Maximizing Spike - Timing Dependent Plasticity after Spinal Cord Injury

脊髓损伤后最大化尖峰 - 时间依赖性可塑性

• 批准号: 8978955
• 负责人: Martin Oudega
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978955
• 关键词: AMPA Receptors; Activities of Daily Living; Adult; Agonist; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Axon; Behavioral; Brain; Cervical spinal cord injury; Chemosensitization; Clinical; Corticospinal Tracts; Cycloserine; Data; Development; Dextromethorphan; Electrophysiology (science); Environment; Forelimb; Frequencies; Generations; Glutamate Receptor; Glutamates; Goals; Hand; Hand functions; Human; Impairment; Intervention; Investigation; Knowledge; Lesion; Measures; Mediating; Methodology; Modeling; Modification; Molecular; Motor; Motor Evoked Potentials; Motor Neurons; Motor Skills; Movement; Multiple Sclerosis; Muscle; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neuronal Plasticity; Neurons; Outcome; Patients; Physiologic pulse; Postsynaptic Membrane; Protocols documentation; Rattus; Recovery; Recovery of Function; Reporting; Research; Residual state; Spinal; Spinal Cord; Spinal cord injury; Stroke; Synapses; Synaptic Transmission; Testing; Time; Training; Translating; Upper Extremity; Work; abstracting; arm function; base; behavioral plasticity; clinically relevant; density; experience; grasp; hand rehabilitation; improved; indexing; motor disorder; motor function recovery; novel; novel strategies; postsynaptic; public health relevance; research study; transmission process

 DESCRIPTION (provided by applicant): Abstract: Our overall goal is to develop new clinical approaches to restore upper-limb function after incomplete cervical spinal cord injury (SCI). Corticospinal tract (CST) axons are involved in controlling upper-limb function. Paired-pulse induced spike-timing dependent plasticity (STDP) enhances synaptic strength between residual CST axons and spinal motoneurons (SMNs) resulting in temporary improvements in upper-limb function in humans with incomplete cervical SCI. Our specific goals are to: 1) develop methodologies to maximize STDP-induced aftereffects in an adult rat model of incomplete SCI and 2) translate this knowledge to humans to maximize STDP-mediated motor function recovery after incomplete cervical SCI. STDP aftereffects depend on the parameters of stimulation and the activation of postsynaptic glutamate NMDA and AMPA receptors causing increased synaptic transmission. In Aim 1, we will use an adult rat model of incomplete cervical SCI to examine the effects of increasing paired-pulse frequencies and duration, and extended use of clinically-relevant NMDA and AMPA receptor agonists on the strength of electrophysiological and forelimb functional STDP aftereffects. Motor training will be combined with paired-pulse STDP stimulation to further enhance plasticity and behavioral recovery. Comprehensive assessment of cellular and molecular plasticity in the brain and spinal cord will be used to study neuronal mechanisms underlying the effects of our approaches. In Aim 2, we will translate the knowledge from Aim 1 to humans with incomplete cervical SCI. The most effective stimulation parameters and pharmacological agent will be used in humans during functionally relevant reach to grasp motor tasks. Motor training of reach and grasp movements will be combined with STDP-paradigms to further enhance behaviorally relevant plasticity and recovery of function. Our experiments will provide new knowledge on STDP-mediated aftereffect mechanisms in an adult rat model of incomplete cervical SCI (Aim 1) which will be used to maximize STDP aftereffects in humans with incomplete cervical SCI (Aim 2). The results may support the development of more effective clinically-relevant STDP protocols to improve daily use of upper-limb function in humans with SCI. The relevance of this proposal is highlighted by the restricted efficacy of current strategies to improve hand function after SCI.

 描述（由申请人提供）： 翻译后摘要：我们的总体目标是开发新的临床方法，以恢复上肢功能不完全性颈脊髓损伤（SCI）后。皮质脊髓束（CST）轴突参与 控制上肢功能配对脉冲诱导的尖峰时间依赖性可塑性（STDP）增强了残留CST轴突和脊髓运动神经元（SMN）之间的突触强度，导致不完全颈脊髓损伤患者上肢功能的暂时改善。我们的具体目标是：1）开发方法，以最大限度地提高成年大鼠不完全SCI模型中STDP诱导的后效，2）将这些知识转化为人类，以最大限度地提高不完全颈部SCI后STDP介导的运动功能恢复。STDP后效应依赖于刺激参数和突触后谷氨酸NMDA和AMPA受体的激活，导致突触传递增加。在目标1中，我们将使用不完全颈脊髓损伤的成年大鼠模型来检查增加成对脉冲频率和持续时间以及延长使用临床相关的NMDA和AMPA受体激动剂对电生理和前肢功能性STDP后效强度的影响。运动训练将与成对脉冲STDP刺激相结合，以进一步增强可塑性和行为恢复。对大脑和脊髓中细胞和分子可塑性的全面评估将用于研究我们方法影响的神经元机制。在目标2中，我们将把目标1中的知识转化为不完全颈椎脊髓损伤患者的知识。最有效的刺激参数和药理学试剂将在功能相关的伸手抓握运动任务期间用于人体。伸展和抓握动作的运动训练将与STDP范式相结合，以进一步增强行为相关的可塑性和功能恢复。我们的实验将提供有关不完全颈部SCI成年大鼠模型中STDP介导的后效机制的新知识（目标1），该模型将用于最大限度地提高不完全颈部SCI患者的STDP后效（目标2）。研究结果可能支持开发更有效的临床相关STDP方案，以改善SCI患者上肢功能的日常使用。目前改善SCI后手部功能的策略的有限功效突出了这一建议的相关性。