Neurotrophins Support Spinal Cord Learning and Rehabilitation

描述（由申请人提供）：最近的研究表明，受伤的脊髓具有学习运动任务的能力，表明脊髓学习是功能恢复的内在组成部分。重复活动增强脊髓损伤受试者运动学习的生理和分子机制尚不清楚。我们目前的研究清楚地表明，运动对学习和记忆中突触可塑性相关的分子系统有影响。特别是，运动可以提高脊髓中的BDNF。一些研究已经证明BDNF对突触促进和神经元兴奋性的有效作用，表明BDNF具有调节学习和记忆等高级神经功能的能力。事实上，我们最近的研究表明，运动诱导的BDNF的产生促进了海马的学习。此外，大量的工作已经证明BDNF的治疗潜力，以减轻与神经创伤或疾病相关的神经损失。因此，本研究的中心主题是研究运动诱导的BDNF与脊髓学习之间的关系。我们建议研究确定运动如何通过激活内源性BDNF和NT-3调节下的信号系统来促进脊髓的学习。为了实现这一目标，我们将依靠我们从目前对运动诱导的BDNF参与介导突触可塑性和学习的理解中获得的经验。我们将使用定义良好的定量行为范式来评估脊髓学习。我们假设运动和学习共享分子机制，BDNF在损伤脊髓中调节这些机制中起核心作用。这些研究的重点是有可能评估运动对学习的影响，以及运动对同一动物行走表现的影响。我们将利用血清素能系统的药理学来促进完全横切动物的运动，以及它与BDNF系统的密切相互作用。所提出的研究的成功将为开发改善脊髓损伤后功能恢复的治疗提供新的策略。公共卫生相关性：受损脊髓学习运动任务的潜力提供了精心设计方案以增强功能恢复的可能性。我们目前的研究表明，运动影响了一些分子系统，如脑源性神经营养因子（BDNF），这些分子系统与学习和记忆基础上的突触可塑性有关。我们建议研究确定运动如何通过激活bdnf介导的突触可塑性来促进脊髓的学习。我们将使用定义良好的定量行为范式来确定脊髓学习，并将依靠我们在研究运动诱导的BDNF的中心效应方面获得的经验。我们假设运动和学习共享分子机制，BDNF在损伤脊髓中调节这些机制中起核心作用。这些研究的重点是有可能评估运动对学习的影响以及运动对同一动物行走表现的影响。我们将利用血清素能系统的药理学来促进全横切动物的运动，以及它与BDNF系统的密切相互作用。所提出的研究的成功将为开发改善脊髓损伤后功能恢复的治疗提供新的策略。

DESCRIPTION (provided by applicant): Recent studies showing that the injured spinal cord has the capacity to learn motor tasks, suggest that spinal learning is an intrinsic component of functional recovery. The physiological and molecular mechanisms by which repeated activity can enhance locomotor learning in spinal cord injured subjects remain elusive. Our current research clearly indicates that exercise has an effect on select molecular systems involved with synaptic plasticity underlying learning and memory. In particular, exercise elevates BDNF in the spinal cord. Several studies have demonstrated the potent effect of BDNF on synaptic facilitation and neuronal excitability, indicating that BDNF has the capacity to mediate higher order neural function such as learning and memory. In fact, we have recently shown that exercise-induced BDNF production facilitates hippocampal learning. In addition, a large body of work has demonstrated the therapeutic potential of BDNF to attenuate neural loss associated with neural trauma or disease. Therefore, a central theme of this proposal is to examine the relationship between exercise-induced BDNF and learning in the spinal cord. We propose studies to determine how exercise can facilitate learning in the spinal cord by activating signaling systems under the modulation of endogenous BDNF and NT-3. To accomplish this goal, we will rely on our experience gained from pioneering the current understanding of the involvement of exercise-induced BDNF in mediating synaptic plasticity and learning. We will use a well-defined quantitative behavioral paradigm to assess spinal cord learning. We hypothesize that exercise and learning share molecular mechanisms and that BDNF plays a central role in modulating these mechanisms in the injured spinal cord. The highlight of these studies is the possibility to evaluate the effects of exercise on learning, in conjunction with its effects on stepping performance in the same animals. We will take advantage of the pharmacology of the serotonergic system to facilitate locomotion in complete transected animals, and its close interaction with the BDNF system. Success in the proposed investigations should provide new strategies for the development of treatments to improve functional recovery after spinal cord injury. PUBLIC HEALTH RELEVANCE: The potential of the injured spinal cord to learn motor tasks offers the possibility to elaborate programs to enhance functional recovery. Our current research indicates that exercise impacts select molecular systems such as brain-derived neurotrophic factors (BDNF) involved with synaptic plasticity underlying learning and memory. We propose studies to determine how exercise can facilitate learning in the spinal cord by activating BDNF-mediated synaptic plasticity. We will use a well-defined quantitative behavioral paradigm to determine spinal cord learning, and will rely on our experience gained studying the central effects of exercise-induced BDNF. We hypothesize that exercise and learning share molecular mechanisms and that BDNF plays a central role in modulating these mechanisms in the injured spinal cord. The highlight of these studies is the possibility to evaluate the effects of exercise on learning in conjunction with its effects on stepping performance in the same animals. We will make use of the pharmacology of the serotonergic system to facilitate locomotion in complete transected animals, and its close interaction with the BDNF system. Success in the proposed investigations should provide new strategies for the development of treatments to improve functional recovery after spinal cord injury.