Neuronal and behavioral responses to spinal cord injury

项目摘要/摘要 脊髓损伤对人们和社会造成的损失是巨大的，尤其是手功能 受到了损害，失去了独立性。我们在非人类中使用明确的脊髓损伤(SCI)模型 灵长类和啮齿动物来描述主要上行和下行区域的反应， 损伤后的组织重组和调节手功能的恢复。我们过去的研究表明，脊椎 从相反的手指失去感觉输入的损伤，可能会导致手功能的初始缺陷， 在损伤后的几周和几个月里，猴子会从中恢复。这种恢复是在 永久性丧失手的大部分原有感觉神经。我们已经证明了 皮质脊髓束(CST)萌芽的初级运动(M1)和躯体感觉(S1)皮质亚区 广泛地和双边地超出其在绳索内的正常终端领土 去传入损伤，但仅当损伤涉及中枢神经系统时。相似的反应 可以在大鼠身上表现出来，这表明这种反应在哺乳动物中是强健和保守的 物种。在这笔赠款中，我们将解决我们对 恢复过程。我们将通过确定在神经元电路水平上发生什么，在 外周，以及在涉及感觉和运动部件的更临床相关的损害之后。 我们的主要关注点是猴子，我们的发现是直接翻译的，以及亚慢性和 受伤后的慢性时间点。在这些时候，患者更容易接受干预， 尤其是慢性时间点，人们对此知之甚少。概括地说，我们的具体目标是 如下：1.传入神经损伤后，中枢神经回路发生了什么变化？在这里我们 将针对脊髓的主要输入(来自手和皮质)及其连接，以 评估它们如何重组以调节手功能的恢复。2.周围神经和 受体补偿失去的神经，以支持手部感觉的显著恢复？ 在我们的损伤模型中增加一个小的运动部件，如何改变恢复过程和 潜在的联系？要使用的损伤模型定义得特别好，涉及 外周和中枢，以及感觉和运动部件，这使得它们在临床上具有相关性。 我们使用行为学、电生理学和一系列神经解剖学技术(包括高 分辨率共聚焦显微镜)，以及强大的多因素统计建模 改变。我们的发现将提高我们对临床损伤发生的变化的理解，以及 更好地为未来发展脊髓损伤患者提供有效的治疗方法。发现 将设置在更广泛的行为恢复和全系统神经元反应的背景下。

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.