Neurotrophins Support Spinal Cord Learning and Rehabilitation

描述（由申请人提供）：最近的研究表明，受伤的脊髓有能力学习运动任务，这表明脊髓学习是功能恢复的内在组成部分。重复活动可以增强脊髓损伤受试者的运动学习的生理和分子机制仍然难以捉摸。我们目前的研究清楚地表明，运动对参与学习和记忆的突触可塑性的选择分子系统有影响。特别是，运动会提高脊髓中的BDNF。一些研究已经证明了BDNF对突触易化和神经元兴奋性的有效作用，表明BDNF具有介导高阶神经功能如学习和记忆的能力。事实上，我们最近已经证明，运动诱导的BDNF产生促进海马学习。此外，大量的工作已经证明了BDNF在减轻与神经创伤或疾病相关的神经损失方面的治疗潜力。因此，本研究的一个中心主题是研究运动诱导的BDNF与脊髓学习之间的关系。我们提出研究，以确定如何运动可以促进学习在脊髓激活信号系统的内源性BDNF和NT-3的调制下。为了实现这一目标，我们将依靠我们的经验，从开拓目前的理解参与运动诱导的BDNF介导突触可塑性和学习。我们将使用定义明确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，并且BDNF在损伤的脊髓中调节这些机制中起核心作用。这些研究的亮点是可以评估运动对学习的影响，以及对相同动物的踏步表现的影响。我们将利用神经元能系统的药理学来促进完全横断动物的运动，以及它与BDNF系统的密切相互作用。这些研究的成功将为开发改善脊髓损伤后功能恢复的治疗方法提供新的策略。公共卫生相关性：受伤的脊髓学习运动任务的潜力提供了可能性，以制定计划，以加强功能恢复。我们目前的研究表明，运动影响选择的分子系统，如脑源性神经营养因子（BDNF）参与突触可塑性的学习和记忆。我们提出研究，以确定如何运动可以促进学习在脊髓激活BDNF介导的突触可塑性。我们将使用一个定义明确的定量行为范式来确定脊髓学习，并将依赖于我们的经验，研究运动诱导的BDNF的中枢作用。我们假设运动和学习共享分子机制，并且BDNF在损伤的脊髓中调节这些机制中起核心作用。这些研究的亮点是可以评估运动对学习的影响以及对相同动物的踏步性能的影响。我们将利用多巴胺能系统的药理学来促进完全横断动物的运动，以及它与BDNF系统的密切相互作用。这些研究的成功将为开发改善脊髓损伤后功能恢复的治疗方法提供新的策略。

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.