The mechanical control of neuronal maturation

在神经系统的发育过程中，数十亿的神经元必须延伸长的过程（树突和轴突），这些过程长得很远，变得电活跃，连接到正确的伙伴并与他们交流。通过这些连接，神经元形成高度组织化的网络，并以电信号和化学信号的形式传输信息，这些信号控制着我们的功能。这些发育步骤中的每一个都是至关重要的，任何失败都可能对整个生物体产生毁灭性的后果。我们所知道的关于这些过程的几乎所有东西都与神经元和它们的环境之间通过分子和电信号进行的通信有关，这是生物学在过去几十年中所关注的。然而，神经元生活在物理世界中，并遵守物理定律。当神经元在组织中生长时，它们不仅在化学上而且在机械上与环境相互作用。由于在公路沿着骑自行车比在桑迪上骑自行车更容易，神经元生长的组织的机械特性也会强烈影响神经元的生长和发育速度。重要的是，脑组织的局部硬度因大脑区域而异，并且在发育、衰老、神经系统疾病和受伤后都会发生变化。虽然脑组织通常非常柔软，但随着年龄的增长，它会变得更硬（男性比女性更硬），在病理条件下，它的结构和硬度会发生显着变化。突出的例子是受伤或中风后的疤痕，以及阿尔茨海默氏症等疾病中刚性斑块或缠结的形成。局部组织硬度的这些变化可能强烈影响神经元功能。随着神经元成熟而发展的神经元功能的特征在于它们产生和传输电信号的能力。然而，机械环境如何调节神经元的电活动及其与其他神经元（突触）的连接的成熟尚不清楚。为了填补我们知识中的这一重要空白，这不仅对神经系统的发育，而且对不同的神经系统疾病都有重要意义，我们组建了一个多学科团队，拥有多年的神经科学和生物物理学经验。拟议的项目涉及尖端的神经生物学，机械生物学，电生理学，分子生物学，生物物理学和工程方法，其组合将推进该领域，并提供强大的工具，超越了最先进的状态。我们将首先确定哪些机械性能的环境必须有最佳促进神经元的成熟和活动，通过比较神经元如何在机械不同的定制环境中发展。然后，我们将使用一个微小的片簧（“悬臂”）来推拉神经元，其力控制良好，与细胞通常施加在其环境上的力一样小，同时测量流经这些神经元的电流。这些实验将揭示机械信号如何改变神经元的活动和成熟。最后，我们想了解神经元如何感知和翻译这些机械刺激。为此，我们将识别神经元中的力传感器，并研究它们的特定激活如何改变细胞功能。在这个项目中获得的知识不仅将照亮神经系统发育的一个新方面。机械信号也可能是理解不同发育障碍和神经系统疾病的缺失环节。我们的研究弥合了生命科学和物理科学之间的差距，因此可能最终导致我们治疗神经系统疾病患者的方式发生重要变化。

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.