CRCNS: Defining the role of astrogenesis in cortical folding

胶质细胞，包括星形胶质细胞，是迄今为止在大脑中最常见的细胞类型，它们的功能障碍 已知在许多神经发育、神经退行性变、神经免疫和 神经再生疾病和障碍。然而，相对于神经元，对它们的研究一直很少， 目前还不清楚它们在大脑皮层折叠中扮演什么角色，如果有的话。因此，迫切需要 更深入地了解神经胶质细胞在健康和疾病中大脑发育中的作用。 PI和co-I的长期目标是利用他们的背景，在计算力学和 分子神经科学和细胞神经科学，分别了解皮质折叠的过程。在这里，他们 结合他们互补的专业知识来研究星形胶质细胞在脑回中的作用 计算-实验相结合的方法。CRCNS提案的总体目标是 微观尺度上的细胞行为和宏观尺度上的大脑形态和皮质折叠。 特别是，我们将评估星形胶质细胞增殖的两种潜在机制：1)星形胶质细胞推动 或2)大脑皮层拉动星形胶质细胞，使其相应生长。为此，我们 将在子宫内对发育中的雪貂大脑中的星形胶质细胞进行实验操作和跟踪 电穿孔(目标1)，开发和校准星形胶质细胞两种机制的计算模型 皮质折叠中的行为(目标2)，并使用我们的模型来评估它们的可能性(目标3)。这项建议 是建立在我们之前的工作基础上的，这项工作已经表明，脑回下星形胶质细胞的增殖是 在雪貂大脑中形成皮质褶皱所必需的，而且是由实验校准的 计算模型可以捕捉细胞行为的动态以及由此产生的组织水平 力学和形态。这里提出的实验和计算相结合的方法将 有助于我们从根本上理解神经胶质细胞在大脑发育中的作用，这可能是 在神经发育疾病和紊乱的研究中很重要，先进的诊断和有效的 治疗。此外，我们经过实验验证的计算框架可以用于设计 检验机械假说和确定治疗空间或时间特定事件的路径的实验方法，如产前感染、疾病或暴露。

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.