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）： 摘要：我们的总体目标是开发新的临床方法来恢复不完整的宫颈脊髓损伤（SCI）后恢复上LIMB功能。皮质脊髓区（CST）轴突参与 控制上LIMB功能。配对脉冲诱导的峰值依赖性可塑性（STDP）增强了残留的CST轴突和脊柱运动神经元（SMN）之间的突触强度，从而在人体中暂时改善颈椎SCI的上LIMB功能的暂时改善。我们的具体目标是：1）开发方法在不完整的SCI的成年大鼠模型中最大化STDP诱导的应有效应，并2）将此知识转化为人类，以最大化STDP介导的运动功能在不完整的宫颈SCI后恢复。 STDP Dueffects取决于刺激的参数以及突触后谷氨酸NMDA和AMPA受体的激活，导致突触传播增加。在AIM 1中，我们将使用不完整的宫颈SCI的成年大鼠模型来检查成对脉冲频率和持续时间增加的影响，并扩展使用与临床上相关的NMDA和AMPA受体激动剂对电生理学和前肢功能性STDP DUDFFFFFFECT的强度。运动训练将与配对的脉冲组织刺激结合使用，以进一步增强可塑性和行为恢复。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作用的基础的神经元机制。在AIM 2中，我们将把知识从AIM 1转换为不完整的宫颈的人类。科学。最有效的刺激参数和药理学剂将在功能相关的覆盖范围内使用，以掌握运动任务。覆盖范围和掌握运动的运动训练将与STDP-Paradigms结合使用，以进一步增强行为相关的可塑性和功能的恢复。我们的实验将提供有关不完全宫颈SCI的成年大鼠模型中STDP介导的后效应机制的新知识（AIM 1），该模型将用于最大化颈椎不完全SCI的人类中的STDP应有效应（AIM 2）。该结果可能支持开发更有效的临床相关性STDP方案，以改善SCI人类中LIMB功能的日常使用。当前的策略在SCI后提高手部功能的效率限制了这一建议的相关性。