异常代谢产物的正常化相关。 皮质活动,表明运动网络过度兴奋和运动受损之间的关系 行为然而,我们对髓鞘缺失如何影响单个神经元或神经元活动的理解, 大脑灰质中的神经回路非常有限悬而未决的问题,如, 脱髓鞘对完整CNS神经生理学的影响,脱髓鞘损伤如何影响新的 能够增强髓鞘再生的治疗方法能够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鞘,少突胶质细胞, 前体在完整的小鼠大脑,以及纵向的方法来记录和监测神经活动, 行为动物我们还确定了新的行为干预,增强髓鞘修复。在这 应用,我们建议利用这些技术揭示的动态来辨别 髓鞘损失和修复对局部回路活动和运动行为的影响。本提案的目标是:1) 评估髓鞘丢失如何影响神经元回路功能; 2)阐明髓鞘再生的有效性 治疗恢复神经功能和行为。这项提案将证明脱髓鞘的影响, 对皮质神经元和回路功能的影响。这些研究将验证体内小鼠模型平台, 测试MS新治疗候选药物的疗效,并提供有关MS疗效的临床相关数据。 刺激MS中内源性髓鞘再生的疗法对恢复神经和行为功能的作用。

项目成果

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Ethan Garrett Hughes其他文献

Ethan Garrett Hughes的其他文献

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{{ truncateString('Ethan Garrett Hughes', 18)}}的其他基金

In vivo three-photon microscopy of the cortical gray and white matter
皮质灰质和白质的体内三光子显微镜
  • 批准号:
    10712406
  • 财政年份:
    2023
  • 资助金额:
    $ 39.23万
  • 项目类别:
Precision of Myelin Plasticity in Health and Disease
健康和疾病中髓磷脂可塑性的精确性
  • 批准号:
    10345911
  • 财政年份:
    2021
  • 资助金额:
    $ 39.23万
  • 项目类别:
Precision of Myelin Plasticity in Health and Disease
健康和疾病中髓磷脂可塑性的精确性
  • 批准号:
    10529323
  • 财政年份:
    2021
  • 资助金额:
    $ 39.23万
  • 项目类别:
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:
    10087980
  • 财政年份:
    2020
  • 资助金额:
    $ 39.23万
  • 项目类别:
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:
    10524761
  • 财政年份:
    2020
  • 资助金额:
    $ 39.23万
  • 项目类别:
Oligodendrocytes and their Precursors in a Novel Model of Antibody-Mediated Cortical Demyelination
抗体介导的皮质脱髓鞘新模型中的少突胶质细胞及其前体
  • 批准号:
    9507374
  • 财政年份:
    2018
  • 资助金额:
    $ 39.23万
  • 项目类别:
NG2 cell dynamics in the normal and injured adult central nervous system
正常和受损成人中枢神经系统中的 NG2 细胞动力学
  • 批准号:
    8201323
  • 财政年份:
    2011
  • 资助金额:
    $ 39.23万
  • 项目类别:
NG2 cell dynamics in the normal and injured adult central nervous system
正常和受损成人中枢神经系统中的 NG2 细胞动力学
  • 批准号:
    8318445
  • 财政年份:
    2011
  • 资助金额:
    $ 39.23万
  • 项目类别:
The role of astrocytes in inhibitory synaptogenesis
星形胶质细胞在抑制性突触发生中的作用
  • 批准号:
    7661597
  • 财政年份:
    2007
  • 资助金额:
    $ 39.23万
  • 项目类别:
The role of astrocytes in inhibitory synaptogenesis
星形胶质细胞在抑制性突触发生中的作用
  • 批准号:
    7591798
  • 财政年份:
    2007
  • 资助金额:
    $ 39.23万
  • 项目类别:

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