Cerebellar folding is initiated by mechanical constraints on a fluid-like layer without a cellular pre-pattern

The human brain has a characteristic pattern of ridges and grooves that make up its folded shape. Folds in the outer layer of the brain, known as the cortex, increase the surface area and make more space for cells to connect and form complex circuitries. Different models have been put forward to explain how these folds form during development. Examples include tension from cells pulling areas of the cortex together, or layers of the cortex growing at different rates, causing the cortex to buckle and create folds. Discriminating between these different models requires biological information about the cells and tissue of the brain at the start of the folding process. However, it has been difficult to extract this information when considering the development of the human brain in three dimensions. Lawton et al. have overcome these difficulties by using a part of the mouse brain called the cerebellum as a simpler system. As in humans, the mouse cerebellum is a densely folded structure, sitting underneath the brain, that plays a major role in regulating movements, as well as cognition. The symmetrical structure of the mouse cerebellum means it can be analyzed in two dimensions, making it easier to track the mechanics of folding. By applying the extracted biological data onto a mathematical model, Lawton et al. showed folding was driven by a combination of previously unknown features. For instance, that cells in the outer layer of the cerebellum grow faster than cells in the center, with cells growing uniformly across the outer layer. Other features include the fluid-like composition of the outer layer, which allows cells to move freely and regularly change position, and tensions surrounding the cerebellum mechanically straining its growth. Notably, the pattern of cells and tissue fibers in the cortex had no influence over these mechanical properties and provided no pre-indication of where the sites of folding would occur. The data collected deviates from other models, and has led Lawton et al. to propose a new explanation for how the brain folds, incorporating these newly found features. Problems with brain folding during human development can lead to debilitating conditions. Applying this new model to folding disorders of the human brain could help scientists to understand how these folding defects arise.