Promoting and understanding recovery of breathing after chronic spinal cord injury

项目概要/摘要 超过50%的脊髓损伤发生在颈椎节段。在这个层面是膈神经运动 支配横膈膜的神经元。因此，这种程度的损伤可能导致无法呼吸。 这项拨款建议的总体目标是研究长期以来在 脊髓膈神经回路对颈髓损伤的反应，并研究和优化潜力 可以在受伤后很长时间内恢复呼吸的疗法。通过这些研究，有效的干预措施可以 在脊髓损伤人群中有很大的影响。在本提案中，我们将利用 慢性颈脊髓半切动物，其中有一半的隔膜麻痹。在我们早期 我们的研究观察到，酶（软骨素酶ABC）去除细胞外基质分子，称为 硫酸软骨素蛋白聚糖，阻止可塑性，再生和发芽，导致恢复， 当在受伤时或接近受伤时给药时，曾经麻痹的半横膈膜的功能。回收 脑电活动是有节奏和同步的。与此形成鲜明对比的是，当脊髓长期 用硫酸软骨素酶ABC和间歇性低氧训练刺激损伤动物， 结果是无组织的活动，表明对损伤的反应缓慢发展和潜在的适应不良。 然而，在慢性阶段单独使用软骨素酶可以促进正常节律， 促进适当模式的功能恢复。这项拨款建议旨在：1）了解时间进程 并仔细描述发生的适应不良过程; 2）了解潜在的机制 在慢性时间点产生这种新发现的非典型活性;以及3）学习如何克服 这些对伤害的负面反应，使干预和康复策略可以变得更加 有效，从而改善功能结果。总的来说，这些研究将提供关于 适应不良的基本机制，以及功能上有益的可塑性，可以导致强大的 脊髓损伤慢性阶段的功能性呼吸运动恢复。

PROJECT SUMMARY/ABSTRACT More than 50% of all spinal cord injuries occur at the cervical level. At this level are the phrenic motor neurons which innervate the diaphragm. Therefore, injuries at this level can lead to the inability to breathe. The overall objective of this grant proposal is to examine the changes which take place chronically in the phrenic circuitry of the cord in response to cervical spinal cord injury and investigate and optimize potential therapies that can restore breathing long after injury. Through these studies, an effective intervention can be translated to a significant population of the spinal cord injured community. In this proposal we will utilize chronic cervical spinal cord-hemisected animals which have half of the diaphragm paralyzed. In our earlier studies we observed that enzymatic (chondroitinase ABC) removal of extracellular matrix molecules, called chondroitin sulfate proteoglycans, which block plasticity, regeneration, and sprouting, led to restoration of function of the once paralyzed hemidiaphragm when administered at or near the time of injury. Recovered diaphragmatic activity was rhythmic and synchronized. In stark contrast, when the spinal cord of chronically injured animals was stimulated with chondroitinase ABC and intermittent hypoxia training, chaotic and unstructured activity resulted, suggesting slowly developing and potentially maladaptive responses to injury. However, the use of chondroitinase alone at chronic stages can promote normal rhythm and dramatically enhance properly patterned functional recovery. This grant proposal seeks to: 1) understand the time course and carefully describe the maladaptive processes that take place; 2) understand the mechanisms underlying the production of this newly discovered atypical activity at chronic time points; and 3) learn how to overcome these negative responses to injury so that interventions and rehabilitative strategies can become more effective, thereby leading to improved functional outcomes. Overall, these studies will provide insight on the basic mechanisms that underlie maladaptive, as well as functionally beneficial plasticity that can lead to robust functional respiratory motor recovery at chronic stages of spinal cord injury.