Mechanisms of Locomotor Recovery after SCI in Cats

将神经营养因子输送到脊髓是一种很有前途的重新启动运动回路的技术 在脊髓损伤后，它们的使用可以增加在体重支持下获得的恢复， 跑步机训练神经营养因子促进运动恢复的机制尚不清楚，但我们的研究表明， 模型研究表明，传入系统传递的可塑性与恢复有关。目标1将 获得关于运动神经元和中间神经元的传入传递的变化的信息， 神经营养因子递送到脊髓，并将其与体重支持的情况下获得的结果进行比较。 跑步机训练获得这些信息将为相关的神经机制提供新的见解 与SCI后的恢复有关，并作为新疗法的新结果指标。我们建议使用 细胞内和多单位记录技术，以表征和比较传入的变化， 通过体重支持的跑步机训练或产生神经营养因子的细胞获得的传递 移植此外，我们将描述神经元间的活动模式和传入效应， 治疗方式后的活动。我们假设运动神经元的传入传递 和中间神经元被神经营养因子移植物修饰的方式类似于 体重支持的跑步机训练，但影响更广泛的神经营养因子 治疗的动物，因为用这种方法的神经营养蛋白的分布更广。在我们的第二个目标，我们 我打算改进我们的移植技术，使产生神经营养因子的移植物能够 在临床上尝试，对患者的风险最小。我们假设神经营养素可以通过 通过腰椎穿刺注射经修饰以表达神经营养因子的自体细胞，并且这些细胞将 促进足底负重步行的恢复，而无需进行急性和 长期受伤的动物 相关性（参见说明）： 该项目的目标与NINDS减轻神经系统负担的使命一致。 疾病，并将进一步了解神经营养素促进运动的机制 恢复并建立这种治疗疗法的临床可转化应用的功效。

Delivery of neurotrophins to the spinal cord is a promising technique to re-engage the locomotor circuitry following spinal cord injury and their use may augment the recovery obtained with body-weight supported treadmill training. The mechanism by which neurotrophins promote locomotor recovery is unknown, but our modeling work suggests that plasticity in the afferent system transmission is involved in recovery. Aim 1 will obtain information about the changes in afferent transmission to motoneurons and interneurons following neurotrophin delivery to the spinal cord and compare those to the ones obtained with body-weight supported treadmill training. Acquiring this information will provide new insights into the neural mechanisms associated with recovery after SCI and serve as a novel outcome measure for new therapies. We propose to use intracellular and multiunit recording techniques to characterize and compare the changes in afferent transmission obtained with body-weight supported treadmill training or neurotrophin producing cellular transplants. In addition, we will characterize the interneuronal activity patterns and afferent effects on this activity following to thetiA/otreatment modalities. We hypothesize that afferent transmission to motoneurons and interneurons is modified by neurotrophin transplants in a manner similar to the way it is affected by body-weight supported treadmill training, but that the effects are more widespread in the neurotrophin treated animals due to a wider distribution of the neurotrophins with this methodology. In our second aim, we intend to refine our transplant technique to the point where neurotrophin producing transplants could be attempted in the clinic with minimal risks for the patient. We hypothesize that neurotrophins can be delivered via lumbar puncture injection of autologous cells modified to express neurotrophins and that these cells will promote the recovery of plantar weight-bearing stepping without the need for training in acutely and chronically injured animals. RELEVANCE (See instructions): The aims of this project are consistent with the NINDS' mission of reducing the burden of neurological diseases and will further our understanding of the mechanism by which neurotrophins promote locomotor recovery and establish the efficacy of a clinically translatable application of this treatment therapy.