Exercise, neurotrophins, and axon regeneration in the PNS

描述(由申请人提供)：通过每天适度的跑步机训练，周围神经中的轴突再生可以通过锻炼来增强。这个项目将研究运动的三个相互关联的方面，作为治疗周围神经损伤的潜在疗法，以帮助它更接近实际的翻译。在促进轴突再生的不同训练模式的有效性上存在显著的性别差异，并且雄激素在两性中都有牵连。在目标1中，将在条件性雄激素受体基因敲除小鼠中研究运动对雄激素的依赖作用。在全身性基因敲除和神经元特异性基因敲除中，研究不同运动模式对再生轴突长度、轴突再生成功的神经元数目以及运动神经元、背根神经节神经元和再生轴突生长锥体中脑源性神经营养因子(BDNF)及其受体TrkB表达的影响。作为一种治疗方法，当不同的神经损伤时，需要使用不同的运动范例。为它们的设计确立指导原则将是重要的。这些原理中最明显的可能是，轴突正在再生的神经元的活动对于增强运动产生的再生既是必要的，也是充分的，但这一点尚未在体内进行研究。在Aim 2的实验中，将利用光遗传技术直接激活切断轴突的神经元，以模拟其在跑步机训练中的活动，并将通过测量再生轴突的生长以及神经元和生长锥体中BDNF和TrkB的表达来评估这种激活的充分性。在不同的小鼠身上使用类似的技术，在运动过程中神经元活动将被阻断，其效果也将得到类似的分析 以确定锻炼效果的活动需求。目标3将研究运动或光学激活神经元是否也能促进轴突再生，从而改善功能恢复。神经传导研究将用于监测运动小鼠和光学激活小鼠肌肉神经再生和H反射恢复的时间进程。在不同坡度上行走时肢体运动的运动学分析将被用来衡量这些对功能恢复行为的影响。性别和训练/激活范式的影响将被分开研究。运动的这种潜在的治疗用途 解决了一个重要的公共卫生问题。它是低技术的，只需要熟练的从业者进行适度的监督。患者可以为自己的功能恢复承担很大责任。在这项研究结束时，我们将获得支持锻炼有效性的三个重要方面的证据，这将增加其翻译承诺。

DESCRIPTION (provided by applicant): Axon regeneration in peripheral nerves is enhanced by exercise in the form of modest daily treadmill training. This project will study three inter-related aspects of exercise as a potential therapy for treatment of peripheral nerve injuries to help move it closer to actual translation. Marked sex differences in the efficacy of different training paradigms to promote axon regeneration exist and androgens are implicated in both sexes. In Aim 1, the androgen dependence of the effect of exercise will be studied in conditional androgen receptor knockout mice. The effects of different exercise paradigms on the lengths of regenerating axons, the numbers of neurons whose axons regenerate successfully, and the expression of brain derived neurotrophic factor (BDNF) and its receptor, trkB, in motoneurons, dorsal root ganglion neurons, and growth cones of regenerating axons will be studied both in systemic and neuron-specific knockouts. As a therapy, different exercise paradigms will be needed for use when different nerves are injured. Establishing guiding principles for their design will be important. The most obvious of these principles may be that the activity of neurons whose axons are regenerating is both necessary and sufficient for the enhancement of regeneration produced by the exercise, but this has not been studied in vivo. In the experiments in Aim 2, axotomized neurons will be activated directly using optogenetic technologies, to simulate their activity during treadmill training in male and female mice, and the sufficiency of this activation will be assayed by measuring the growth of regenerating axons and the expression of BDNF and trkB in neurons and growth cones. Using similar technologies in different mice, neuronal activity will be blocked during exercise and the effects assayed similarly to determine the requirement for activity for the effects of exercise. Whether exercise or optical activation of neurons that results in enhanced axon regeneration also leads to improved functional recovery will be studied in Aim 3. Nerve conduction studies will be used to monitor the time course of muscle reinnervation and H reflex restoration in exercised mice and optically activated mice. Kinematic analyses of limb movements during walking on different slopes will be used to measure these effects on functional recovery behaviorally Effects of sex and training/activation paradigm will be studied separately. This potential therapeutic use of exercise addresses an important public health issue. It is low-tech and requires only modest supervision by skilled practitioners. Patients can assume a lot of the responsibility for their own functional recovery. At the end of this study we will have acquired evidence in support of three significant aspects of the efficacy of exercise that will add to its translational promise.