Injury and adaptation in the developing rat corticospinal and rubrospinal tracts

发育中的大鼠皮质脊髓和红核脊髓束的损伤和适应

• 批准号: 8523984
• 负责人: Jason Brant Carmel
• 金额: $ 18.46万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523984
• 关键词: Adult; Affect; Area; Axon; Birth; Brain; Brain Injuries; Bypass; Cerebral Palsy; Child; Chronic; Corticospinal Tracts; Electric Stimulation; Figs - dietary; Financial compensation; Food; Goals; Hand; Human; Hyperreflexia; Implanted Electrodes; Infant; Injury; Ipsilateral; Learning; Limb structure; Logic; Measures; Mediating; Methods; Modeling; Motor; Motor Cortex; Motor Pathways; Motor Skills; Movement; Neonatal; Paralysed; Pathway interactions; Pattern; Perinatal Brain Injury; Physical therapy; Plastics; Posture; Rattus; Recovery; Red nucleus structure; Reflex action; Relative (related person); Side; Spinal; Spinal Cord; Structure of rubrospinal tract; Suid Herpesvirus 1; System; Techniques; Testing; Time; Viral; Walking; base; density; disability; feeding; functional restoration; grasp; improved; inhibitor/antagonist; injured; juvenile animal; mature animal; motor control; motor function recovery; neural circuit; novel; relating to nervous system; repaired; response; response to injury; skills; visual motor

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.

描述（由申请人提供）： 摘要：大多数大脑或脊髓损伤都会保留启动运动的大脑区域和产生运动的脊髓区域之间的一些连接。运动恢复的一个关键问题是备用连接可以在多大程度上补偿受伤的连接。我们将研究幸存的运动通路对皮质脊髓束（CST）损伤的适应，皮质脊髓束是人类自主运动的主要通路。 CST 连接运动皮层和脊髓，控制精细的手部运动并调节脊髓反射。我们将切断来自一个半球的 CST，并测试备用电路接管丢失功能的能力。具体来说，我们将检查两个回路：1）未受伤的一半 CST 通过其稀疏的同侧投影，2）受伤侧从皮质到红核到脊髓的旁路回路。我们会在老鼠出生后不久伤害老鼠，此时这些联系是可塑的，获得补偿的机会最高。然后，我们使用两种新技术测量这些幸免系统的反应——使用伪狂犬病病毒的逆行突触追踪和轴突连接的体视定量。因此，我们将确定哪个幸存的系统会在受伤时产生更多的连接。在一半 CST 受到新生损伤的成年大鼠中，我们将测试通路补偿的功能极限。我们将使用关键依赖于 CST 的新颖且经过验证的功能测试：伸手抓握、在梯子上行走、食物操作和脊髓反射的控制。我们预测专业运动技能的恢复将不完全。对于确实恢复的功能，我们将通过注入神经活动抑制剂来暂时灭活两条幸存的通路，以测试它们对恢复的贡献。我们预计恢复的功能将在显示出最大程度的损伤诱导可塑性的途径中短暂丧失。最后，我们将有选择地激活最具适应性的电路，以尝试改善内源性恢复。通过植入电极进行慢性刺激，我们打算利用活动依赖性可塑性来加强运动连接。我们预测，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（通过追踪和刺激技术测量），并根据上述运动任务帮助恢复功能。许多人类婴儿，尤其是早产婴儿，CST 都会受到损伤。这通常会导致身体一侧瘫痪和痉挛。物理治疗和非侵入性大脑刺激形式的活动可用于改变人类的联系。这些研究将有助于确定应在何处进行活动，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。