Repairing maladaptive corticospinal tract development

修复适应不良的皮质脊髓束发育

• 批准号: 8842211
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842211
• 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; Health; Human; 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; 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）：皮质脊髓道（CST）是熟练运动控制的关键。在开发过程中，由于开发CST轴突以建立与脊柱运动电路的连接之间，CST损伤可能比成熟度相似的损害更复杂。在建立脊柱连接方面，更多的活性CST神经元比不活跃的CST神经元更具有竞争力。与脊柱电机电路的连接丧失导致受损或移动损失。通过反应性轴突在脊髓中发芽的新CST连接的竞争增益会导致新的，潜在的适应不良功能。在人类中，发育过程中的CST损伤会产生脑瘫，这是一种常见且毁灭性的发育性运动障碍。人们认为痉挛，肢体不合规，刻板印象的运动协同作用和脑瘫中的镜像运动被认为是由新的不良适应性CST连接产生的。 要测试的总体假设是，发育过程中的单侧CST损伤保留了容易受到进一步损失的对侧CST轴突。保险的CST轴突在建立对侧连接方面的竞争力较低，因为它们在激活脊柱电机电路中的效率较低。我们建议，随着无参与半球的完整CST的完整CST会形成强大的同侧脊柱连接，从而加强并消除受损的CST，因此这种竞争不利的劣势会恶化。我们进一步提出，完整的脑干途径也施加了竞争压力。我们旨在通过使保留的CST轴突通过直接激活或通过停用和失效来建立脊柱连接的竞争力来修复损坏的CST连接并恢复运动功能。 AIM 1直接检验以下假设：从每个半球发育中的CST之间的活动依赖性竞争中的不平衡会产生一个恶性循环：开发早期受伤的CST逐渐失去了其驱动对侧脊柱运动回路的能力，因为未经损害的CST发展了新的双边连接和双侧运动控制功能。我们的目标是通过重定向活动依赖性竞争来恢复受损方面的对侧连接和功能。我们将使用我们开发的慢性电生理记录技术测定连通性和功能的变化。这种新方法将允许对发展可塑性进行实时评估，并在分阶段的急性实验中实现测试假设。 AIM 2使用带有双侧CST和镜像运动的新小鼠模型来检验假设，如脑瘫。双侧CST和异常控制是表达的，不是像其他模型那样对损伤或不活动的反应，而是通过对EPHA4受体的条件切除产生的CST轴突引导缺陷。反应性模型在临床上是相关的，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，因此其连接和功能丢失了。使用这种新模型，我们取消了这些替代方案和利用活动依赖性竞争，以促进对侧CST功能。 AIM 3测试了发育中的皮质脊髓和脑干系统之间的新型活动依赖性竞争。我们将检验以下假设：发育中的CST，Rubrospinal道（RST）和网状脊髓区域（REST）竞争获得脊柱运动电路的竞争。限制皮质脊髓系统活动，导致CST脊柱连接和运动障碍异常，将使RST/REST能够胜任CST进行脊柱连接。尽管这可能有助于恢复功能，因为与CST相比，RST和REST功能受到限制，因此运动技能仍然受损。我们建议，更强的脑干系统意味着CST弱。