Exercise, neurotrophins, and axon regeneration in the PNS

描述（由申请人提供）：外周神经轴突再生可以通过适度的日常跑步机训练来增强。本项目将研究运动作为治疗周围神经损伤的潜在疗法的三个相互关联的方面，以帮助其更接近实际的转化。不同训练模式促进轴突再生的效果存在显著的性别差异，雄激素在两性中都有涉及。在Aim 1中，将在条件雄激素受体敲除小鼠中研究运动效果的雄激素依赖性。不同运动模式对再生轴突长度、成功再生的神经元数量、运动神经元、背根神经节神经元和再生轴突生长锥中脑源性神经营养因子（BDNF）及其受体trkB表达的影响将在全身性和神经元特异性敲除中进行研究。作为一种治疗方法，不同的神经损伤需要使用不同的运动模式。为它们的设计建立指导原则是很重要的。这些原理中最明显的可能是，轴突再生的神经元的活动对于增强运动产生的再生是必要和充分的，但这还没有在体内进行研究。在Aim 2的实验中，将使用光遗传学技术直接激活轴突切除的神经元，以模拟雄性和雌性小鼠在跑步机训练期间的活动，并通过测量再生轴突的生长以及神经元和生长锥中BDNF和trkB的表达来检测这种激活的充分性。在不同的老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，并对效果进行类似的分析

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because there are more than 100,000 new traumatic peripheral nerve injuries in the US each year, only a very small percentage of affected individuals ever recover full function, and there is no medical (non surgical) treatment for them. The scientific discoveries expected from the experiments in this proposal will represent new knowledge that could be applied to reduce the burdens of disability for these victims.