Neuronal and behavioral responses to spinal cord injury

 描述(申请人提供)：脊神经和脊髓损伤部分传入前肢和手指后，手的功能可能受到严重损害，这种缺陷在依赖持续感觉反馈的体力劳动中尤为明显。我们在猕猴身上的研究表明，在颈后根和脊髓损伤后，躯体感觉和运动通路经历了实质性的重组，这种重组 有助于恢复手的功能(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，这条通路至少起源于9个功能皮质亚区。每一个都有不同的脊椎投射，只有30%的CST起源于运动皮质。尽管如此，脊髓损伤(SCI)后，脊髓束的运动部分往往是唯一被考虑的部分。我们在猴子身上的研究表明，仅在背根切断后，运动(M1)CST投射保持健壮，甚至可能在脊髓内萌发，而体感(S1)CST投射收缩40%。这表明，M1CST，而不是S1CST，有助于外周损伤后的恢复。与之形成直接对比的是，当一个中枢部分与相同的背根切断术相结合时，S1和运动性CST都会大量和双侧萌发，并且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S1CST也是在一些(也许是所有)包括中心组件的SCI之后观察到的恢复/补偿的关键参与者。由于CST萌发被用作脊髓损伤(从大鼠到灵长类动物)后手/爪恢复的解剖学生物标志物，也是治疗发展的靶点，因此了解不同功能亚组分所起的作用至关重要。这笔拨款将对此进行调查。我们的具体目标概括如下：1.S1CST和M1CST对猴子明确的外周和中枢性脊髓损伤模型的反应如何？2.损伤诱导的CST终末萌芽形成功能性突触吗？如果是，与什么形成？3.由于CST在大鼠中被广泛用于定义脊髓损伤后的恢复，在类似的SCI后，大鼠的运动和S1CST的反应与猴子有多大的可比性？老鼠和猴子都将接受行为测试，并将检查亚慢性和慢性时间段，以确定随着时间的推移反应的变化。我们还将跟踪这两个物种的增殖性炎症反应，以便这些反应可以与行为和末梢萌芽相关。要使用的病变模型定义良好，既涉及外周成分，也涉及中枢成分，因此具有临床意义。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。我们的发现将提高我们对临床损伤发生的变化的理解，并更好地使未来开发有效的治疗方法 脊髓损伤。

 DESCRIPTION (provided by applicant): Hand function can be seriously impaired following spinal nerve and cord injuries that partially deafferent the forelimb and fingers, and the deficit will be particularly evident in manual tasks that depend on continuous sensory feedback. Our work in the macaque monkey has shown that somatosensory and motor pathways undergo substantial reorganization following cervical dorsal root and cord lesions, and 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). Our work has shown in monkeys that following a dorsal rhizotomy alone, the motor (M1) CST projection remains robust and may even sprout within the cord, while the somatosensory (S1) CST projection retracts by 40%. This suggests that the M1 CST, not the S1 CST, contributes to recovery following this peripheral injury. In direct contrast, when a central component is combined with the same dorsal rhizotomy, both the S1 and motor CSTs sprout massively and bilaterally, and well beyond their normal range in the cord. This means that the S1 CST, which is generally overlooked, is also a key player in the recovery/compensation observed following some (and perhaps all) SCIs that include a central component. 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 critical that the role played by is different functional subcomponents is understood. This grant will investigate this. Our specific aims in summary are as follows: 1. How do the S1 and M1 CSTs each 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 define recovery after spinal injury, how comparable (to the monkey) are the rat motor and S1 CST responses following analogous SCIs? Both rats and monkeys will be tested behaviorally and subchronic and chronic time periods will be examined to determine changes in response over time. We will also track proliferative inflammatory responses in both species 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.