DESCENDING SPINAL PATHWAYS AND NEUROMUSCULAR PLASTICITY

在各种各样的脊髓损伤（SCI）后，如果给予人类和动物适当的使用依赖性台阶训练，他们可以恢复更高水平的功能性台阶。完全SCI后，感觉运动通路的实质性重组发生在病变的尾部。步训练显著影响这种重组。SCI和台阶训练的行为和生理效应反映在大多数（如果不是全部）内在脊髓神经递质系统的适应中。该项目的先前研究已经描述了完全SCI后广泛的神经肌肉可塑性。我们对参与神经肌肉可塑性的内在脊髓系统与部分SCI后幸存或实验干预后再生的下行轴突的相互作用的潜力知之甚少。本研究将探讨不同的下行脊髓通路的步进控制的贡献，并确定不同的路径的病变如何影响神经肌肉可塑性SCI和步骤训练后。了解哪些下行脊髓通路对控制后肢运动的特定方面很重要，以及哪些通路应该特别针对再生，将代表一个重要的进展。此外，我们将研究转基因靶向消融瘢痕形成反应性星形胶质细胞后部分轴突再生的效果。我们假设下行通路的部分再生将与诱导的脊髓神经肌肉可塑性协同作用 通过步进训练，并将加强对SCI后步进的控制。这些研究将利用最近开发的机器人辅助评估步进，并将联合收割机与成年转基因小鼠的视频分析和肌电图记录相结合。小鼠将被用作实验动物，因为小鼠转基因技术为精确的细胞和分子操作提供了强有力的手段，其效果可以在体内系统水平上进行评估。这项技术对于剖析SCI后的特定分子和细胞机制具有相当大的希望。本研究的结果将建立一个框架， 定量评估的神经肌肉控制的步进在小鼠中，并将提供重要的信息（i）如何病变的不同脊髓通路影响神经肌肉可塑性和控制的步进，（ii）部分轴突再生如何可能改善这种控制，以及（iii）如何步骤训练增强这些过程。

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.