Injury and adaptation in the developing rat corticospinal and rubrospinal tracts

描述(由申请人提供)：摘要：大多数脑或脊髓损伤在启动运动的大脑区域和产生运动的脊髓区域之间保留了一些连接。运动恢复的一个关键问题是，备用连接能在多大程度上补偿受伤的连接。我们将研究备用运动通路对皮质脊髓束(CST)损伤的适应性，皮质脊髓束损伤是人类自主运动的主要途径。CST连接运动皮质和脊髓，控制细微的手部运动并调节脊髓反射。我们将切断从一个半球发出的CST，并测试备用电路接管丢失功能的能力。具体地说，我们将研究两个回路：1)CST的健侧通过其稀疏的同侧投射，以及2)损伤侧从皮质到红核到脊髓的旁路。我们将在老鼠出生后不久伤害老鼠，那时这些连接是可塑性的，获得赔偿的机会最大。然后，我们使用两种新技术测量这些备用系统的反应--使用伪狂犬病病毒的逆行跨突触追踪和轴突连接的体视学量化。因此，我们将确定哪个备用系统在受伤时会萌发出更大的连接。在新生大鼠CST损伤到一半的成年大鼠中，我们将测试功能极限的途径代偿。我们将对关键依赖于CST的功能进行新颖和经过验证的测试：伸手抓握、爬梯子、食物操纵和控制脊髓反射。我们预测，专业运动技能的恢复将是不完全的。对于确实恢复的功能，我们将通过注射神经活动抑制剂来暂时使两条备用路径中的每一条都失活，以测试它们对恢复的贡献。我们预计，在显示最大程度的损伤诱导可塑性的途径中，恢复的功能将暂时丧失。最后，我们将有选择地激活最适应的回路，试图改善内源性恢复。通过植入电极的慢性刺激，我们打算利用依赖活动的可塑性来加强运动联系。我们预测，根据追踪和刺激技术的测量，这些有针对性的操作将创建一种更具适应性的脑-脊髓连接模式，并有助于基于上述运动任务恢复功能。许多人类婴儿，特别是那些早产的婴儿，都会受到CST的损伤。这通常会导致身体一侧瘫痪和痉挛。以物理治疗和非侵入性脑刺激的形式的活动可以用来改变人类的连接。这些研究将有助于确定应该在哪里进行活动，以加强调节自发恢复的回路。因此，我们使用解剖学上的精确损伤、追踪、失活和刺激来确定修复运动系统的电路级逻辑。这可以提高我们恢复早期脑损伤患者功能的能力。

DESCRIPTION (provided by applicant): Summary: Most injuries to the brain or spinal cord spare some connections between the areas of brain that initiate movement and the areas of spinal cord that produce movement. A pivotal question for recovery of movement is the degree to which spared connections can compensate for injured ones. We will study the adaptation of spared motor pathways to injury of the corticospinal tract (CST), the principal pathway for voluntary movement in humans. The CST, which connects the motor cortex to the spinal cord, controls fine hand movements and modulates spinal cord reflexes. We will cut the CST emanating from one hemisphere and test the ability of spared circuits to take over the lost function. Specifically, we will examine two circuits: 1) the uninjured half of the CST through its sparse ipsilateral projections, and 2) a bypass circuit on the injured side from cortex to red nucleus to spinal cord. We will injure rats soon after birth, a time when these connections are plastic and the opportunity for compensation is highest. We then measure the response of these spared systems using two novel techniques-retrograde transsynaptic tracing using pseudorabies virus, and stereological quantification of axonal connections. Thus, we will determine which spared system sprouts greater connections in response to injury. In adult rats with neonatal injury to one half of the CST, we will test the functional limits of pathway compensation. We will use both novel and proven tests of functions that depend critically on the CST: reaching to grasp, walking over a ladder, food manipulation, and control of a spinal cord reflex. We predict that there will be incomplete recovery of the specialized motor skills. For functions that do recover, we will temporarily inactivate each of the two spared pathways, by infusing an inhibitor of neural activity, to test their contribution to recovery. We expect that the recovered functions will be lost transiently in the pathway that shows the greatest amount of injury-induced plasticity. Finally, we will selectively activate the most adaptive circuit to try to improve upon endogenous recovery. Using chronic stimulation through an implanted electrode, we intend to harness activity-dependent plasticity to strengthen motor connections. We predict that these targeted manipulations will create a more adaptive pattern of brain- spinal cord connections, as measured by tracing and stimulation techniques, and help to restore function, based on the aforementioned motor tasks. Many human infants, especially those born prematurely, sustain injury to the CST. This often results in paralysis and spasticity on one side of the body. Activity, in the form of physical therapy and non-invasive brain stimulation can be used to alter connections in humans. These studies will help to determine where activity should be applied in order to strengthen the circuits that mediate spontaneous recovery. Thus, we use anatomically precise injury, tracing, inactivation, and stimulation to determine the circuit-level logic for repair of the motor systems. This could improve our ability to restore function in people with early brain injury.