Hand use and neuronal plasticity after spinal cord injury

描述（由申请人提供）：脊神经和脊髓损伤导致前肢和手的部分传入神经丧失，可严重损害手功能，特别是依赖于持续感觉反馈的手动任务的执行。我们对猕猴的研究表明，在背根损伤后，体感觉和运动通路经历了实质性的重组，这种重组有助于手部功能的恢复（这可能是戏剧性的）。皮质脊髓束（CST）是调节灵长类动物手功能的主要下行通路，其在脊髓损伤后的反应被广泛用作康复的生物标志物。在猕猴（和人类）中，这一通路起源于至少9个功能性皮层分支。每一个都有不同的脊髓投射，只有30%的CST来自运动皮层。尽管如此，脊髓束的运动部分通常是脊髓损伤（SCI）后唯一考虑的部分。我们最近在猴子身上证明，在脊背根切断术后，运动CST投射在脊髓内发芽，而体感（S1） CST投射收缩40%。这表明是运动CST，而不是S1 CST有助于外周损伤后的恢复。然而，对猴子的初步研究表明，当一个中心成分被添加到相同的背根切断术中时，情况就大不相同了。当这种情况发生时，S1和运动cst都大量地和双侧发芽，远远超出了它们在脊髓中的正常范围。这意味着通常被忽视的S1 CST也可能是SCI后观察到的恢复/补偿的关键参与者。由于CST发芽被用作脊髓损伤（从大鼠到灵长类动物）后手/爪恢复的解剖学生物标志物，以及治疗开发的靶标，因此了解其不同功能子组分所起的作用是必要的。这笔拨款将对此进行调查。我们的具体目标总结如下：不同的皮质脊髓束成分如何对猴子周围和中枢脊髓损伤的明确模型做出反应？2. 损伤诱导的CST末端芽是否形成功能性突触？如果是，与什么形成功能性突触？3。由于CST在大鼠中广泛用于确定脊髓损伤后的恢复情况，那么在类似的SCIs后，大鼠的运动和S1 CST反应（与猴子）的可比性如何？将对所有动物进行行为测试，并对亚慢性和慢性时间段进行检查，以确定反应的短暂性/持久性。我们还将跟踪增殖性炎症反应，以便这些可以与行为和终末发芽相关联。所使用的病变模型定义明确，包括外周和中枢成分，因此具有临床相关性。我们使用强大的多因素统计模型来评估物种内部和物种之间的变化。我们的研究结果将提高我们对临床损伤中发生的变化的理解，并更好地使未来开发有效的治疗方法

DESCRIPTION (provided by applicant): Spinal nerve and cord injuries that result in the partial deafferentation of the forelimb and hand can severely impair hand function, especially the execution of manual tasks that depend on continuous sensory feedback. Our studies in the macaque monkey have shown that somatosensory and motor pathways undergo substantial reorganization following a dorsal root lesion, and that this reorganization contributes to the recovery of hand function (which can be dramatic). The corticospinal tract (CST) is the major descending pathway mediating hand function in the primate and its response following spinal injury is widely used as a biomarker of recovery. In the macaque monkey (and human), this pathway originates from at least 9 functional cortical subdivisions. Each has a different spinal projection, and only 30% of the total CST originates from the motor cortex. Despite this, the motor component of the tract is often the only part considered following spinal cord injury (SCI). We have recently demonstrated in monkeys that following a dorsal rhizotomy, the motor CST projection sprouts within the cord, while the somatosensory (S1) CST projection retracts by 40%. This suggests it is the motor CST, not the S1 CST that contributes to recovery following this peripheral injury. However, preliminary studies in the monkey show a very different story when a central component is added to the same dorsal rhizotomy. When this occurs, both the S1 and motor CSTs sprout massively and bilaterally, well beyond their normal range in the cord. This means that the S1 CST, which is generally overlooked, may also be a key player in the recovery /compensation observed following SCI. Since CST sprouting is used as an anatomical biomarker of hand/paw recovery following SCI (from rats to primates), as well as a target in therapeutic development, it is imperative that the role played by its different functional subcomponents is understood. This grant will investigate this. Our specific aims in summary are as follows: 1. How do the different corticospinal tract components respond to well defined models of peripheral and central SCI in the monkey? 2. Do the injury induced CST terminal sprouts form functional synapses, and if so, with what?, and 3. Since the CST is used extensively in the rat to determine recovery after spinal injury, how comparable (to the monkey) are the rat motor and S1 CST responses following analogous SCIs? All animals will be tested behaviorally and subchronic and chronic time periods will be examined to determine any transience/permanence of response. We will also track proliferative inflammatory responses so that these can be correlated with behavior and terminal sprouting. The lesion models to be used are well defined, involve both peripheral and central components, and as such are clinically relevant. We use powerful multifactorial statistical modeling to assess changes within and between species. Our findings will improve our understanding of the changes that occur in clinical injuries, and better enable the future development of effective treatments for people with spinal cord injury.