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

脊髓部分切断后运动可塑性的机制：神经活动的作用

• 批准号: RGPIN-2015-03860
• 负责人: Martinez, Marina
• 金额: $ 2.11万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=589430
• 关键词: Mechanisms; locomotor; plasticity; after; partial

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.

在包括人类在内的所有脊椎动物中，运动由三个部分控制：1）位于腰骶脊髓的脊髓运动回路（SLC）； 2）外围感觉输入； 3) 下降的脊髓上输入。运动控制研究中一个长期存在的基本问题是：每个组件对运动控制的相对贡献是什么？这个问题很复杂，因为三个控制组件不断相互作用以使运动模式适应我们环境所施加的限制。通过实际上将一些组件彼此隔离，损伤研究为运动控制提供了重要的见解。在完整的脊柱切片将 SLC 与脊柱上结构隔离的情况下，后肢运动可以在药理学、电和/或传入输入刺激下重新表达。这些研究表明，只要 SLC 保持在足够的兴奋状态，SLC 本身就能够自主生成基本运动模式。然而，部分脊髓切片后运动的重新表达是否依赖于类似的机制仍不清楚。我之前的工作表明，在脊髓半切切断一侧的感觉运动束后，运动的重新表达会在三周内以最小的感觉输入自发地发生。支持重建运动控制的机制是什么？哪些结构做出了贡献？可能性包括：a）位于半截面下方的 SLC 在生成后肢运动模式方面可以发挥更大的作用； b) 一些脊髓上结构可以补偿其他下行通路的损失，前提是它们能够以某种方式到达 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，表明重建运动控制的关键环节是 SLC 和运动皮层内的可塑性。然而，这些结构对重建运动控制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以时间精度操纵脊髓和皮质神经元的能力。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。这个完全原创的提议有可能极大地扩展我们对脊柱切片后重建运动控制所涉及的可塑性机制的认识。