Training Effects on Recovery of Balance and Limb Accuracy in Cats Post-SCI

描述（由申请人提供）： 摘要由于脊髓损伤后发生的事件多种多样，因此促进损伤后恢复的最有效方法可能是使用多种策略。因此，在确定有前途的战略时，关键是要确定它们可以与哪些其他方法有效地联合收割机结合，以及这些结合是互补的、相加的还是协同的。所提出的研究的目标是确定针对步行的适应性特征的新训练策略是否单独或与脊髓损伤（SCI）后的软骨素酶ABC（Ch'ABC）的脊柱内递送相结合是有益的。虽然在人类和猫的运动不完全性SCI中恢复自主运动功能的潜力要大得多，但自主运动的适应性特征仍然受损。因此，这些研究将解决和目标恢复临床上重要的技能，有效的家庭和社区amberment后SCI，目前没有解决的康复。 Ch'ABC和技能培训是两种不同但可能互补的方法。Ch'ABC用于促进受损神经系统内轴突生长的更容许底物。具体而言，它切割已知在脊髓损伤部位增加的大分子家族的抑制性硫酸软骨素糖胺聚糖（CS GAG）侧链。相比之下，不断发展的基本运动训练方法通过活动依赖机制以备用脊髓回路为目标，以促进功能恢复。我们的指导性假设是，旨在针对平衡和肢体轨迹的技能训练将增强SCI后复杂运动任务所需的自发和Ch'ABC介导的适应性恢复。技能训练将针对运动的适应性特征，包括步长和高度，肢体准确性和平衡，允许更复杂的环境谈判。这些研究是从我们最近发表的使用Ch'ABC的猫模型工作以及我们的人类运动研究发展而来的。拟议的研究分为两组实验。第一组将比较运动恢复（Aim 1a），并评估可能有助于结构可塑性（Aim 1b）的解剖学基质的差异，这些差异在未接受训练、基本运动训练（水平跑道）和技能训练（需要在步进循环中适应的多跑道）的猫之间。第二组实验将比较三组猫的运动恢复：仅Ch'ABC、Ch'ABC +基本运动训练和Ch'ABC +技能训练（目标2a）。这些研究还将评估结构可塑性（目标2b）。为了评估结构可塑性，将使用逆行和顺行追踪方法。逆行追踪将重点关注在病变下方递送FluoroGold示踪剂后标记本体脊髓以及皮质、红核和vesitibulospinal神经元。这些系统是特别感兴趣的，因为它们可以在病变部位提供新的椎管内回路，或者可以分别与正常猫的各种熟练运动功能相关联。顺行追踪将集中在短的本体脊髓连接的轨迹和终止。将在所有目标方面进行各组之间的比较。总的来说，这些研究将为运动技能的循证康复提供重要信息（目标1a），两种治疗方法（训练和椎管内Ch'ABC）如何相互补充（目标2a），以及这些方法如何单独和联合影响节段和超节段结构变化（目标1b和2b）。 公共卫生相关性： 脊髓损伤和疾病护理系统的使命是支持，促进和维护SCI退伍军人的健康，独立性，生活质量和生产力。目前的研究提案通过基础动物研究来满足这些需求，这些研究评估了两种治疗方法对受伤脊髓内连接再生和行走恢复的影响。将单独和联合评估的两种治疗方法是：1）针对社区步行所需的步进适应所需的运动特征的运动训练; 2）分解抑制受损脊髓生长的因子的酶的脊柱内递送。这些潜在的治疗方法也可能与其他导致连接丢失和行走困难的神经系统疾病相关。

DESCRIPTION (provided by applicant): ABSTRACT Due to the varied and numerous events that occur in the spinal cord following injury, it is likely that the most effective approaches to promote recovery following injury will use multiple strategies. Thus, as promising strategies are identified, it is critical to determine what other approaches they can effectively combine with and whether the combinations are complementary, additive, or synergistic. The goal of the proposed research is to determine if a new training strategy targeting adaptive features of walking is beneficial alone or in combination with intraspinal delivery of chondroitinase ABC (Ch'ABC) following spinal cord injury (SCI). Although the potential to recover voluntary locomotor function is much greater with motor incomplete SCI in humans and cats, voluntary adaptive features of locomotion remain impaired. As such, these studies will address and target recovery of clinically important skills for effective home and community ambulation following SCI that are not currently addressed in rehabilitation. Ch'ABC and skill training are two diverse, but likely complementary, approaches. Ch'ABC is used to promote a more permissive substrate for axonal growth within the injured nervous system. Specifically, it cleaves the inhibitory chondroitin sulfate glycoaminoglycan (CS GAG) side chains of a large family of molecules that are known to increase at the site of spinal cord injury. In contrast, evolving basic locomotor training approaches target spared spinal circuitry through activity dependent mechanisms to promote functional recovery. Our guiding hypothesis is that skill-training, designed to target balance and limb trajectories, will enhance spontaneous and Ch'ABC-mediated recovery of adaptations necessary for complex locomotor tasks following SCI. Skill training will target adaptive features of locomotion including step length and height, limb accuracy, and balance that permit negotiation of more complex environments. These studies have evolved from our recently published work in the cat model using Ch'ABC as well as our human locomotor studies. The proposed studies are divided into two sets of experiments. The first set will compare the locomotor recovery (Aim 1a) and assess differences in anatomical substrates likely to contribute to structural plasticity (Aim 1b) between cats that receive no training, basic locomotor training (horizontal runway) and skill- training (multiple runways requiring adaptations in the stepcycle). The second set of experiments will compare the locomotor recovery of three groups of cats: Ch'ABC-only, Ch'ABC + basic locomotor training and Ch'ABC + skill-training (Aim 2a). These studies also will assess structural plasticity (Aim 2b). For assessment of structural plasticity, both retrograde and anterograde tracing approaches will be used. Retrograde tracing will focus on labeling of propriospinal as well as cortico-, rubro- and vesitibulospinal neurons after FluoroGold tracer delivery below the lesion. These systems are of particular interest because they may provide novel intraspinal circuitry at the lesion site or may be associated with various skilled locomotor features in normal cats respectively. Anterograde tracing will focus on trajectories and terminations of short propriospinal connections. Comparisons will be made across groups in all aims. Collectively, these studies will provide important information for evidence-based rehabilitation of motor skills (Aim1a), how two therapeutic approaches (training and intraspinal Ch'ABC) complement each other (Aim 2a) and how these approaches individually and combined may impact segmental and supra-segmental structural changes (Aims 1b and 2b). PUBLIC HEALTH RELEVANCE: The mission of the Spinal Cord Injury & Disorders System of Care is to support, promote, and maintain the health, independence, quality of life, and productivity of veterans with SCI throughout their lives. The current research proposal addresses these needs through basic animal studies which assess the effects of two therapeutic treatments on re-growth of connections within the injured spinal cord and recovery of walking. The two therapeutic treatment approaches that will be assessed alone and in combination are: 1) motor training targeting features of locomotion required for stepping adaptations necessary for community walking; 2) intraspinal delivery of an enzyme that breaks down factors inhibiting growth in the injured spinal cord. These potential treatments also may be relevant for other neurologic disorders which result in loss of connections and walking difficulty.