Neurobehavioral Dynamics Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Schwerzenbach 8603, Switzerland.
Rehabilitation Engineering Laboratory (RELab), Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Zürich 8008, Switzerland.
J Neurosci. 2022 Aug 10;42(32):6243-6257. doi: 10.1523/JNEUROSCI.0705-22.2022. Epub 2022 Jul 5.
The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation. The ability to perform skilled, adaptable movements is a fundamental part of daily life, and is impaired in common neurologic diseases such as stroke. Maintaining motor adaptation is thus of great interest, but the necessary brain components remain incompletely identified. We found that impaired motor adaptation results from disruption of cells not previously implicated in this pathology: hypothalamic orexin/hypocretin neurons (HONs). We show that temporally confined HON signals are associated with skilled movements. Without these newly-identified signals, a resistance to movement that is normally rapidly overcome leads to prolonged movement impairment. These results identify natural brain signals that enable rapid and effective motor adaptation.
执行熟练手臂动作的能力是日常生活的核心，因为常见神经疾病（如中风）中的肢体障碍就证明了这一点。熟练的手臂动作需要根据期望运动和实际运动之间的差异（称为感觉误差）来调整运动指令。人类研究表明，这涉及到对这些错误的预测性和反应性运动适应，并且还需要移动的一般动机。由于缺乏允许进行神经水平研究的实验动物模型中的等效研究，因此这些不同方面如何映射到定义明确的神经信号仍然不清楚。因此，我们改编了人类研究中使用的机器人技术，使其适用于小鼠，从而可以深入了解运动适应的动机，反应性和预测性方面的神经基础。在这里，我们证明了前肢运动适应受到先前与动机和觉醒有关但与前肢运动控制无关的神经元调节：下丘脑食欲素/下丘脑分泌素神经元（HONs）。通过研究雄性小鼠中以目标为导向的鼠标-机器人交互作用，我们发现前肢运动和运动适应过程中会出现不同的 HON 信号。对这些与运动相关的 HON 信号进行时间限定性光沉默会损害基于感觉误差的运动适应。出乎意料的是，光沉默既不会影响任务奖励或执行率，也不会影响不需要适应的任务中的运动性能，这表明我们在这里研究的时间限定性 HON 信号与控制一般任务参与或感觉运动控制的信号不同。总的来说，这些结果揭示了调节前肢运动适应的下丘脑神经基质。执行熟练，适应性强的运动能力是日常生活的基本组成部分，在常见的神经疾病（如中风）中受到损害。因此，维持运动适应具有重要意义，但必要的大脑成分仍未完全确定。我们发现，运动适应受损是由于破坏了先前未涉及该病理的细胞所致：下丘脑食欲素/下丘脑分泌素神经元（HONs）。我们表明，时间限制的 HON 信号与熟练运动有关。没有这些新发现的信号，通常会迅速克服的对运动的阻力会导致运动障碍持续时间延长。这些结果确定了可实现快速有效的运动适应的天然脑信号。
