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

人类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，并细分了大脑的电路。然而，人们对这些褶皱是如何形成的，以及它们是如何塑造大脑功能的知之甚少。该项目研究了发育中的脑组织的生长速率，张力和材料特性，这些脑组织相互作用以诱导和塑造脑折叠的模式。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，以确定在发育过程中折叠的组织力学如何受到不同的调节。与大鼠小脑折叠的比较还将揭示力学是如何调整的，以调节物种之间的折叠模式变化。该项目将推进对大脑折叠的发育和调控理解，并为理解神经发育，改善组织工程和阐明进化大脑变化的机制做出根本性贡献。该项目包括一个研究为基础的课程，为本科生谁将直接参与收购和拟议的实验分析，并发展他们的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工作者及其学生，通过动手参与更新教师的科学经验，并合作开发初中科学课的补充课程。对大脑形态发生的研究由于几乎只关注大脑皮层以及难以获得发育数据而受到限制。这项提议将通过开发小鼠小脑作为大脑折叠的易处理模型来应对这些挑战。以前，小脑已经被证明在折叠开始时经历差异扩张。此外，小脑处于张力下，并且具有外部流体状层。预测这些组织特性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品系以及大鼠中以二维和三维分析差异扩增（预测的可调折叠量驱动因素）。小脑张力（预测在折叠进展期间降低）将用机械测定法进行研究，该测定法检查折叠量以及可能介导张力的纤维轴突和树突成分。将使用活体离体成像和药理学扰动分析小脑组织的流动性。这些实验将展示在发育过程中如何产生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化，以及组织力学如何进化调制以建立物种之间的折叠变化。更广泛地说，这项提案的结果将提供深入了解如何在发展过程中出现的紧急机制，以影响神经组织的形式和功能。该项目是由神经系统集群的组织计划，激励竞争研究计划（EPSCoR）该奖项反映了NSF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进行评估，被认为值得支持审查标准。

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.