Foundations of Neuromechanical Systems Biology

了解动物如何运动是现代科学的重大挑战之一。它对社会有广泛的影响：它影响我们解释生物世界的能力，治疗人类和动物疾病，并帮助那些从伤害中恢复的人。我们对生物系统如何控制它们的运动以及不同器官如何促进运动的了解越多，我们就越能更好地治疗那些患有神经系统疾病或肌肉骨骼损伤的人，并激发新技术，如腿式机器人。面对不可预测的环境，来自感觉器官的嘈杂信号和来自肌肉的嘈杂力量，动物能够快速，灵活和健壮地移动。然而，对于最重要的运动类型之一，腿上的快速地面运动，我们不知道感官信息是如何用来稳定身体的，或者我们如何管理我们嘈杂的肌肉。稳定性可能主要由身体的力学来处理;感觉输入可能仍然被纳入，但在更长的时间尺度上;或者，快速运动可能受到运动噪声的限制。这个项目将测试这些不同的预测。一个主要的障碍站在我们的理解如何神经和肌肉骨骼系统一起工作，以产生运动的方式。问题是，运动是大脑、脊髓、肌肉骨骼系统和外部世界相互作用的结果。这意味着，为了准确地解释每个子系统的作用，我们需要独立地检查和操纵每个子系统，在一个完整的，自由行为的动物中，以道德的方式。了解每个子系统在所有这些子系统的背景下如何工作是很重要的，这不仅是因为历史告诉我们，跨子系统的连接是了解整个系统的可靠方法，而且因为疾病和损伤通常只影响这些子系统中的一个，或者一个子系统中的器官。这样做，我们相信我们正在为一个新的科学分支奠定基础：神经机械系统生物学。该领域将神经元，肌肉，骨骼和外部环境视为导致运动的复杂相互作用成分，其方式类似于细胞和分子水平上的系统生物学。如果我们想真正了解每个器官的功能，就必须在奔跑动物的整个背景下考虑每个器官的功能，我们将把这种综合方法与精确干扰奔跑动物的强大新方法结合起来。我们将结合联合收割机光遗传神经操纵与实时跟踪和机械扰动，使自由奔跑的小鼠的因果，神经机械扰动成为可能。通过梳理神经和机械对运动的贡献，我们将清楚地了解神经系统在运动过程中执行的计算。有了这种理解，我们将证实，反驳，或完善最佳反馈控制理论的预测，运动协调的领先理论。测试这一理论是这项提议的第二个主要目的。光遗传学是一项非凡的新技术，为研究和操纵神经系统提供了前所未有的新方法。光遗传学允许特定的神经元被打开和关闭，非常快，使用光。它依赖于我们的遗传学知识，在特定神经元的膜中放置分子，光依赖的开关。它正在彻底改变神经科学，因为它使我们能够以因果关系的方式研究神经系统各部分的功能。在这里，我们建议将联合收割机光遗传学与神经力学方法结合起来研究运动。我们坚信，这种结合将彻底改变我们对生物系统如何运动的理解，并为我们提供重要的医学新工具。

Understanding how animals move is one of the grand challenges of modern science. It has broad impact on society: it affects our ability to explain the biological world, to treat human and animal disease, and to aid those recovering from injury. The more we know about how biological systems control their movement, and how different organs contribute to locomotion, the better we will be able to treat those with neurological disorders or musculoskeletal injury, and to inspire new technologies, such as legged robots.Locomotion is the signature behavior of animals. In the face of an unpredictable environment, noisy signals from sense organs and noisy forces from muscles, animals are able to move with speed, dexterity and robustness. Yet for one of the most important types of movement, fast terrestrial locomotion on legs, we do not know how sensory information is used to stabilise the body, or how we manage our noisy muscles. Stability may be largely handled by the mechanics of the body; sensory input may still be incorporated, but on longer time-scales; or, rapid locomotion may be constrained by motor noise. This project will test these divergent predictions.A major obstacle stands in the way of our understanding of how the nervous and musculoskeletal systems work together to produce locomotion. The problem is that locomotion results from the interaction of the brain, spinal cord, musculoskeletal system, and external world. This means that for us to accurately interpret what the role of each of these subsystems is, we need to independently examine and manipulate each subsystem, in an intact, freely behaving animal, in an ethical way. Understanding how each subsystem works in the context of all of them is important not just because history teaches us that linking across subsystems is a reliable way of gaining insight into the whole system, but because disease and injury frequently affect only one of these subsystems, or organs within a subsystem, at a time.The first major aim of this proposal is to develop the technologies we need to overcome this limitation. In doing so, we believe we are laying the foundation for a new branch of science: neuromechanical systems biology. This field will treat neurons, muscles, skeletons, and the external environment as complex interacting constituents that result in locomotion, in a manner akin to systems biology at the cellular and molecular levels. Considering the function of each organ in the full context of the running animal is important if we are to gain a true picture of what each organ does.We will couple this integrative approach with powerful new ways to precisely perturb running animals. We will combine optogenetic neural manipulation with real-time tracking and mechanical perturbation to make possible causal, neuromechanical perturbations of freely running mice. By teasing apart the neural and mechanical contributions to locomotion we will gain a clear understanding of the computations performed by the nervous system during locomotion. With this understanding we will confirm, refute, or refine the predictions of optimal feedback control theory, a leading theory of motor coordination. Testing this theory is the second major aim of this proposal.Optogenetics is an extraordinary new technology that provides unprecedented new ways to study and manipulate the nervous system. Optogenetics allows specific neurons to be turned on and off, extremely quickly, using light. It relies on our knowledge of genetics to place molecular, light-dependent on/off switches in the membranes of specific neurons. It is revolutionizing neuroscience, because it allows us to study the function of parts of the nervous system in a causal manner. Here we propose to combine optogenetics with a neuromechanical approach to locomotion. We firmly believe that this combination will revolutionize our understanding of how biological systems move, and give us important new tools for medicine.