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

所有脊椎动物都必须每天应对不稳定的来源：在行驶的火车上行走或在冻土带跟踪猎物是非常不同但同样具有挑战性的任务。本体感觉丧失(感觉自己身体部位位置的能力)可能会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，人们对本体感觉在运动模式微调中的作用知之甚少。从基因上移除小鼠的本体感受器，结合引入随机扰动，是强调运动控制机制的两种强有力的方法。在最新技术的帮助下，这个项目旨在对本体感觉和运动之间的联系提供新的见解。在这个项目中，一群成年小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)和内侧(右/左)方向产生突然运动。对一系列意想不到的干扰的反应将以肌电(EMG，肌肉电活动)和后肢运动学的形式记录下来。然后，在选择性遗传消除肌梭(一类本体感受器)后，将对同一组动物进行测量。在一项翻译工作中，将在德国柏林的健康人身上进行同样的测量，肌梭完好。脊椎动物体内大量的肌肉和关节提醒人们，运动的产生和控制是多么复杂。肌肉协同效应理论认为，运动是通过以共同的模式激活一组功能相关的肌肉(称为协同效应)来实现的，而不是通过单独控制肌肉来实现的。将从肌电数据中提取协同效应，以评估运动的模块化组织。运动的动态稳定性将使用最大Lyapunov指数的概念来估计，最大Lyapunov指数是表示动态系统随时间变化的稳定性的指标。在我攻读博士学位期间，我发现在人类中引入随机扰动会导致增强的“稳健性”(处理错误的能力)。这在更长时间和更不准确的肌肉激活模式中是明显的。然而，很难确定健壮性增加的原因，也很难确定它是否与本体感觉反馈的变化有关。比较移除肌梭前后运动的模块化组织将提供对本体感觉在非稳定运动调节中的作用的更深层次的了解。与人类数据的直接比较将支持该项目的翻译性质。这个假设是，野生型小鼠和健康的人类一样，会通过增加运动输出的健壮性来应对意想不到的干扰，这一特征可能在肌梭缺陷的动物身上可以看到，无论是在受干扰的运动中还是在未受干扰的运动中。

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.