Neuronal and behavioral responses to spinal cord injury

对脊髓损伤的神经元和行为反应

• 批准号: 8857019
• 负责人: CORINNA DARIAN-SMITH
• 金额: $ 62.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857019
• 关键词: Affect; Animals; Area; Basic Science; Behavior; Behavioral; Bilateral; Biological Markers; Cervical; Chronic; Clinical; Contralateral; Corticospinal Tracts; Data; Deafferentation procedure; Development; Dorsal; Financial compensation; Fingers; Forelimb; Future; Grant; Hand; Hand functions; Human; Individual; Inflammatory Response; Inhibitory Synapse; Injury; Interneurons; Lesion; Link; Macaca; Manuals; Mediating; Modeling; Monkeys; Motor; Motor Cortex; Motor Pathways; Neurons; Normal Range; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nerves; Phenotype; Play; Presynaptic Terminals; Primates; Protocols documentation; Quality of life; Rattus; Recovery; Recovery of Function; Rhizotomy procedure; Rodent; Role; Sensorimotor functions; Sensory; Side; Site; Spinal; Spinal Injuries; Spinal cord injury; Spinal nerve structure; Statistical Models; Sum; Synapses; Testing; Time; Work; behavioral outcome; behavioral response; clinically relevant; dorsal column; dorsal horn; effective therapy; improved; insight; microstimulation; neuromechanism; nonhuman primate; novel; postsynaptic; presynaptic; public health relevance; response; restoration; sensory feedback; sensory input; somatosensory; spinal nerve posterior root; statistical center; therapeutic development; tool

 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.

 描述（由申请人提供）：在脊髓神经和脊髓损伤导致前肢和手指部分传入神经切断后，手功能可能严重受损，并且这种缺陷在依赖于连续感觉反馈的手动任务中尤其明显。我们对猕猴的研究表明，在颈后根和脊髓损伤后，躯体感觉和运动通路发生了实质性的重组， 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。我们的研究表明，在猴子中，单独进行背根切断术后，运动（M1）CST投射仍然很强大，甚至可能在脊髓内发芽，而体感（S1）CST投射则收缩了40%。这表明，M1 CST，而不是S1 CST，有助于这种外周损伤后的恢复。与此形成直接对比的是，当中央成分与相同的背根切断术相结合时，S1和运动CSTs都大量地向两侧发芽，并且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也是在一些（也许是所有）包含核心组成部分的SCI之后观察到的恢复/补偿中的关键角色。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，以及治疗开发中的靶点，因此理解不同功能子成分所起的作用至关重要。这笔赠款将调查这一点。我们的具体目标概括如下：1. S1和M1 CST如何分别对明确定义的猴外周和中枢SCI模型作出反应？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被广泛用于大鼠脊髓损伤后的恢复，在类似的SCI后，大鼠运动和S1 CST反应的可比性如何（与猴子）？将对大鼠和猴进行行为测试，并检查亚慢性和慢性时间段，以确定反应随时间的变化。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