Career: The Role of Tissue Mechanics in Brain Folding During Development

职业：组织力学在发育过程中大脑折叠中的作用

• 批准号: 2045759
• 负责人: Andrew Lawton
• 金额: $ 87.09万
• 依托单位: Mississippi State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2045759&HistoricalAwards=false
• 关键词: Career; Role; Tissue; Mechanics; Brain

The human brain has a beautiful folded structure which has long attracted curiosity. Its complex folding patterns create more space for neural connections and subdivide the brain’s circuitry. Yet little is known about how these folds are created or how they shape brain function. This project examines growth rates, tensile forces, and material properties of the developing brain tissue that interact to induce and shape the patterns of brain folding. The folded mouse cerebellum will be used as the experimental system for studying these mechanical aspects of brain folding. Mouse strains with different patterns of cerebellar folding will be compared to determine how the tissue mechanics of folding are regulated differently during development. Comparison with rat cerebellar folding will additionally reveal how the mechanics are adjusted to regulate folding pattern changes between species. The project will advance the developmental and regulatory understanding of brain folding, and make fundamental contributions toward understanding neural development, improving tissue engineering, and elucidating the mechanisms underlying evolutionary brain changes. This project includes a research-based course for undergraduate students who will directly participate in the acquisition and analysis of the proposed experiments and develop their public-facing communication skills. Through a partnership with the local school district, this project will also support junior high science educators and their students by refreshing teacher science experience through hands-on participation, and the collaborative development of supplemental curricula for junior high science classes. Research into the morphogenesis of the brain has been limited due to an almost exclusive focus on the cerebral cortex, as well as the difficulty of acquiring developmental data. This proposal will meet these challenges by developing the murine cerebellum as a tractable model of brain folding. Previously, the cerebellum has been shown to undergo differential expansion at the time of folding initiation. Additionally, the cerebellum is under tension and has an outer fluid-like layer. These tissue properties are predicted to regulate folding as well as the partitioning of functional brain circuitry. Differential expansion, the predicted tunable driver of folding amount, will be analyzed in two- and three-dimensions in both wild-type and mutant strains of mice, as well as in rats. Cerebellar tension (predicted to decrease during folding progression) will be investigated with mechanical assays that examine folding amount as well as the fibrous axonal and dendritic components potentially mediating tension. The fluidity of cerebellar tissue will be analyzed using live ex vivo imaging and pharmacological perturbations. These experiments will demonstrate how tissue-specific forces are created and regulated during development to shape the folding brain and produce the variation seen within species, and how tissue mechanics are evolutionarily modulated to set up the folding variation seen between species. More broadly, the results of this proposal will provide insight into how emergent mechanisms arise during development to impact neural tissue form and function.This project is jointly funded by the Organization Program in the Neural Systems Cluster, and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

人类大脑具有美丽的折叠结构，这一直吸引着人们的好奇心。它复杂的折叠模式为神经连接创造了更多的空间，并细分了大脑的电路。然而，关于这些褶皱是如何产生的，或者它们是如何影响大脑功能的，人们知之甚少。这个项目研究了发育中的脑组织的生长速度、张力和材料属性，这些组织相互作用，诱导和塑造大脑折叠的模式。折叠的小鼠小脑将被用作研究大脑折叠的这些力学方面的实验系统。具有不同小脑折叠模式的小鼠品系将被比较，以确定折叠的组织机制在发育过程中如何受到不同的调节。与大鼠小脑折叠的比较将进一步揭示机制是如何调整的，以调节物种之间的折叠模式变化。该项目将促进对大脑折叠的发育和调节的理解，并在了解神经发育、改进组织工程和阐明进化大脑变化的机制方面做出基础性贡献。该项目包括一门面向本科生的研究性课程，他们将直接参与所提议的实验的获取和分析，并培养他们面向公众的沟通技能。通过与当地学区的合作，该项目还将通过亲身参与更新教师的科学体验，以及合作开发初中科学班的补充课程，为初中科学教育工作者及其学生提供支持。由于几乎只关注大脑皮层，以及难以获得发育数据，对大脑形态发生的研究一直受到限制。这项提议将通过将小鼠小脑开发为易于处理的大脑折叠模型来应对这些挑战。以前，小脑在折叠开始时经历了差异扩张。此外，小脑处于紧张状态，并有一层类似液体的外层。这些组织特性被预测为调节折叠以及大脑功能回路的分区。差异膨胀是折叠量的预测可调驱动因素，将在野生型和突变品系的小鼠以及大鼠身上进行二维和三维分析。小脑张力(预计将在折叠过程中降低)将通过机械分析来检查折叠量以及潜在调节张力的纤维性轴突和树突成分。小脑组织的流动性将使用活体成像和药理学扰动进行分析。这些实验将展示在发育过程中如何创建和调节组织特异性力量，以塑造折叠大脑并产生物种内的变异，以及组织力学如何在进化上被调制，以建立物种之间的折叠变异。更广泛地说，这项提案的结果将提供关于在发展过程中出现的紧急机制如何影响神经组织形式和功能的洞察。该项目由神经系统集群中的组织计划和既定的激励竞争研究计划(EPSCoR)共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。