Hand Use and Neuronal Plasticity after Dorsal Rhizotomy

描述(申请人提供)：导致手指失去传入的颈后根损伤会严重损害手的功能，特别是执行依赖于连续感觉反馈的手动任务(即处理和识别触手可及的物体)。此类损伤的外科修复几乎不会成功，灵活性的恢复通常也是有限的。我们在成年猕猴身上的研究表明，在背根损伤后，体感通路经历了实质性的重组，这种重组有助于手功能的恢复(有时是戏剧性的)。考虑到所有的操控任务本质上都是感觉运动，现在重要的是理解对损伤的‘运动’反应。这构成了拟议调查的重点。长期目标是(1)确定手失去传入后感觉运动通路中发生的结构和功能变化，这些变化有助于手部灵巧性的自发恢复；(2)确定可以通过治疗靶向促进功能恢复的内源性机制。在拟议的研究中，将使用一种独特的背根损伤模型，允许我们选择和阻止猴子手的一个离散部分(即拇指和食指及其周围区域)的感觉输入。生理学和解剖学分析将能够确定运动神经元回路的变化，这将与几个月内手动灵活性的行为缺陷和恢复相关。具体目标概括如下：1.皮质脊髓和其他下行皮质运动通路是否取代了背根损伤后的手部自主运动？2.红-橄榄-小脑-皮质环的连接是否因颈后根损伤后感觉输入的丧失而重组？在高级灵长类动物和人类中，这个前馈系统是改善手的自主功能所必需的，它的主要感觉输入在去传入损伤后从手指失去。3.下行皮质纤维是否形成新的功能性突触(在背角和腹角、楔状核和红核内)，对背根损伤做出反应？我们将使用EM分析来回答这个问题。这项拟议的工作将有助于对中枢神经机制的重要新见解，这些中枢神经机制负责明确的去传入损伤后发生的行为适应。该实验设计模拟了脊神经根性撕脱伤的临床情况，使研究复杂系统中的机械变化成为可能。由此得出的发现将使我们了解临床损伤中发生的变化，并更好地使未来开发有效的治疗方法来治疗牙根撕脱和其他脊髓和中枢神经系统损伤的人。公共卫生相关性 颈髓神经损伤可导致严重的、永久性的手功能丧失，而这种功能很少能通过手术成功修复。这种残疾可以在受控实验模型中准确地在猴子身上复制，这使得能够分析受伤后几个月内重组的大脑。我们目前和拟议中的研究集中于检查阻碍或促进手功能恢复的因素，我们的发现将有助于开发更有效的颈神经和脊髓损伤治疗方法。

DESCRIPTION (provided by applicant): Cervical dorsal root injuries that result in the deafferentation of the fingers can severely impair hand function, especially the execution of manual tasks that depend on continuous sensory feedback (i.e. the handling and identification of objects within reach). Surgical repair of such injuries is rarely, if ever, successful, and the recovery of dexterity is typically limited. Our studies in the adult macaque monkey show that somatosensory pathways undergo substantial reorganization following a dorsal root lesion, and that this reorganization contributes to the recovery of hand function (which is sometimes dramatic). Given that all manipulative tasks are inherently sensorimotor, it is now important that the 'motor' responses to the injury are understood. This forms the focus of the proposed investigations. The long term objectives are (1) to identify the structural and functional changes that occur in the sensorimotor pathways following deafferentation of the hand, that contribute to the spontaneous recovery of manual dexterity, and (2) to identify endogenous mechanisms that could be targeted therapeutically to promote functional recovery. In the proposed studies, a unique dorsal root lesion model will be used that allows us to select and block sensory input from a discrete part of the monkey hand (namely the thumb and index finger, and surrounding regions). Physiological and anatomical analyses will allow the determination of changes in the motor neuronal circuitry and this will be correlated with the behavioral deficit and recovery of manual dexterity over a period of several months. The specific aims in summary are as follows: 1. Do the corticospinal and other descending cortical motor pathways subserve voluntary hand movements following a dorsal root lesion? 2. Do the connections of the rubro-olivary- cerebello-cortical loop reorganize in response to the loss of sensory input following a cervical dorsal root lesion? This feedforward system is necessary to fine voluntary hand function in the higher primates and human, and its major sensory input from the digits is lost following a deafferentation injury, and 3. Do descending cortical fibers form new functional synapses (within the dorsal and ventral horn, cuneate nucleus and red nucleus), in response to a dorsal root lesion? EM analysis will be used to answer this question. The proposed work will contribute important new insight into the central neural mechanisms responsible for the behavioral adaptations that occur following a well defined deafferentation injury. The experimental design simulates aspects of the clinical condition of spinal root avulsion, and makes the study of the mechanistic changes in a complex system possible. The resulting findings will inform our understanding of the changes that occur in clinical injuries, and better enable the future development of effective treatments for people with avulsed root and other spinal and central nervous system injuries. PUBLIC HEALTH RELEVANCE Cervical spinal nerve injuries can result in a severe and permanent loss of hand function which is rarely repaired successfully by surgery. This disability can be accurately reproduced in the monkey in a controlled experimental model, which enables the analysis of the reorganized brain in the months following injury. Our current and proposed studies focus on examining factors that impede or promote the recovery of hand function, and our findings will enable the development of more effective treatments of cervical nerve and spinal injury