Hand Use and Neuronal Plasticity after Dorsal Rhizotomy

描述（由申请人提供）：颈椎背根损伤导致手指的神经分化，可严重损害手部功能，特别是依赖于持续感官反馈的手动任务的执行（即处理和识别触手可及的物体）。这种损伤的手术修复很少成功，而且灵巧的恢复通常是有限的。我们对成年猕猴的研究表明，在背根损伤后，体感觉通路经历了实质性的重组，这种重组有助于手部功能的恢复（有时是戏剧性的）。鉴于所有的操作任务都是固有的感觉运动，现在重要的是要理解对损伤的“运动”反应。这是拟议调查的重点。长期目标是(1)确定手部神经分化后感觉运动通路中发生的结构和功能变化，这些变化有助于手工灵巧的自发恢复；(2)确定可靶向治疗促进功能恢复的内源性机制。在提出的研究中，将使用一种独特的背根损伤模型，使我们能够选择和阻止来自猴子手的离散部分（即拇指和食指及其周围区域）的感觉输入。生理和解剖分析将允许确定运动神经元回路的变化，这将与几个月后的行为缺陷和手灵巧的恢复相关。具体目的总结如下：1。背根损伤后，皮质脊髓和其他下行皮质运动通路是否支持随意的手部运动？2. 颈背根损伤后感觉输入丧失时，红橄榄-小脑-皮质回路的连接是否重组？2 .这种前馈系统对于高级灵长类动物和人类的手部随意功能是必要的，其主要的来自手指的感觉输入在传入神经损伤后丢失。是否下行皮质纤维形成新的功能性突触（在背角和腹角、楔形核和红核内），作为对背根损伤的反应？EM分析将用于回答这个问题。提出的工作将有助于重要的新见解，负责行为适应的中枢神经机制，发生在一个明确定义的脱神经损伤。实验设计模拟了脊柱根撕脱伤的临床情况，使研究复杂系统的机制变化成为可能。由此产生的发现将有助于我们理解临床损伤中发生的变化，并更好地促进未来对撕脱性根和其他脊髓和中枢神经系统损伤患者的有效治疗。公共卫生相关性

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