Foundations of Neuromechanical Systems Biology

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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.