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: 8240682
• 负责人: Jason Brant Carmel
• 金额: $ 17.18万
• 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/8240682
• 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; 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. PUBLIC HEALTH RELEVANCE: Perinatal brain injury affects more than two in a thousand infants and can cause lasting paralysis and spasticity. In identifying alterations in brain-spinal cord connections caused by neonatal injury, these studies will help to understand why paralysis occurs and which connections need to be repaired. New strategies to selectively and non-invasively stimulate the brain can then be used to support certain brain-spinal cord connections and possibly restore function.!

描述（由申请人提供）：摘要：大脑或脊髓的大部分受伤避免了启动运动的大脑区域与产生运动的脊髓区域之间的一些联系。恢复运动的关键问题是避免的连接可以补偿受伤的连接的程度。我们将研究不受欢迎的运动途径对皮质脊髓束损伤（CST）的适应，这是人类自愿运动的主要途径。将电动机皮质连接到脊髓的CST控制精细的手动运动并调节脊髓反射。我们将从一个半球中切掉CST发出的CST，并测试蓄能电路接管丢失功能的能力。具体来说，我们将检查两个电路：1）CST的一半未受伤的同侧投影，以及2）受伤侧的旁路电路，从皮质到红色核到脊髓。我们将在出生后不久伤害大鼠，这些连接是塑料，赔偿机会最高的时候。然后，我们使用两种新型技术 - 反射式透射式追踪使用伪标记病毒和轴突连接的立体定量来测量这些较低的系统的响应。因此，我们将确定响应伤害的较高的系统芽型较高的连接。在新生儿损伤到CST的一半的成年大鼠中，我们将测试途径补偿的功能限制。我们将同时使用新颖的和经过验证的功能测试，这些功能严重取决于CST：伸手抓住，走过梯子，食物操纵以及控制脊髓反射的功能。我们预测，专业运动技能将不完整。对于确实恢复的功能，我们将通过注入神经活动的抑制剂来测试其对恢复的贡献，从而暂时使两种幸运的途径中的每一个失活。我们预计恢复的功能将在显示最大损伤引起的可塑性的途径中瞬时丢失。最后，我们将选择性地激活最适应性的电路，以尝试在内源性恢复后改善。通过植入电极使用慢性刺激，我们打算利用活动依赖性可塑性来增强运动连接。我们预测，这些有针对性的操作将创建一种通过追踪和刺激技术来衡量的脑脊髓连接模式，并根据上述运动任务有助于恢复功能。许多人，尤其是那些过早出生的婴儿对CST的伤害。这通常会导致身体一侧的瘫痪和痉挛。以物理疗法和非侵入性脑刺激的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哪里应用活动，以加强介导自发恢复的电路。因此，我们使用解剖上精确的损伤，追踪，灭活和刺激来确定电路级逻辑以修复运动系统。这可以提高我们恢复早期脑损伤患者功能的能力。 公共卫生相关性：围产期脑损伤影响一千个婴儿的两名以上，并可能导致持久的瘫痪和痉挛。在确定由新生儿损伤引起的脑脊髓连接的改变时，这些研究将有助于理解瘫痪的原因以及需要修复哪些连接。然后可以使用新的策略和非侵入性刺激大脑，以支持某些脑脊髓连接并可能恢复功能。