Mechanisms of locomotor plasticity after partial section of the spinal cord: role of neural activity

在包括人类在内的所有脊椎动物中，运动由三个组成部分控制：1)位于腰骶脊髓的脊髓运动回路（SLC）；2)外周感觉输入；3)下行棘上输入。运动控制研究中一个长期存在的基本问题是：每个部件对运动控制的相对贡献是什么？这个问题很复杂，因为这三个控制组件不断相互作用，使运动模式适应我们的环境所施加的约束。损伤研究，实际上是将一些成分彼此隔离开来，为运动控制提供了重要的见解。在将SLC与棘上结构分离的完整脊柱切片的情况下，后肢运动可以在药物、电和/或传入输入刺激下重新表达。这些研究表明，只要SLC保持足够的兴奋性状态，SLC本身能够自主产生运动的基本模式。然而，部分脊柱切除后运动的重新表达是否依赖于类似的机制尚不清楚。我之前的工作表明，在脊髓半球切断一侧的感觉运动束后，运动的重新表达在三周内自发地以最小的感觉输入发生。支持运动控制重建的机制是什么？哪些结构起作用？可能包括：a)半切面以下的SLC在产生后肢运动模式中发挥更大作用；b)一些棘上结构可以补偿其他下行通路的损失，只要它们能以某种方式到达SLC。通过使用双损伤方法和电生理学技术，我们的工作提供了证据，表明运动控制重建的关键环节是SLC和运动皮层的可塑性。然而，这些结构对运动控制重建的相对或共同贡献尚不清楚。这部分是由于目前用于运动研究的慢性哺乳动物模型缺乏直接和选择性地操纵脊髓和皮质神经元的时间精度的能力。为了规避这些限制，我们将使用远程激活方法来操纵小鼠的皮质和脊髓活动。与传统方法相比，这些技术独特地能够选择性地操纵神经元的兴奋性，将回路与行为联系起来。这一完全原创的建议有可能极大地扩展我们对脊柱切除术后运动控制重建所涉及的可塑性机制的认识。

In all vertebrates including humans, locomotion is controlled by three components: 1) a spinal locomotor circuitry (SLC) localized in the lumbosacral spinal cord; 2) peripheral sensory inputs; 3) descending supraspinal inputs. A long-standing and fundamental question in motor control research is: What is the relative contribution of each component to the control of locomotion? This question is complex since the three control components continuously interact to adapt the locomotor pattern to the constraints imposed by our environment. Lesion studies, by virtually isolating some components from each others, have provided important insights in the control of locomotion. In case of complete spinal sections isolating the SLC from supraspinal structures, hindlimb locomotion can be re-expressed under pharmacological, electrical and/or or afferent input stimulation. These studies demonstrate that the SLC itself is able to autonomously generate the basic pattern of locomotion, provided that the SLC is maintained in a sufficient state of excitability. However, whether the re-expression of locomotion after partial spinal sections relies on similar mechanisms is still unclear. My previous work shows that, after spinal cord hemisections severing sensorimotor tracts on one side, re-expression of locomotion occurs spontaneously with minimal sensory inputs within three weeks. What are the mechanisms supporting the re-establishment of locomotor control and what structures contribute? Possibilities include: a) the SLC below the hemisection that can assume a greater role in generating the hindlimb locomotor pattern; b) several supraspinal structures that can compensate for the loss of other descending pathways provided they can somehow reach the SLC. By using dual lesion approaches and electrophysiology techniques, our work has provided evidence that a critical link to the re-establishment of locomotor control is plasticity within both the SLC and the motor cortex. However, the relative or joint contribution of these structures to the re-establishment of locomotor control is unknown. This is in part due to the lack of ability to directly and selectively manipulate spinal and cortical neurons with temporal precision in the chronic mammal models currently used for locomotion studies. To circumvent these limitations, we will use remote activation approaches to manipulate cortical and spinal activity in mice. Over traditional approaches, these technologies uniquely enable to selectively manipulate the excitability of neurons to link circuits with behaviour. This completely original proposal has the potential to greatly expand our knowledge on the plasticity mechanisms involved in the reestablishment of locomotor control after spinal sections.