Injury and adaptation in the developing rat corticospinal and rubrospinal tracts

描述（由申请人提供）：总结：大多数脑或脊髓损伤在大脑发起运动的区域和脊髓产生运动的区域之间都没有一些连接。运动恢复的一个关键问题是保留的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，这是人类自主运动的主要途径。连接运动皮层和脊髓的CST控制精细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失去功能的能力。具体来说，我们将检查两个回路：1)通过其稀疏的同侧投影的未受伤的CST的一半，以及2)从皮层到红核到脊髓的受伤侧旁路回路。我们会在老鼠出生后不久伤害它们，因为那时这些联系是可塑的，获得补偿的机会是最高的。然后，我们使用两种新技术-利用伪狂犬病毒逆行跨突触追踪和轴突连接的立体学量化来测量这些免疫系统的反应。因此，我们将确定哪个幸免系统在对损伤作出反应时产生更大的连接。在新生时一半CST损伤的成年大鼠中，我们将测试通路补偿的功能极限。我们将使用新的和成熟的功能测试，这些功能主要依赖于CST：伸手抓握，在梯子上行走，食物操作和脊髓反射的控制。我们预测会有不完全的特殊运动技能恢复。对于恢复的功能，我们将通过注入一种神经活动抑制剂来暂时停用两条未激活的通路，以测试它们对恢复的贡献。我们预计，恢复的功能将在表现出最大数量的损伤诱导可塑性的通路中短暂丧失。最后，我们将有选择地激活适应性最强的回路，试图改善内源性恢复。通过植入电极的慢性刺激，我们打算利用活动依赖的可塑性来加强运动连接。我们预测，通过追踪和刺激技术测量，这些有针对性的操作将创造一种更具适应性的脑脊髓连接模式，并有助于恢复基于上述运动任务的功能。许多人类婴儿，特别是早产儿，会遭受CST损伤。这通常会导致身体一侧的麻痹和痉挛。活动，以物理治疗和非侵入性脑刺激的形式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，以加强介导自发恢复的回路。因此，我们使用解剖学上精确的损伤、追踪、失活和刺激来确定运动系统修复的回路级逻辑。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.