Periodic Reporting for period 1 - UNFOLD (Unfolding the dynamic interplay of mechanical and molecular processes in brain folding)
Reporting period: 2024-04-01 to 2025-09-30
Mammals with large brains and higher cognitive functions have a richly folded cerebral cortex. Folding abnormalities are linked to various cognitive disabilities. Despite its relevance in clinical diagnostics, the causes and consequences of cortex folding remain poorly understood. We propose that cortex folding emerges from a dynamic interplay between mechanical and molecular processes, and that it has major consequences for brain organization and function. This project tests this hypothesis by integrating genomics, cell biology, mechanics of brain development and computational modeling. By using a variety of technologies, animal models and manipulations, our interdisciplinary team will first map molecular, cellular, and mechanical events accompanying cortex folding. Next, we will investigate the effects of genetic perturbations on tissue mechanics, and vice versa, to identify key mechanisms leading to cortex folding and identify their interactions. Then, we will test if these mechanisms are universal by trying to induce folds in species with a smooth brain. Finally, we will decipher the consequences of cortex folding on neural circuit function and animal behavior. Our project integrates current, opposing concepts of cortex folding by adopting an interdisciplinary and multiscale perspective. Results from this project will provide unprecedented insights into the determinants of cortical anatomy and brain organization. Our work, bridging physical and life sciences, will lead to new insights into normal and pathological brain development, paving the way to a new research area of integrated neurobiology with potential applications in modern medicine.
During this initial period of the project, our consortium of four teams has focused on three main aims: Aim 1, 3 and 4. Most of the progress has been made in Aim1, where we have begun mapping the multiple parameters of the developing cortex proposed to participate in the establishment and development of folds, ranging from overall distribution and density of cells and specific cell populations, neuronal connectivity at mid- and long-range, mechanical stiffness, ECM composition, neuronal migration and transcriptomic profiling of cells in the different layers of the developing cortex. This work is still very much in the early stages, but some interesting trends in our data are beginning to become evident, correlated with the size and degree of folding of the cerebral cortex. In Aim 3, we have begun testing the effects of mechanical forces on the biology and genetics of cortical progenitor cells, focused on mouse and ferret, with only preliminary results so far. In Aim 4, we have begun testing the effects of some genetic perturbations on the development of the chick and zebrafish nervous system, with very interesting results; namely, we have identified a molecular signaling mechanism sufficient to induce folding of the chick optic tectum (otherwise smooth), with bona-fide physiological folds. Ongoing work focuses on understanding the cellular and molecular mechanisms of action that underly the tissue deformation.
One aspect with marketing potential is the set-up for scanning slides under polarized light imaging (PLI), developed by one of the UNFOLD partners; this is currently under consideration.