Unfolding the dynamic interplay of mechanical and molecular processes in brain folding

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. While cortex folding was long assumed to result from a limited skull volume, it is a developmental process intrinsic to the cortex. We hypothesize that cortex folding emerges from a dynamic interplay between mechanical and molecular processes, and that far from being an epiphenomenon, it has major consequences for brain architecture and function. UNFOLD will test this hypothesis by integrating genomics, cell biology, mechanics of brain development and computational modeling. Our interdisciplinary team will apply in vitro, in vivo and in silico approaches to brain tissue of strategically selected animal models. First, we will map molecular, cellular, and mechanical events accompanying cortex folding. Next, we will investigate the effects of genetic perturbations of cell biological processes on tissue mechanics, and vice versa, to identify key mechanisms leading to cortex folding and elucidate their dynamic interactions. Then, we will test the universality of these mechanisms by inducing 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. Unraveling the dynamic interactions between molecular, cellular, and mechanical events during development 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.