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: 10175060
• 负责人: CORINNA DARIAN-SMITH
• 金额: $ 65.15万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10175060
• 关键词: Address; Afferent Neurons; Anatomy; Animals; Behavior; Behavioral; Bilateral; Brain; Brain Stem; Cervical; Chronic; Clinical; Complement; Confocal Microscopy; Corticospinal Tracts; Data; Deafferentation procedure; Development; Digit structure; Electron Microscopy; Electrophysiology (science); Esthesia; Evoked Potentials; Fingers; Future; Goals; Grant; Hand; Hand functions; Human; Hypersensitivity skin testing; Impairment; Individual; Injury; Intervention; Lesion; Macaca; Maps; Measures; Mediating; Modeling; Monkeys; Motivation; Motor; Motor Pathways; Nerve; Nerve Fibers; Neural Conduction; Neuraxis; Neurons; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Population; Primates; Process; Rattus; Recovery; Recovery of Function; Reproducibility; Research; Resolution; Rodent; Role; Sensory; Shapes; Skin; Societies; Specificity; Spinal Cord; Spinal Injuries; Spinal cord injury; Spinal cord injury patients; Statistical Models; Synapses; System; Techniques; Thumb structure; Time; Tracer; Work; behavioral response; clinically relevant; confocal imaging; effective therapy; experimental study; hand dysfunction; hand rehabilitation; improved; indexing; insight; nerve supply; neuromechanism; neuronal circuitry; nonhuman primate; novel; receptor; response; sensory input; somatosensory; therapy development; treatment optimization

Project Summary/Abstract The toll of spinal cord injury on people and society is substantial, and particularly so when hand function is impaired and independence lost. We use well defined spinal cord injury (SCI) models in nonhuman primates and rodents to delineate the responses of major ascending and descending tracts, that reorganize post-injury and that mediate the recovery of hand function. Our past work shows that spinal injuries that remove sensory input from the opposing digits, can cause an initial deficit in hand function, from which monkeys recover over weeks and months post-lesion. This recovery occurs despite the permanent loss of most of the original sensory innervation to the hand. We have shown that spared primary motor (M1) and somatosensory (S1) cortical subdivisions of the corticospinal tract (CST) sprout extensively and bilaterally beyond their normal terminal territory within the cord following a deafferentation injury, but only when the injury involves the central nervous system. Similar responses can be demonstrated in rats which indicates the response is robust and conserved across mammalian species. In this grant, we will address some major gaps that remain in our understanding of the recovery process. We will do this by determining what happens at the neuronal circuit level, at the periphery, and following a more clinically relevant lesion involving both sensory and motor components. Our main focus is on monkeys, where our findings are directly translational, and on sub-chronic and chronic time points following injury. These are times when patients are more accessible to intervention, and the chronic time point in particular is poorly understood. Our specific aims in summary are as follows: 1. What happens to the central neuronal circuitry following a deafferentation injury? Here we will target the major inputs to the spinal cord (from the hand and cortex) and their connections, to assess how they reorganize to mediate the recovery of hand function. 2. How do peripheral nerves and receptors compensate for lost innervation to support significant recovery of sensation in the hand? 3. How does the addition of a small motor component to our lesion model, alter the recovery process and underlying connections? The lesion models to be used are particularly well defined, and involve peripheral and central, as well as sensory and motor components, which makes them clinically relevant. We use behavioral, electrophysiological, and a range of neuroanatomical techniques (including high resolution confocal microscopy), as well as powerful multifactorial statistical modeling to assess changes. 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. Findings will be set in a broader context of behavioral recovery and system wide neuronal responses.

项目总结/摘要 脊髓损伤对人类和社会的影响是巨大的，特别是当手功能受损时。 失去了独立性，失去了独立性。我们在非人类中使用定义明确的脊髓损伤（SCI）模型， 灵长类和啮齿类动物描绘的主要上升和下降的反应， 重组损伤后和介导的手功能的恢复。我们过去的研究表明， 从相对的手指移除感觉输入的损伤，可以引起手功能的初始缺陷， 猴子在损伤后数周和数月内恢复。这种复苏发生，尽管 手部大部分原始感觉神经支配的永久性丧失。我们已经证明， 皮质脊髓束（CST）的初级运动（M1）和躯体感觉（S1）皮质分支萌芽 广泛和双边超出其正常的终端领土内的索后， 神经传入阻滞损伤，但只有当损伤涉及中枢神经系统时。类似的反应 可以在大鼠中得到证实，这表明在哺乳动物中， 物种在这项资助中，我们将解决一些主要的差距，仍然在我们的理解， 恢复过程。我们将通过确定在神经元回路水平上发生了什么来做到这一点， 外周，以及涉及感觉和运动组件的临床相关性更高的病变。 我们的主要重点是猴子，我们的发现是直接翻译，以及亚慢性和 损伤后的慢性时间点。这些时候病人更容易接受干预， 尤其是慢性时间点，我们知之甚少。我们的具体目标概括如下： 如下：1.传入神经阻滞损伤后中枢神经回路会发生什么变化？这里我们 将针对脊髓的主要输入（来自手和皮层）及其连接， 评估它们是如何重组以调解手部功能的恢复。2.周围神经和 感受器补偿失去的神经支配以支持手部感觉的显著恢复？3. 在我们的损伤模型中增加一个小的运动组件，如何改变恢复过程， 潜在的联系待使用的病变模型特别明确，并且涉及 外周和中枢，以及感觉和运动成分，这使得它们具有临床相关性。 我们使用行为、电生理和一系列神经解剖学技术（包括高分辨率）， 分辨率共聚焦显微镜），以及强大的多因素统计模型，以评估 变化我们的发现将提高我们对临床损伤中发生的变化的理解， 更好地使未来开发有效的治疗脊髓损伤的人。结果 将在行为恢复和系统范围内的神经元反应的更广泛的背景下设置。