Exercise, Intraspinal Transplants and Spinal Cord Plasticity

实验性脊髓损伤（SCI）模型有助于定义结构和功能可塑性水平 在脊髓和受影响的肌肉中。周围神经移植物（PNGs）支持神经再生。 急性和慢性损伤的神经元，尽管在移植物之外的生长，回到脊髓，是有限的 在轴突延伸的数量和长度方面。用酶消化抑制性蛋白聚糖 软骨素酶在增加轴突生长方面是部分有效的，并且有证据表明软骨素酶对轴突生长有功能性影响。 再生轴突和脊髓神经元之间的突触连接。化疗诱导的 胸、腰段脊髓中神经营养因子与运动神经元的恢复相关 兴奋性（脊髓反射）接近正常活动。尽管取得了这些成功， 不参与受损脊髓重组和修复的受损神经元。我们的目标 是为了解决与运动提供营养因子线索的潜力有关的机械问题， 潜在地促进受损神经元的再生反应和/或激活脊髓网络， 促进再生轴突的感受性。目标1将解决的假设，运动将促进 急性和/或慢性损伤的轴突再生为PNG，使用成年大鼠下胸部水平 横断损伤，分离PNG以支持下行轴突与上行轴突的生长和跑步机步 训练束追踪方法将定义运动和感觉神经元的再生努力。目标2将 测试运动是否会增加PNG轴突生长，并确定可能的功能改善- 通过执行感觉运动行为、运动学和电生理学与再生轴突相关的动作 分析。在不同的组中，我们将测试活动依赖性可塑性是否通过以下方式实现： 急性或延迟治疗方法。为了推进我们治疗策略的临床前转化，结果 来自SCI大鼠的脊髓损伤将应用于脊髓化的猫制剂，以测试运动和移植是否 在大型动物模型中促进基于再生的功能恢复。总的来说，这些实验将 提供有关急性脊髓损伤后脊髓重组的细胞和功能方面的基本信息。 以及SCI的慢性阶段，这将有助于设计修复策略。

Experimental spinal cord injury (SCI) models have helped define levels of structural and functional plasticity within the spinal cord and affected muscles. Peripheral nerve grafts (PNGs) support the regeneration of acute and chronically injured neurons although growth beyond the graft, back into the spinal cord, is limited in terms of the number and length of axonal extension. Digestion of inhibitory proteoglycans with Chondroitinase is partially effective in increasing axonal outgrowth and there is evidence of functional synaptic connection between regenerated axons and spinal cord neurons. Exercise-induced increase of neurotrophic factors in thoracic and lumbar spinal cord is correlated with the restoration of motoneuron excitability (spinal reflexes) to near normal activity. Despite these successes there remain thousands of injured neurons that are not involved in reorganization and repair of the injured spinal cord. Our objectives are to address mechanistic questions related to the potential for exercise to provide trophic factor cues to potentially promote the regenerative response of injured neurons and/or to activate spinal networks to facilitate receptivity of regenerating axons. Aim 1 will address the hypothesis that exercise will promote regeneration of acute and/or chronically injured axons into a PNG, using an adult rat lower thoracic level transection injury, separate PNGs to support growth of descending vs. ascending axons and treadmill step training. Tract tracing methods will define the regenerative effort of motor and sensory neurons. Aim 2 will test whether exercise increases axonal outgrowth from a PNG and determine possible functional improve- ment related to regenerated axons by performing sensorimotor behavior, kinematic and electrophysiological analyses. In separate groups we will test whether activity-dependent plasticity is achieved with either/or an acute or delayed treatment approach. To advance the preclinical translation of our treatment strategy, results from SCI rats will be applied to a spinalized cat preparation to test whether exercise and transplantation promote regeneration-based functional recovery in a large animal model. Overall, these experiments will provide fundamental information about cellular and functional aspects of spinal cord reorganization in acute and chronic stages of SCI that will be instrumental in designing strategies for repair.