Exercise, neurotrophins, and axon regeneration in the PNS

描述（由申请人提供）：通过适度的日常跑步机训练形式的运动增强外周神经中的轴突再生。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，以帮助将其更接近实际翻译。不同训练模式促进轴突再生的功效存在显著的性别差异，并且雄激素在两性中都有牵连。在目的1中，将在条件性雄激素受体敲除小鼠中研究运动效应的雄激素依赖性。将在系统性和神经元特异性敲除中研究不同运动模式对再生轴突的长度、轴突成功再生的神经元的数量以及脑源性神经营养因子（BDNF）及其受体trkB在运动神经元、背根神经节神经元和再生轴突的生长锥中的表达的影响。作为一种治疗方法，当不同的神经受伤时，需要使用不同的锻炼模式。为它们的设计制定指导原则将是重要的。这些原则中最明显的可能是，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的和充分的，但这还没有在体内进行过研究。在目标2的实验中，将使用光遗传学技术直接激活轴突切断的神经元，以模拟它们在雄性和雌性小鼠中跑步机训练期间的活动，并且将通过测量再生轴突的生长以及神经元和生长锥中BDNF和trkB的表达来测定这种激活的充分性。在不同的小鼠中使用类似的技术，神经元活动将在运动期间被阻断，并且效果进行了类似的测定 以确定运动效果对活动的要求。在目标3中将研究导致增强的轴突再生的神经元的运动或光学激活是否也导致改善的功能恢复。神经传导研究将用于监测运动小鼠和光学激活小鼠中肌肉神经再支配和H反射恢复的时间过程。在不同的斜坡上行走时的肢体运动的运动学分析将用于测量这些对功能恢复行为的影响，性别和训练/激活范式的影响将分别进行研究。这种运动的潜在治疗用途 解决了一个重要的公共卫生问题。它技术含量低，只需要熟练的从业人员进行适度的监督。患者可以为自己的功能恢复承担很多责任。在本研究结束时，我们将获得证据，支持三个重要方面的功效，运动，这将增加其翻译的承诺。

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.