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

About This Grant

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.