CRCNS: Defining the role of astrogenesis in cortical folding

CRCNS：定义星形发生在皮质折叠中的作用

• 批准号: 10831118
• 负责人: Maria Holland
• 金额: $ 14.43万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831118
• 关键词: Area; Astrocytes; Autocrine Communication; Behavior; Biochemical; Biological; Brain; Calibration; Cell Density; Cell division; Cells; Central Nervous System; Cerebrum; Collaborations; Computer Models; Coupled; Couples; Development; Developmental Process; Diagnostic; Disease; Electroporation; Event; Experimental Designs; Ferrets; Functional disorder; Genetic; Goals; Growth; Health; Image; Infection; Investigation; Knowledge; Measures; Mechanics; Mission; Modeling; Molecular; Morphology; Motion; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodevelopmental Disorder; Neuroglia; Neuroimmune; Neuronal Plasticity; Neurons; Neurosciences; Oligodendroglia; Pathologic Processes; Pathway interactions; Pattern; Physiological Processes; Play; Population; Process; Proliferating; Public Health; Publications; Research; Role; Structure; Surface; Testing; Time; Tissues; Work; biomechanical model; cell behavior; cell motility; cell type; computer framework; cost; data modeling; effective therapy; experience; experimental study; in silico; in utero; in vivo; insight; mechanical force; nervous system disorder; novel; prenatal; response; risk prediction; spatiotemporal; subventricular zone; white matter

Glial cells, including astrocytes, are the most prevalent cell type in the brain by far, and their dysfunctions are known to play a role in a host of neurodevelopmental, neurodegenerative, neuroimmune, and neuroplastic diseases and disorders. However, they have been greatly understudied relative to neurons, and it remains unclear what role, if any, they play in cortical folding. Therefore, there is a critical need for deeper mechanistic understanding of the role of glial cells in brain development across health and disease. The long-term goals of the PI and co-I are to use their backgrounds, in computational mechanics and molecular and cellular neuroscience, respectively, to understand the process of cortical folding. Here they combine their complementary expertise to investigate the role of astrocytes in gyrification using a combined computational-experimental approach. The overall objective of this CRCNS proposal is to relate cellular behavior at the microscale to cerebral morphology and cortical folding at the macroscale. In particular, we will evaluate two potential mechanisms of astrocyte proliferation: 1) that astrocytes push on the cortex or 2) that the cortex pulls on astrocytes, causing them to grow in response. To that end, we will experimentally manipulate and track astrocytes in the developing ferret brain using in utero electroporation (Aim 1), develop and calibrate computational models of both mechanisms of astrocyte behavior in cortical folding (Aim 2), and use our models to evaluate their likelihood (Aim 3). This proposal is strongly founded on our own prior work, which has shown that astrocyte proliferation under gyri is necessary for the formation of cortical folds in the ferret brain, and that an experimentally-calibrated computational model can capture the dynamics of cellular behavior and the resulting tissue-level mechanics and morphology. The combined experimental-computational approach proposed here will contribute to our fundamental understanding of the role of glial cells in brain development, which could be important in the study of neurodevelopmental diseases and disorders, advanced diagnostics, and effective treatments. Furthermore, our experimentally-validated computational framework could be used to design experimental approaches to test mechanistic hypotheses and to identify pathways for treatment in spatio- or temporally-specific events such as prenatal infection, illness, or exposure.

神经胶质细胞，包括星形胶质细胞，是迄今为止大脑中最普遍的细胞类型，其功能障碍 众所周知，可以在神经发育，神经退行性，神经免疫性和 神经塑性疾病和疾病。但是，它们相对于神经元而被大大研究了 目前尚不清楚它们在皮质折叠中扮演什么角色。因此，对 对神经胶质细胞在健康和疾病脑发育中的作用的更深入的理解。 PI和CO-I的长期目标是在计算技节和 分子和细胞神经科学分别了解皮质折叠的过程。他们在这里 结合其互补专业知识，以使用A 合并的计算实验方法。此CRCN提案的总体目标是联系 在微观尺度上，在宏观上进行脑形态和皮质折叠的细胞行为。 特别是，我们将评估星形胶质细胞增殖的两个潜在机制：1）星形胶质细胞推 在皮质上，或2）皮层拉在星形胶质细胞上，从而使它们生长出来。为此，我们 将使用子宫中的雪貂大脑中的星形胶质细胞进行实验操纵和跟踪星形胶质细胞 电穿孔（AIM 1），开发和校准星形胶质细胞两种机制的计算模型 皮质折叠的行为（AIM 2），并使用我们的模型评估其可能性（AIM 3）。这个建议 是在我们自己的先前工作中坚固建立的，这表明在Gyri下的星形胶质细胞增殖 雪貂大脑中皮质褶皱的形成所必需的，并且是经过实验校准的 计算模型可以捕获细胞行为的动力学和所得组织级别 力学和形态。此处提出的合并实验计算方法将 有助于我们对神经胶质细胞在大脑发育中作用的基本理解，这可能是 在研究神经发育疾病和疾病，高级诊断和有效的研究中很重要 治疗。此外，我们的实验验证计算框架可用于设计 测试机理假设并确定在时空特异性事件（例如产前感染，疾病或暴露）中进行治疗途径的实验方法。