Exercise, Intraspinal Transplants and Spinal Cord Plasticity

实验性脊髓损伤(SCI)模型有助于确定结构和功能的可塑性水平 在脊髓和受影响的肌肉中。周围神经移植物(PNG)支持再生 急性和慢性损伤的神经元，尽管在移植物之外的生长，回到脊髓中是有限的 在轴突延伸的数目和长度方面。抑制性蛋白多糖的消化 软骨素酶在促进轴突生长方面部分有效，有证据表明 再生轴突和脊髓神经元之间的突触联系。运动性增加 胸腰段脊髓神经营养因子与运动神经元修复的关系 兴奋性(脊椎反射)接近正常活动。尽管取得了这些成功，但仍有数千人 损伤的神经元不参与损伤脊髓的重组和修复。我们的目标 是为了解决与运动提供营养因子提示的可能性有关的机械性问题 潜在地促进受损神经元的再生反应和/或激活脊髓网络以 促进再生轴突的接受性。目标1将解决这样的假设：运动将促进 利用成年大鼠下胸水平将急性和/或慢性损伤的轴突再生为PNG 横断损伤，分离PNG以支持下行轴突和上行轴突的生长和跑台台阶 训练。轨迹追踪方法将定义运动神经元和感觉神经元的再生努力。目标2将 测试运动是否增加PNG的轴突生长，并确定可能的功能改善- 通过执行感觉运动行为、运动学和电生理与再生轴突相关 分析。在不同的小组中，我们将测试活动依赖的可塑性是否通过 急性或延迟治疗方法。以推进我们的治疗策略、结果的临床前翻译 将从脊髓损伤大鼠身上提取的数据应用于棘化的CAT准备中，以测试运动和移植 在大型动物模型中促进基于再生的功能恢复。总体而言，这些实验将 提供有关急性脊髓重排的细胞和功能方面的基本信息 以及脊髓损伤的慢性阶段，这将有助于制定修复策略。

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.