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。重复活动可以增强脊髓损伤受试者运动学习的生理和分子机制仍然不清楚。我们目前的研究清楚地表明，运动对涉及学习和记忆基础的突触可塑性的特定分子系统有影响。特别是，运动会增加脊髓中的脑源性神经营养因子。多项研究表明，BDNF对突触易化和神经元兴奋性有很强的作用，表明BDNF具有调节学习记忆等高级神经功能的能力。事实上，我们最近已经证明，运动诱导的脑源性神经营养因子的产生促进了海马体的学习。此外，大量工作已经证明了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，这项建议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。我们建议进行研究，以确定运动如何通过在内源性BDNF和NT-3的调节下激活信号系统来促进脊髓中的学习。为了实现这一目标，我们将依靠我们的经验，开创目前对运动诱导的BDNF参与调节突触可塑性和学习的理解。我们将使用定义明确的量化行为范式来评估脊髓学习。我们假设，运动和学习具有共同的分子机制，BDNF在调节损伤脊髓的这些机制中发挥着核心作用。这些研究的重点是评估运动对学习的影响，以及它对相同动物的步态表现的影响。我们将利用5-羟色胺能系统的药理学来促进完全横断动物的运动，以及它与脑源性神经营养因子系统的密切相互作用。拟议研究的成功将为脊髓损伤后改善功能恢复的治疗方法的发展提供新的策略。公共卫生相关性：损伤的脊髓学习运动任务的潜力提供了详细计划以促进功能恢复的可能性。我们目前的研究表明，运动影响与学习和记忆相关的突触可塑性的分子系统，如脑源性神经营养因子(BDNF)。我们建议进行研究，以确定运动如何通过激活BDNF介导的突触可塑性来促进脊髓中的学习。我们将使用定义明确的量化行为范式来确定脊髓学习，并将依赖于我们在研究运动诱导的BDNF的中枢影响方面获得的经验。我们假设，运动和学习具有共同的分子机制，BDNF在调节损伤脊髓的这些机制中发挥着核心作用。这些研究的亮点是评估运动对学习的影响以及对相同动物的步态表现的影响的可能性。我们将利用5-羟色胺能系统的药理学来促进完全横断动物的运动，以及它与脑源性神经营养因子系统的密切相互作用。拟议研究的成功将为脊髓损伤后改善功能恢复的治疗方法的发展提供新的策略。

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.