Repairing maladaptive corticospinal tract development

修复适应不良的皮质脊髓束发育

基本信息

批准号：
9256549
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256549
关键词：
Ablation Abnormal coordination Acute Affect Age Anatomy Animal Model Axon Behavioral Bilateral Biological Assay Birth Brain Stem Cerebral Palsy Chronic Complement Complex Contralateral Corticospinal Tracts Defect Development Disadvantaged Electrophysiology (science)EphA4 Receptor Excision Felis catus Fostering Genes Genetic Human Impairment Infarction Injury Interruption Intervention Ipsilateral Lead Lesion Limb structure Mammals Methods Modeling Motor Motor Cortex Motor Skills Movement Mus Muscle Neurons Paralysed Pathway interactions Pattern Plasticizers Reaction Side Spastic Spinal Spinal Cord Stroke Structure of rubrospinal tract System Techniques Testing Time Visual system structure awake axon guidance base brain repair central nervous system injury clinically relevant developmental disease developmental plasticity experimental study 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 public health relevance receptor repaired reticulospinal tract spasticity spinal tract synergism therapeutic target

项目摘要

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，CST 损伤可能比成熟时的类似损伤产生更复杂的影响，因为发育中的 CST 轴突之间存在激烈的活动依赖性竞争，以建立与脊髓运动回路的连接。更活跃的 CST 神经元在建立脊髓连接方面比不活跃的 CST 神经元更具竞争力。 CST 与脊髓运动回路失去连接会导致运动受损或丧失。通过脊髓中的反应性轴突萌发，竞争性获得新的 CST 连接会导致新的、潜在的适应不良功能。在人类中，发育过程中的 CST 损伤可导致脑瘫，这是一种常见且具有破坏性的发育性运动障碍。脑瘫中的痉挛、肢体不协调、刻板运动协同和镜像运动被认为是由新的适应不良的 CST 连接产生的。要测试的总体假设是，发育过程中的单侧 CST 损伤会使幸存的对侧 CST 轴突容易进一步损失。幸存的 CST 轴突在建立对侧连接方面竞争力较差，因为它们在激活脊髓运动回路方面不如正常轴突有效。我们认为，随着来自非受累半球的完整 CST 发展出强大的同侧脊柱连接，增强并超越受损 CST，这种竞争劣势会恶化。我们进一步提出，完整的脑干通路也可以施加竞争压力。我们的目标是通过直接激活使幸存的 CST 轴突在建立脊柱连接方面更具竞争力，或通过失活和废弃来降低未受损系统的竞争力，从而修复受损的 CST 连接并恢复运动功能。目标 1 直接检验了以下假设：每个半球发育中的 CST 之间的活动依赖性竞争不平衡会造成恶性循环：在发育早期受伤的 CST 逐渐失去驱动对侧脊髓运动回路的能力，因为未受损的 CST 会发展出新的双边连接和双边运动控制功能。我们的目标是通过重新定向依赖于活动的竞争来打断循环，以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通性和功能的变化。这种新方法将允许实时评估发育可塑性，并能够测试分阶段的急性实验中不可能的假设。目标 2 使用具有双侧 CST 和镜像运动（如脑瘫）的新小鼠模型来测试该假设。双侧 CST 和异常控制的表达不是像其他模型那样通过对损伤或不活动的反应，而是通过条件性切除 EphA4 受体基因产生的 CST 轴突引导缺陷来表达。反应性模型具有临床相关性，但无法区分同侧 CST 是否由于异常连接而适应不良，或者因为它胜过对侧 CST，从而导致其连接和功能丧失。使用这个新模型，我们将这些替代方案解耦，并利用依赖于活动的竞争来促进更大的对侧 CST 功能。目标 3 测试了正在发育的皮质脊髓系统和脑干系统之间的一种新颖的依赖于活动的竞争。我们将检验以下假设：正在发育的 CST、红核脊髓束 (RST) 和网状脊髓束 (ReST) 竞争进入脊髓运动回路。限制皮质脊髓系统活动会导致 CST 脊柱连接异常和运动障碍，这将使 RST/ReST 能够在脊柱连接方面胜过 CST。尽管这可能有助于恢复功能，但由于 RST 和 ReST 功能与 CST 相比有限，因此运动技能仍然受损。我们认为，更强的脑干系统意味着更弱的脑干系统。