CRCNS: Defining the role of astrogenesis in cortical folding

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.