Maximizing Spike - Timing Dependent Plasticity after Spinal Cord Injury

 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全性颈髓损伤(SCI)后的上肢功能。皮质脊髓束(CST)轴突参与 控制上肢功能。成对脉冲诱导的峰时依赖性可塑性(STDP)增强了残留的CST轴突和脊髓运动神经元(SMN)之间的突触强度，导致不完全颈髓损伤患者上肢功能的暂时改善。我们的具体目标是：1)在不完全性脊髓损伤的成年大鼠模型中，开发最大限度地增加STDP诱导的后遗症的方法；2)将这一知识转化为人类，以最大限度地促进STDP介导的不完全性颈脊髓损伤后运动功能的恢复。STDP后效依赖于突触后谷氨酸、NMDA和AMPA受体的刺激和激活，从而导致突触传递增加。在目标1中，我们将使用成年大鼠不完全颈髓损伤模型来检测增加双脉冲频率和持续时间，以及临床相关的NMDA和AMPA受体激动剂的延长使用对电生理和前肢功能性STDP后效的影响。运动训练将与双脉冲STDP刺激相结合，进一步增强可塑性和行为恢复。对大脑和脊髓细胞和分子可塑性的综合评估将被用于研究我们的方法效果背后的神经机制。在目标2中，我们将把目标1的知识翻译给患有不完全性颈椎脊髓损伤的人类。最有效的刺激参数和药剂将在人体功能相关的REACH中使用，以掌握运动任务。伸展和抓握动作的运动训练将与STDP范例相结合，以进一步增强与行为相关的可塑性和功能恢复。我们的实验将为STDP介导的不完全性颈椎脊髓损伤成年大鼠模型(目标1)的后效机制提供新的知识，这将被用来最大限度地增加人类不完全性颈椎脊髓损伤的STDP后效(目标2)。这一结果可能支持开发更有效的临床相关的STDP方案，以改善SCI患者的上肢功能日常使用。当前改善脊髓损伤后手功能的策略效果有限，凸显了这一建议的相关性。

 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.