Neurotrophins Support Spinal Cord Learning and Rehabilitation

神经营养素支持脊髓学习和康复

基本信息

批准号：
7752483
负责人：
Fernando Gomez-Pinilla
金额：
$ 33.35万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752483
关键词：
Abbreviations Affect Animals Area Attenuated Behavior Behavioral Paradigm Brain-Derived Neurotrophic Factor CREB1 gene Ca(2+)-Calmodulin Dependent Protein Kinase Calcium/calmodulin-dependent protein kinase Cyclic AMP-Responsive DNA-Binding Protein Data Disease Enzyme-Linked Immunosorbent Assay Exercise Functional disorder Goals Growth Associated Protein 43 Hippocampus (Brain)Injury Investigation Learning Lesion Link Locomotion Locomotor Recovery MAPK Signaling Pathway Pathway Mediating Memory Mitogens Molecular Motor Neuroglia Neurons Neurophysiology - biologic function Neurotrophin 3 Pathway interactions Pattern Performance Pharmacology Physiological Play Production Proteins Quipazine Receptor Protein-Tyrosine Kinases Recovery Recovery of Function Rehabilitation therapy Research Role Serotonin Serotonin Agonists Signal Transduction Spinal Spinal Cord Spinal Cord Lesions Spinal Cord Plasticity Spinal Ganglia Spinal cord injury Synapses Synapsin I Synaptic plasticity System Therapeutic Trauma Work base calmodulin-dependent protein kinase II design experience extracellular improved inhibitor/antagonist intervention effect motor learning neuronal excitability neurotrophic factor programs public health relevance relating to nervous system spinal cord and brain injury success synaptic function therapy development

项目摘要

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.

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，运动对涉及学习和记忆突触可塑性的特定分子系统有影响。特别是，运动可以提高脊髓中的 BDNF。多项研究证明 BDNF 对突触促进和神经元兴奋性具有强大作用，表明 BDNF 具有介导学习和记忆等高级神经功能的能力。事实上，我们最近发现运动诱导的 BDNF 产生有助于海马体的学习。此外，大量工作已经证明 BDNF 具有减轻与神经创伤或疾病相关的神经损失的治疗潜力。因此，该提案的中心主题是研究运动诱发的 BDNF 与脊髓学习之间的关系。我们提出研究来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学习。为了实现这一目标，我们将依靠我们从开拓当前对运动诱导的 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具有相同的分子机制，并且 BDNF 在调节受损脊髓的这些机制中发挥着核心作用。这些研究的亮点是可以评估运动对学习的影响，以及运动对同一动物的迈步表现的影响。我们将利用血清素能系统的药理学来促进完全横断动物的运动，及其与 BDNF 系统的密切相互作用。拟议研究的成功应该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。公共健康相关性：受伤脊髓学习运动任务的潜力为制定增强功能恢复的计划提供了可能性。我们目前的研究表明，运动会影响选择分子系统，例如与学习和记忆的突触可塑性相关的脑源性神经营养因子（BDNF）。我们提出研究来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。我们将使用明确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发的 BDNF 的中心效应方面获得的经验。我们假设运动和学习具有相同的分子机制，并且 BDNF 在调节受损脊髓的这些机制中发挥着核心作用。这些研究的亮点是可以评估运动对学习的影响及其对同一动物的迈步表现的影响。我们将利用血清素能系统的药理学来促进完全横断动物的运动，及其与 BDNF 系统的密切相互作用。拟议研究的成功应该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。