The mechanical control of neuronal maturation

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During the development of the nervous system, billions of neurons have to extend long processes (dendrites and axons), which grow over large distances, become electrically active, connect to the right partners and communicate with them. Through these connections neurons form highly organised networks and transmit information in form of electrical and chemical signals that govern our functions. Each of these developmental steps is critical, and any failure may have devastating consequences for the whole organism.Almost everything we know about these processes is related to the communication between neurons and their environment via molecules and electrical signals, which is what biology has focused on during the past decades. However, neurons live in a physical world and obey physical laws. When neurons grow through tissue, they not only chemically but also mechanically interact with their environment. As bicycling is easier for us along a paved road than along a sandy beach, the mechanical properties of the tissue through which neurons grow will also strongly influence, for example, how fast they can grow and develop.Importantly, the local stiffness of brain tissue varies depending on the region in the brain, and it changes during development, ageing, neurological diseases and after injuries. While brain tissue is usually extremely soft, it becomes stiffer during ageing (in men more than in women), and under pathological conditions it can change dramatically in structure and stiffness. Prominent examples are scarring after injury or stroke, and the formation of rigid plaques or tangles in diseases such as Alzheimer's. These changes in local tissue stiffness may strongly influence neuronal function. Neuronal function, which develops as neurons mature, is characterised by their capability to generate and transmit electrical signals. However, how the mechanical environment regulates the maturation of the electrical activity of neurons and their connections to other neurons (synapses) is not known.To address this important gap in our knowledge, which has important implications not only for the development of the nervous system but also for different neurological disorders, we have put together a multidisciplinary team with years of experience in neuroscience and biophysics. The proposed project involves cutting edge neurobiology, mechanobiology, electrophysiology, molecular biology, biophysics and engineering approaches, whose combination will advance the field and provide powerful tools beyond the state of the art.We will first determine which mechanical properties the environment must have to optimally promote neuronal maturation and activity, by comparing how neurons develop in mechanically different custom-built environments. We will then use a tiny leaf spring ('cantilever') to push and pull on neurons with well-controlled forces, which are as small as the forces cells usually exert on their environment, and simultaneously measure the electrical currents that flow through these neurons. These experiments will reveal how mechanical signals alter neuronal activity and maturation. Finally, we want to understand how neurons perceive and translate these mechanical stimuli. To do this, we will identify force sensors in the neurons, and investigate how their specific activation changes cellular function.The knowledge gained in this project will not only illuminate a new facet of the development of the nervous system. Mechanical signalling might also be the missing link to understanding different developmental disorders and neurological diseases. Our research, bridging the gap between the life and physical sciences, may thus ultimately lead to important changes in how we treat patients suffering of neurological disorders.