Non-steady locomotion in mice: a translational project on stability and modular organisation

所有脊椎动物每天都必须应对不稳定的来源：在移动的火车上行走或在苔原上跟踪猎物是非常不同但同样具有挑战性的任务。本体感觉（感知自身身体部位位置的能力）的丧失可能严重影响对不稳定运动的控制，这是一种通常与许多神经和骨科疾病相关的症状。然而，本体感觉在运动模式微调中的作用知之甚少。小鼠本体感受器的遗传去除，加上随机扰动的引入，是强调运动控制机制的两种有力方法。借助最先进的方法，该项目旨在为本体感觉和运动之间的联系提供新的见解。在这个项目中，一组成年老鼠将在一种特殊的跑步机上行走，这种跑步机可以在前后（前/后）和中外侧（右/左）方向上产生突然的运动。对一系列意外扰动的反应将以肌电图（EMG，肌肉电活动）和后肢运动学的形式记录下来。然后，对同一组动物进行选择性基因消除肌肉纺锤体（一类本体感受器）后的测量。作为一项转化性的努力，同样的测量将在德国柏林对肌肉纺锤体完整的健康人进行。脊椎动物体内大量的肌肉和关节提醒我们运动的产生和控制是多么复杂。肌肉协同作用理论指出，运动是通过以共同模式激活功能相关的肌肉群（称为协同作用）而不是单独控制肌肉来获得的。将从肌电图数据中提取协同作用，以评估运动的模块化组织。运动的动态稳定性将使用最大李雅普诺夫指数的概念来估计，这是一个代表动力系统随时间稳定性的度量。在读博期间，我发现在人类中引入随机扰动会增加“鲁棒性”（处理错误的能力）。这在较长时间和较不准确的肌肉激活模式中可见。然而，很难确定鲁棒性增加的原因，以及它是否与本体感觉反馈的变化有关。比较肌肉纺锤体去除前后运动的模块化组织将提供更深入地了解本体感觉在非稳定运动调节中的作用。与人类数据的直接比较将支持该项目的翻译特性。假设是野生型小鼠，像健康的人类一样，会通过增加运动输出的稳健性来应对意想不到的扰动，这一特征可能在肌肉纺锤体缺陷的动物在受干扰和未受干扰的运动中都能看到。

All vertebrates must cope daily with sources of instability: walking in a moving train or following prey in the tundra are very different but similarly challenging tasks. The loss of proprioception (ability to sense the position of own body parts) may severely affect the control of unsteady movement and is a symptom commonly associated with numerous neurological and orthopaedic conditions. However, very little is known about the role of proprioception in the fine tuning of locomotor patterns. The genetic removal of proprioceptors in mice, combined with the introduction of random perturbations are two powerful ways to emphasise the control mechanisms of locomotion. With the help of state of the art approaches, this project aims to give new insight into the link between proprioception and locomotion.In this project, a group of adult mice will walk on a special treadmill that can generate sudden movements in the anteroposterior (front/back) and mediolateral (right/left) directions. The response to a set of unexpected perturbations will be recorded in the form of electromyography (EMG, electrical activity of muscles) and hindlimb’s kinematics. Then, the same group of animals will be measured after selective genetic elimination of muscle spindles (a class of proprioceptors). In a translational effort, the same measurements will be conducted on healthy humans with intact muscle spindles in Berlin, Germany.The overwhelming number of muscles and joints in the body of vertebrates is a reminder of how complex the generation and control of movement is. The theory of muscle synergies states that movement is obtained by activating groups of functionally-related muscles in common patterns (called synergies) rather than by controlling muscles individually. Synergies will be extracted from EMG data to assess the modular organisation of movement. The dynamic stability of locomotion will be estimated using the concept of maximum Lyapunov exponent, a metric to represent the stability of a dynamical system over time.During my PhD, I found that the introduction of random perturbations in humans leads to an increased “robustness” (ability to cope with errors). This was visible in longer and less accurate muscle activation patterns. However, it was difficult to determine the reason for the increased robustness and whether it was linked to changes in proprioceptive feedback. Comparing the modular organisation of motion before and after muscle spindle removal will provide a deeper insight into the role of proprioception in the regulation of non-steady locomotion. A direct comparison with human data will support the translational character of the project. The hypothesis is that wild-type mice, like healthy humans, will respond to the unexpected perturbations by increasing the locomotor output’s robustness, a feature that might be visible in muscle spindle-deficient animals both during perturbed and unperturbed locomotion.