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
• 负责人: Ethan Garrett Hughes
• 金额: $ 58.63万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712406
• 关键词: Adult; Age; Area; Axon; Behavior; Behavior Therapy; Behavioral; Biology; Brain; Brain region; Cell Death; Cell Differentiation process; Cell Lineage; Cell Proliferation; Central Nervous System; Communities; Cortical Column; Cues; Data; Demyelinations; Development; Environment; Fluorescence; Future; Generations; Individual; Inflammatory; Injury; Knowledge; Learning; Lesion; Life; Memory; Methodology; Monitor; Multiple Sclerosis; Myelin; Myelin Sheath; Natural regeneration; Neurons; Oligodendroglia; Optics; Pathologic; Patients; Penetration; Persons; Photons; Physics; Recovery of Function; Regulation; Research; Shapes; Structure; Tissue imaging; Tissues; United States; White Matter Disease; cell behavior; central nervous system demyelinating disorder; cognitive function; effectiveness evaluation; efficacy testing; experience; gray matter; illness length; in vivo; in vivo imaging; innovation; insight; motor learning; multiple sclerosis patient; myelination; neuronal cell body; novel; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; precursor cell; regenerative; regional difference; remyelination; repaired; therapeutic candidate; three photon microscopy; tool; white matter; white matter damage

PROJECT SUMMARY Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that afflicts nearly 1 million people in the United States alone. While MS is classically regarded as a white matter disease, gray matter lesion load may exceed that of the white matter in patients with MS. The pathological features of lesions differ between gray and white matter lesions. Interestingly, in lesions that span white and gray matter regions, display pathological hallmarks of white matter-only lesions, suggesting that cellular environments distinctly regulate oligodendrocyte loss and regeneration. Furthermore, attempts at remyelination are more frequent in cortical versus white matter lesions regardless of patient age or disease duration. These findings suggest that remyelination of gray matter regions may be specifically limited by decreased functional integration of new oligodendrocytes compared to white matter regions. Understanding the regional differences in oligodendrocyte loss and regeneration represents a clear unmet need in the MS research community. A major limitation to understanding these regional differences is the inability to monitor the dynamics of oligodendrocytes in white matter in the living brain. To overcome this obstacle, we will use new optical methodologies to determine regional variability in oligodendrocyte cell behavior. We propose to use the superior penetration depth of three- photon excitation fluorescence and longitudinal in vivo imaging to determine the effects of circuit-specific neuronal activity and demyelinating injury on oligodendrocyte lineage cells in both superficial and deep areas of the adult brain. The objectives of this proposal are: 1) evaluate how behaviorally-relevant neuronal activity regulates gray and white matter oligodendrogenesis, 2) to elucidate whether behavioral interventions can equally promote oligodendrocyte regeneration of the gray and white matter. The overall hypothesis of this proposal is region-specific rates of oligodendrocyte precursor differentiation and integration govern the proportion of myelination in healthy, adaptive, and regenerative contexts. This proposal represents a novel synthesis of cutting-edge approaches in optical physics and oligodendrocyte biology, and breaks new ground in understanding the mechanisms underlying the regulation of gray and white matter oligodendrocyte plasticity and regeneration.

项目摘要 多发性硬化症（MS）是一种困扰中枢神经系统的炎症性脱髓鞘性疾病 仅在美国，就有近100万人。尽管MS经典被视为白质疾病，但 灰质病变负荷可能超过MS患者的白质。的病理特征 灰色和白质病变之间的病变不同。有趣的是，在跨越白色和灰质的病变中 区域，显示仅白质病变的病理标志，表明细胞环境 明显调节少突胶质细胞损失和再生。此外，尝试雷髓的尝试更多 无论患者年龄或疾病持续时间如何，皮质与白质病变频繁。这些发现 表明灰质区域的再生可能会受到功能整合降低的特定限制 与白质区域相比，新的少突胶质细胞。了解区域差异 少突胶质细胞损失和再生代表了MS研究界的明显未满足的需求。专业 理解这些区域差异的局限性是无法监测少突胶质细胞的动力学 在活大脑中的白质中。为了克服这一障碍，我们将使用新的光学方法来确定 少突胶质细胞行为的区域变异性。我们建议使用三分之三的高渗透深度 光子激发荧光和体内成像纵向成像，以确定电路特异性的影响 神经元活性和脱髓鞘性损伤在表面和深层区域的少突胶质细胞谱系细胞上 成人大脑。该提案的目标是：1）评估行为与行为相关的神经元活动 调节灰质和白质的寡聚生成，2）阐明行为干预措施是否同样可以 促进灰质和白质的少突胶质细胞再生。该提议的总体假设是 少突胶质细胞前体分化和整合的区域特异性速率控制 健康，适应性和再生环境中的髓鞘形成。该提议代表了一种新颖的综合 光学物理和少突胶质细胞生物学的尖端方法，并在 了解灰质和白质少突胶质细胞可塑性的调节机制和 再生。