Exercise, neurotrophins and axon regeneration in the PNS

描述（由申请人提供）：对于周围神经系统（PNS）损伤后观察到的普遍较差的功能结果，最常见的两个原因是周围神经再生轴突生长缓慢，肌肉经常被功能不合适的运动神经元再神经支配。在手术修复时对切割神经进行电刺激（ES）可促进再生轴突的生长，这是由神经元神经营养因子介导的。然而，在许多情况下，ES可以被使用，并且ES也会导致功能不合适的运动神经元的肌肉再神经支配增加。运动促进脑和脊髓中BDNF的表达，这可能导致刺激再生轴突的生长。这个项目的目的是比较一种形式的运动，跑步机训练和ES对周围神经轴突再生的影响。转基因和基因敲除小鼠的组合将作为一种新的模型系统来研究运动诱导的再生轴突生长的增强是否由神经元神经营养因子介导。通过比较跑步机训练对轴突再生的直接影响和ES产生的影响，我们将评估所产生的轴突再生的增强是否相似。突触重建是PNS损伤后功能恢复的关键部分，在没有干预的情况下，它比再生轴突生长到肌肉所需的时间更长。我们将比较ES和跑步机训练对转基因小鼠神经肌肉突触重建时间过程的影响。因为它通过运动神经元的内在神经回路自然地激活运动神经元，运动可能是一种增强再生的方式，与ES相比，运动可以减少功能不适当的肌肉神经再生。使用逆行荧光标记方法，在未经治疗、电刺激和跑步机训练的小鼠中比较四种不同肌肉靶点的再神经支配的特异性。运动有可能改善导致PNS病变功能恢复不良的两个主要问题。其低成本、高效益的临床应用潜力巨大。这个项目提供了一个独特的机会来提供重要问题的答案，这将加强这种临床应用的基础。

DESCRIPTION (provided by applicant): The two reasons most often given for the generally poor functional outcomes observed after peripheral nervous system (PNS) injury are that regenerating axons in peripheral nerves grow slowly and that muscles are often reinnervated by functionally inappropriate motoneurons. Electrical stimulation (ES) of the cut nerve at the time of its surgical repair promotes a significant enhancement of the growth of regenerating axons that is mediated by neuronal neurotrophins. However, there are many circumstances in which ES could be used and ES also results in an increase in muscle reinnervation by functionally inappropriate motoneurons. Exercise promotes BDNF expression in the brain and spinal cord and this could result in a stimulation of the growth of regenerating axons. The goal of this project is to compare the effects of one form of exercise, treadmill training, to those of ES on axon regeneration in peripheral nerves. A combination of transgenic and knockout mice will be used as a novel model system to investigate whether an exercise- induced enhancement of the growth of regenerating axons is mediated by neuronal neurotrophins. By comparing the effects of treadmill training on axon regeneration directly to those produced by ES, we will evaluate whether the enhancement of axon regeneration produced is similar. Synapse re-formation is a critical part of functional recovery after injury to the PNS, and without intervention, it takes longer than it takes regenerating axons to grow sufficiently to reach the muscles. We will compare the effect of ES and treadmill training on the time course of neuromuscular synapse re-formation in transgenic mice. Because it activates motoneurons naturally via their intrinsic neural circuits, exercise could be a way of enhancing regeneration with less functionally inappropriate reinnervation of muscles than noted with ES. The specificity of reinnervation of four different muscle targets will be compared, using retrograde fluorescent labeling methods, in untreated, electrically stimulated, and treadmill trained mice. Exercise has the potential to ameliorate both of the major issues contributing to poor functional recovery from lesions to the PNS. Its potential for clinical use with low cost and very high benefit is great. This project provides a unique opportunity to provide answers important to questions that will strengthen the basis for such clinical use.