Hand use and neuronal plasticity after spinal cord injury

描述（由申请人提供）：导致前肢和手部部分传入神经阻滞的脊髓神经和脊髓损伤可严重损害手部功能，尤其是执行依赖于连续感觉反馈的手动任务。我们对猕猴的研究表明，背根损伤后，体感和运动通路发生了实质性的重组，这种重组有助于手功能的恢复（这可能是戏剧性的）。皮质脊髓束（CST）是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恢复的生物标志物。在猕猴（和人类）中，这一通路起源于至少9个功能性皮质分区。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，背根切断术后，脊髓内的运动CST投射发芽，而体感（S1）CST投射缩回40%。这表明是运动CST，而不是S1 CST有助于这种外周损伤后的恢复。然而，对猴子的初步研究显示，当在相同的背根切断术中加入中央成分时，情况完全不同。当这种情况发生时，S1和运动CST都会大量地向两侧发芽，远远超出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/补偿的关键角色。由于CST发芽被用作SCI（从大鼠到灵长类动物）后手/爪恢复的解剖学生物标志物，以及治疗开发中的目标，因此必须了解其不同功能子成分所起的作用。这笔赠款将调查这一点。我们的具体目标概括如下：1.不同的皮质脊髓束成分对明确的猴外周和中枢SCI模型有何反应？2.损伤诱导的CST末端芽形成功能性突触吗？如果是，用什么？和3.由于CST广泛用于大鼠确定脊髓损伤后的恢复情况，因此在类似SCI后，大鼠运动和S1 CST反应（与猴）的可比性如何？将对所有动物进行行为测试，并将检查亚慢性和慢性时间段，以确定反应的任何短暂性/持久性。我们还将跟踪增殖性炎症反应，以便这些反应与行为和终末发芽相关。待使用的病变模型定义明确，涉及外周和中心组件，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，并更好地为未来开发有效的治疗方法。 脊髓损伤

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.