Specific spinal locomotor circuit alterations induced by epidural stimulation

摘要 硬膜外刺激(ES)对脊髓损伤后运动功能的恢复有很大的临床应用前景。 在动物模型中。尽管它成功地激活了低于损伤水平的沉默电路，允许 由于瘫痪肢体的运动，其长期影响的机制尚不清楚。中心图案 腰髓中的产生器(CPG)控制着运动的节奏和模式。CPG如下 大多数受伤的程度，因此，相对完好无损，ES可以接近。我们实验室最近所做的努力 确定ES在脊髓运动回路水平上发挥有益作用的机制 已经揭示了脊髓损伤后运动CPG的感觉通路的变化，这些变化要么被阻止 或被运动激活阈值以下的强度的ES逆转(运动阈值下的ES)，而 老鼠在跑步机上。在完整的脊髓横断损伤模型中，这些电路改变是明显的，尽管 跑步机上明显缺乏与运动相关的后肢活动。我们目前的提案将直接测试 仅有运动阈值以下的ES是否足以诱导有益的可塑性和/或防止适应不良 小鼠脊髓运动回路水平的可塑性。在人类中，仅有ES不支持在没有 广泛的伴随康复训练，因为ES的传入激活阻断了正常 本体感觉信号。此外，尽管受伤后可能有一个关键的窗口来最大限度地 在这些早期时间点，以可塑性、广泛活动为基础的康复往往是不可能的。如果电路 在没有运动训练的情况下观察到ES的可塑性，这将提示运动阈值以下的ES 一种可以用于卧床不起的患者的方法，作为未来康复的桥梁。第二个目的是 建议，我们将确定脊髓感觉通路到运动的改变的神经底物 脊髓损伤后和ES后明显的回路。我们将重点介绍CPG神经元和插入的抑制性神经元 CPG神经元和初级传入神经元之间的联系。总之，我们建议揭示亚运动阈值ES 是一种潜在的策略，可以在基于活动的治疗可行之前改变脊髓回路。如果这是 在这种情况下，它将提出一种治疗策略，既可以替代使用，也可以作为桥梁使用，直到活动为止 康复是可能的。此外，我们建议确定参与这种可塑性的关键神经元群体， 从而提出了未来细胞特异性疗法的特定靶点。

ABSTRACT Epidural stimulation (ES) has shown great promise for the restoration of motor functioning after SCI both clinically and in animal models. Despite its success in activating silenced circuits below the level of the injury allowing for movement of paralyzed limbs, the mechanisms contributing to its long-term effects are unknown. Central pattern generators (CPG) in the lumbar spinal cord control both the rhythm and pattern of locomotion. CPGs are below the level of most injuries, and, therefore, relatively intact and accessible by ES. Recent efforts in our lab to determine the mechanisms by which ES exerts its beneficial effects at the level of the spinal locomotor circuit have revealed alterations in sensory pathways to the locomotor CPG following SCI which are either prevented or reversed by ES at intensities that are subthreshold for motor activation (sub-motor-threshold ES) while the mouse is on a treadmill. In a complete transection SCI model, these circuit alterations are evident despite the apparent lack of locomotor-related hindlimb activity on the treadmill. Our current proposal will directly test whether sub-motor-threshold ES alone is sufficient to induce beneficial plasticity and/or prevent maladaptive plasticity at the level of spinal locomotor circuits in mice. In humans, ES alone does not support walking without extensive concomitant rehabilitative training since the afferent activation by ES occludes the normal proprioceptive sensory signal. Additionally, although there may be a post-injury critical window for maximum plasticity, extensive activity-based rehabilitation is often not possible at these early time points. If the circuit plasticity observed with ES occurs in the absence of motor training, this will suggest sub-motor-threshold ES as a method that could be used for bedridden patients as a bridge for future rehabilitation. For the second aim of the proposal, we will determine the neural substrates of the alterations in spinal sensory pathways to locomotor circuits that are evident after SCI and after ES. We will focus on CPG neurons and inhibitory neurons interposed between CPG neurons and primary afferents. Together, we propose to reveal whether sub-motor-threshold ES is a potential strategy to alter spinal circuits prior to the time when activity-based therapies are feasible. If this is the case, it will suggest a treatment strategy that can be used either in place of or as a bridge until active rehabilitation is possible. Further, we propose to identify a key population of neurons involved in this plasticity, thereby suggesting a specific target of future cell-specific therapeutics.