Repetitive Acute Intermittent Hypoxia for Spinal Cord Repair

我们的总体目标是开发有效的、临床适用的恢复上肢功能的方法(REACH- 和抓握)在慢性挫伤性颈髓损伤(CSCI)后。上肢功能障碍 显著降低慢性脊髓损伤患者的生活质量。在动物和人类中，伸手和抓住的动作是 主要由皮质脊髓束(CST)控制。我们认为，促进CST内部的可塑性可能会支持 CSCI后上肢功能恢复情况。反复暴露于急性间歇性低氧(RAIH)联合 运动训练是一种安全的、微创的治疗方法，可以产生神经可塑性，从而改善 在CSCI后恢复，但其总体影响仍然有限。我们的主要目标是：1)增强RAIH/培训诱导 后遗症对成年大鼠前肢功能的影响及对神经元底物的了解 慢性挫伤性CSCI，以及2)使用这些知识来指导更有效的RAIH/训练的发展 改善慢性挫伤性CSCI患者上肢功能的方法。 在特定的目标1，我们将使用一个慢性挫伤性CSCI的成年大鼠模型，我们将研究Raih的作用 训练对受损前肢功能恢复影响的频率和剂量。此外，我们还将结合 用D-环丝氨酸治疗NMDA介导的突触可塑性进行RAIH/训练，并研究其对 前肢功能恢复。将使用免疫细胞化学和成像技术来评估结构 Raih/训练后CST神经元的可塑性。在特定目标2中，在慢性不完全CSCI患者中， 在特定目标1的研究结果的指导下，我们将研究RAIH频率和同时存在的D-环丝氨酸的影响 训练介导的上肢功能恢复的治疗。我们将全面分析这些影响 Raih对上肢电生理强度和功能后遗症的影响。 拟议的研究将提供关于RAIH/训练介导的功能和解剖学的新知识 后遗症(具体目标1)，将用于为患有以下疾病的人制定有效的RAIH/培训方案 挫伤，功能不全，CSCI(特定目标2)。我们实验的数据可能会导致临床上 改善慢性挫伤性CSCI后手臂和手功能恢复的适用方法，这将 对CSCI退伍军人的生活质量产生积极影响。这项建议的相关性由以下方面强调 目前改善CSCI后上肢功能的策略效果有限。

Our overall goal is to develop effective, clinically applicable, approaches to restore upper limb function (reach- and-grasp) after chronic contusive cervical spinal cord injury (cSCI). Impairments in upper limb function significantly reduce the quality of life for people with cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the corticospinal tract (CST). We argue that promoting plasticity within the CST may support the recovery of upper limb function after cSCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive, treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its overall effects remain limited. Our main goals are to: 1) enhance rAIH/training-induced aftereffects on forelimb function and increase our understanding of the neuronal substrates in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the development of more effective rAIH/training approaches to improve upper limb function in humans with chronic contusive cSCI. In Specific Aim 1, using an adult rat model of chronic contusive cSCI, we will investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional recovery of the impaired forelimb. Also, we will combine rAIH/training with NMDA-mediated synaptic plasticity through D-cycloserine treatment and study the effects on recovery of forelimb function. Immunocytochemistry with imaging techniques will be used to assess structural neuronal plasticity in the CST after rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the findings in Specific Aim 1, we will study the effects of rAIH frequency and concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery. We will comprehensively analyze the effects of rAIH on the strength of electrophysiological and functional aftereffects in the upper limb. The proposed research will provide new knowledge on rAIH/training-mediated functional and anatomical aftereffects (Specific Aim 1), which will be used to develop effective rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific Aim 2). The data from our experiments may lead to clinically applicable approaches that improve arm and hand function recovery after chronic contusive cSCI, which would positively impact the quality of life of our Veterans with cSCI. The relevance of this proposal is emphasized by the limited efficacy of current strategies to improve upper limb function after cSCI.