DESCENDING SPINAL PATHWAYS AND NEUROMUSCULAR PLASTICITY

在各种脊髓损伤(SCI)后，如果给予适当的依赖于使用的踏步训练，人类和动物可以恢复更高水平的功能性踏步。完全性脊髓损伤后，感觉运动通路的实质性重组发生在损伤的尾部。阶梯训练对这种重组有很大的影响。脊髓损伤和阶梯训练的行为和生理效应反映在大多数(如果不是全部)固有脊髓神经递质系统的适应中。该项目以前的研究已经确定了完全性脊髓损伤后广泛的神经肌肉可塑性。关于参与神经肌肉可塑性的固有脊髓系统与部分脊髓损伤后幸存或经实验干预后再生的下行轴突之间的相互作用，人们知之甚少。本研究将探讨不同的脊髓下行通路对台阶控制的贡献，并确定不同通路的损伤如何影响脊髓损伤和台阶训练后的神经肌肉可塑性。了解哪些下行脊髓通路对于控制后肢运动的特定方面是重要的，以及哪些通路应该特别针对再生，这将是一项重要的进展。此外，我们还将研究转基因靶向消融瘢痕形成的反应性星形胶质细胞后对部分轴突再生的影响。我们假设下行通路的部分再生将与所诱导的脊髓神经肌肉可塑性协同作用。 通过循序渐进的训练，将加强对脊髓损伤后的步态控制。这些研究将利用最近开发的机器人辅助的步进评估，并将其与成年转基因小鼠的视频分析和肌电记录相结合。小鼠将被用作实验动物，因为小鼠的转基因技术为精确的细胞和分子操作提供了强大的手段，其效果可以在体内的系统水平上进行评估。这项技术为剖析脊髓损伤后特定的分子和细胞机制提供了相当大的希望。本研究的结果将建立一个框架，以 对小鼠踏步的神经肌肉控制进行了定量评估，并将提供关于(I)不同脊髓通路的损伤如何影响神经肌肉可塑性和踏步控制的重要信息，(Ii)部分轴突再生如何改善这种控制，以及(Iii)步骤训练如何增强这些过程。

After a wide variety of spinal cord injuries (SCI), humans and animals can recover a greater level of functional stepping if they are given appropriate use-dependent step training. Following complete SCI, substantial reorganization of sensorimotor pathways occurs caudal to the lesion. Step training significantly influences this reorganization. Behavioral and physiological effects of SCI and step training are reflected in adaptations in most, if not all, intrinsic spinal neurotransmitter systems. Previous studies in this program have characterized extensive neuromuscular plasticity following complete SCI. Little is known about the potential for interactions of intrinsic spinal systems involved in neuromuscular plasticity with descending axons that are spared after partial SCI or are regenerating after experimental interventions. The present study will examine the contribution of different descending spinal pathways to the control of stepping and determine how lesions of different pathways influence neuromuscular plasticity after SCI and step training. Understanding which descending spinal pathways are important for control of specific aspects of hindlimb movement, and which pathways should be particularly targeted for regeneration, would represent an important advance. In addition, we will study the effects of partial axon regeneration achieved after transgenically targeted ablation of scar forming, reactive astrocytes. We hypothesize that partial regeneration of descending pathways will interact synergistically with the spinal neuromuscular plasticity that is induced by step training and will augment control of stepping after SCI. These studies will take advantage of recently developed, robot-assisted evaluation of stepping, and combine this with video analysis and electromyographic recordings in adult transgenic mice. Mice will be used as experimental animals because transgenic technology in mice provides a powerful means for precise cellular and molecular manipulations whose effects can be evaluated at the systems level in vivo. This technology holds considerable promise for dissecting out specific molecular and cellular mechanisms after SCI. Results from the present study will establish a framework for quantitative evaluation of the neuromuscular control of stepping in mice, and will provide important information about (i) how lesions of different spinal pathways influence neuromuscular plasticity and the control of stepping, (ii) how partial axon regeneration may improve this control, and (iii) how step training augments these processes.