Repairing maladaptive corticospinal tract development

修复适应不良的皮质脊髓束发育

• 批准号: 8597664
• 负责人: John H Martin
• 金额: $ 33.47万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597664
• 关键词: Ablation; Abnormal coordination; Acute; Affect; Age; Animal Model; Axon; Behavioral; Bilateral; Biological Assay; Birth; Brain Stem; Cerebral Palsy; Chronic; Complement; Complex; Contralateral; Corticospinal Tracts; Defect; Development; Disadvantaged; EphA4 Receptor; Excision; Felis catus; Fostering; Genes; Genetic; Human; Impairment; Infarction; Injury; Intervention; Ipsilateral; Lead; Lesion; Limb structure; Mammals; Methods; Modeling; Motor; Motor Cortex; Motor Skills; Movement; Mus; Muscle; Neurons; Paralysed; Pathway interactions; Pattern; Plastics; Reaction; Side; Spinal; Spinal Cord; Staging; Stroke; Structure of rubrospinal tract; System; Techniques; Testing; Time; Visual system structure; awake; axon guidance; base; central nervous system injury; clinically relevant; developmental disease; developmental plasticity; functional restoration; injured; loss of function; mature animal; motor control; motor disorder; motor impairment; mouse model; novel; novel strategies; novel therapeutics; partial recovery; postnatal; pressure; programs; public health relevance; receptor; repaired; research study; reticulospinal tract; therapeutic target

DESCRIPTION (provided by applicant): The corticospinal tract (CST) is key to skilled motor control. During development, CST damage can have more complex effects than similar damage in maturity because of robust activity-dependent competition between developing CST axons for establishing connections with spinal motor circuits. More active CST neurons are more competitive than less active CST neurons in establishing spinal connections. Loss of CST connections with spinal motor circuit's leads to impaired or loss of movement. Competitive gain of new CST connections by reactive axon sprouting in the spinal cord leads to new, potentially maladaptive, functions. In humans, CST injury during development can produce cerebral palsy, a common and devastating developmental motor disorder. Spasticity, limb incoordination, stereotypic motor synergies, and mirror movements in cerebral palsy are thought to be produced by new maladaptive CST connections. The overall hypothesis to be tested is that unilateral CST injury during development leaves spared contralateral CST axons vulnerable to further loss. Spared CST axons are less competitive in establishing their contralateral connections because they are less effective than normal in activating spinal motor circuits. We propose that this competitive disadvantage worsens as the intact CST from the noninvolved hemisphere develops robust ipsilateral spinal connections that strengthen and out compete the damaged CST. We further propose that competitive pressure is also exerted by the intact brain stem pathways. We aim to repair damaged CST connections and restore motor function by making spared CST axons more competitive in establishing spinal connections through direct activation or by making the undamaged systems less competitive by deactivation and disuse. Aim 1 directly tests the hypothesis that imbalance in activity-dependent competition between the developing CSTs from each hemisphere creates a vicious circle: the CST injured early in development progressively loses its capacity to drive contralateral spinal motor circuits, as the undamaged CST develops new bilateral connections and bilateral motor control functions. We aim to interrupt the circle to restore contralateral connections and function of the impaired side by redirecting activity-dependent competition. We will assay changes in connectivity and function in awake behaving cats using chronic electrophysiological recording techniques we have developed. This new approach will allow real-time assessment of developmental plasticity and enable testing hypotheses not possible in staged, acute experiments. Aim 2 tests the hypothesis using a new mouse model with bilateral CSTs and mirror movements, as in cerebral palsy. Bilateral CSTs and aberrant control are expressed, not by reaction to injury or inactivity as in other models, but by a CST axon guidance defect produced by conditional excision of the gene for EphA4 receptor. Reactive models are clinically relevant but cannot distinguish if the ipsilateral CST is maladaptive because of aberrant connections or, because it outcompetes the contralateral CST, so that its connections and functions are lost. Using this new model, we uncouple these alternatives and harness activity-dependent competition to promote greater contralateral CST function. Aim 3 tests a novel activity-dependent competition between the developing corticospinal and brain stem systems. We will test the hypothesis that the developing CST, rubrospinal tract (RST) and reticulospinal tracts (ReST) compete for access to spinal motor circuits. Restricting corticospinal system activity, which leads to aberrant CST spinal connections and motor impairment, will enable the RST/ReST to outcompete the CST for spinal connections. Whereas this could help restore function, since the RST and ReST functions are limited compared with the CST, motor skills remain impaired. Stronger brain stem systems, we propose, means a weakened CST. !

描述（由申请人提供）：皮质脊髓束（CST）是熟练运动控制的关键。在发育过程中，由于发育中的CST轴突之间建立与脊髓运动回路的连接的强大的活动依赖性竞争，CST损伤可能比成熟时的类似损伤具有更复杂的影响。在建立脊髓连接方面，更活跃的CST神经元比不太活跃的CST神经元更具竞争力。CST与脊髓运动回路连接的丧失导致运动受损或丧失。通过脊髓中的反应性轴突发芽竞争性获得新的CST连接，导致新的潜在适应不良的功能。在人类中，发育期间的CST损伤可导致脑瘫，这是一种常见的破坏性发育运动障碍。痉挛，肢体不协调，刻板的运动协同作用，并在脑瘫镜像运动被认为是由新的适应不良的CST连接。 待检验的总体假设是，发育过程中单侧CST损伤使对侧CST轴突易于进一步丧失。脊髓背角CST轴突在建立对侧连接方面的竞争力较低，因为它们在激活脊髓运动回路方面不如正常人有效。我们认为，这种竞争劣势是由于来自未受累半球的完整CST发展了强大的同侧脊髓连接，加强并超越受损的CST。我们进一步提出，竞争压力也施加了完整的脑干通路。我们的目标是修复受损的CST连接和恢复运动功能，使备用的CST轴突更有竞争力，通过直接激活建立脊髓连接或通过使未受损的系统失活和废用竞争力降低。 目的1直接测试的假设，即不平衡的活动依赖的竞争之间的发展中的CST从每个半球创建一个恶性循环：在发展早期受损的CST逐渐失去其能力，以驱动对侧脊髓运动回路，作为未受损的CST开发新的双边连接和双边运动控制功能。我们的目标是中断循环，通过重新定向活动依赖性竞争来恢复受损侧的对侧连接和功能。我们将使用我们开发的慢性电生理记录技术来分析清醒行为猫的连接和功能的变化。这种新方法将允许实时评估发育可塑性，并使测试假设不可能在分阶段，急性实验。 目的2使用双侧CST和镜像运动的新小鼠模型来测试这一假设，如脑瘫。双侧CST和异常控制的表达，而不是在其他模型中的损伤或不活动的反应，但CST轴突导向缺陷产生的EphA 4受体基因的条件切除。反应性模型具有临床相关性，但无法区分同侧CST是否因异常连接而适应不良，或者因为它胜过对侧CST，因此其连接和功能丢失。使用这个新的模型，我们解开这些替代品和利用活动依赖的竞争，以促进更大的对侧CST功能。 目的3测试一种新的活动依赖性竞争之间的发展皮质脊髓和脑干系统。我们将测试的假设，发展中的CST，红核脊髓束（RST）和网状脊髓束（ReST）竞争进入脊髓运动回路。限制皮质脊髓系统的活动，导致异常的CST脊髓连接和运动障碍，将使ESTA/ReST竞争脊髓连接的CST。虽然这可能有助于恢复功能，但由于与CST相比，ESTA和ReST功能有限，运动技能仍然受损。我们认为，更强的脑干系统意味着更弱的CST。!