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

人类的大脑有一个美丽的折叠结构，长期以来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，并细分了大脑的回路。然而，对于这些褶皱是如何形成的，以及它们是如何影响大脑功能的，我们知之甚少。该项目研究了发育中的脑组织的生长速度、拉伸力和材料特性，这些因素相互作用，诱导和塑造了大脑折叠的模式。折叠的小鼠小脑将被用作研究大脑折叠这些机械方面的实验系统。将比较具有不同小脑折叠模式的小鼠品系，以确定折叠的组织力学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还将揭示如何调节机制来调节物种之间折叠模式的变化。该项目将促进对大脑折叠的发育和调控的理解，并为理解神经发育、改进组织工程和阐明大脑进化变化的机制做出根本性贡献。本项目包括一门研究型课程，面向本科生，学生将直接参与拟议实验的获取和分析，并培养他们面向公众的沟通技巧。通过与当地学区的合作，该项目还将支持初中科学教育者及其学生，通过亲身参与来刷新教师的科学经验，并合作开发初中科学课程的补充课程。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。这一建议将通过发展小鼠小脑作为大脑折叠的可处理模型来应对这些挑战。先前，小脑已被证明在折叠开始时经历不同的扩张。此外，小脑处于紧张状态，有一外层流体状层。预计这些组织特性会调节折叠以及功能性脑回路的划分。将在野生型和突变型小鼠以及大鼠的二维和三维空间中分析折叠量的预测可调驱动因素微分膨胀。小脑张力（预计在折叠过程中降低）将通过机械分析来研究折叠量以及纤维轴突和树突成分可能介导张力。小脑组织的流动性将分析使用活体离体成像和药理学扰动。这些实验将证明，在发育过程中，组织特异性的力量是如何产生和调节的，以形成折叠的大脑，并产生物种内部的变化，以及组织力学是如何进化调节的，以建立物种之间的折叠变化。更广泛地说，这一建议的结果将提供深入了解在发育过程中出现的紧急机制如何影响神经组织的形式和功能。该项目由神经系统集群的组织计划和刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.