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

所有的脊椎动物每天都必须科普不稳定的来源：在移动的火车上行走或在苔原上跟随猎物是非常不同但同样具有挑战性的任务。本体感觉丧失（感知自身身体部位位置的能力）可能严重影响对不稳定运动的控制，并且是与许多神经和骨科疾病相关的常见症状。然而，很少有人知道本体感受的运动模式的微调中的作用。从基因上去除小鼠的本体感受器，再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。本项目旨在通过最先进的方法，对本体感觉和运动之间的联系提供新的见解。在本项目中，一组成年小鼠将在一个特殊的跑步机上行走，该跑步机可以产生前后（前/后）和中/外侧（右/左）方向的突然运动。将以肌电图（EMG，肌肉电活动）和后肢运动学的形式记录对一组意外扰动的反应。然后，在选择性遗传消除肌梭（一类本体感受器）后，对同一组动物进行测量。在一项转化工作中，将在德国的柏林对具有完整肌梭的健康人进行相同的测量。脊椎动物体内的肌肉和关节数量之多提醒人们，运动的产生和控制是多么复杂。肌肉协同作用理论认为，运动是通过以共同的模式激活功能相关的肌肉群（称为协同作用）而不是通过单独控制肌肉来实现的。将从EMG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，最大李雅普诺夫指数是一种表示动态系统随时间变化的稳定性的度量。在我的博士学位期间，我发现在人类中引入随机扰动会导致增加“鲁棒性”（科普错误的能力）。这在较长和较不准确的肌肉激活模式中是可见的。然而，很难确定增加鲁棒性的原因，以及它是否与本体感受反馈的变化有关。比较模块化组织的运动之前和之后的肌梭去除将提供一个更深入的了解本体感觉的作用，在非稳态运动的调节。与人类数据的直接比较将支持该项目的翻译特征。假设是野生型小鼠，像健康的人类一样，将通过增加运动输出的鲁棒性来响应意外的扰动，这一特征在肌梭缺陷的动物中在扰动和未扰动的运动期间都可以看到。

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.