Repairing maladaptive corticospinal tract development

修复适应不良的皮质脊髓束发育

• 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
• 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

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）是熟练控制运动的关键。在发育过程中，CST损伤可能比成熟时的类似损伤具有更复杂的影响，因为在发育中的CST轴突之间存在强大的活动依赖性竞争，以建立与脊髓运动回路的连接。在建立脊髓连接方面，活跃的CST神经元比不活跃的CST神经元更具竞争性。CST与脊髓运动回路的连接缺失导致运动受损或丧失。通过反应性轴突在脊髓中萌发，竞争性地获得新的CST连接，导致新的、潜在的不适应功能。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。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不适应CST连接产生的。要验证的总体假设是，发育过程中单侧CST损伤使对侧CST轴突免于进一步损失。不受影响的CST轴突在建立对侧连接方面的竞争力较弱，因为它们在激活脊髓运动回路方面不如正常的有效。我们认为，当来自非受累半球的完整CST发展出强大的同侧脊髓连接时，这种竞争劣势会加剧，从而加强并淘汰受损的CST。我们进一步提出，竞争压力也由完整的脑干通路施加。我们的目标是修复受损的CST连接并恢复运动功能，通过直接激活使未受损的CST轴突在建立脊髓连接时更具竞争力，或通过失活和废弃使未受损的系统降低竞争力。Aim 1直接验证了一个假设，即来自两个半球的CST在活动依赖性竞争中的不平衡造成了一个恶性循环：在发育早期受损的CST逐渐失去驱动对侧脊髓运动回路的能力，而未受损的CST则发展出新的双侧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中断这个循环，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检测清醒行为猫的连接和功能变化。这种新方法将允许对发育可塑性进行实时评估，并使在分阶段的急性实验中无法测试的假设成为可能。目的2使用具有双侧CSTs和镜像运动的新小鼠模型（如脑瘫）来验证这一假设。与其他模型不同，双侧CST和异常控制不是通过损伤或不活动的反应表达的，而是通过条件切除EphA4受体基因产生的CST轴突引导缺陷表达的。反应性模型在临床上是相关的，但不能区分同侧CST是由于异常连接而适应不良，还是因为与对侧CST竞争而失去连接和功能。使用这个新模型，我们解开了这些选择，并利用活动依赖的竞争来促进更大的对侧CST功能。目的3测试在发育中的皮质脊髓和脑干系统之间的一种新的活动依赖性竞争。我们将检验发育中的CST、rubrospinal tract （RST）和网状脊髓束（ReST）竞争进入脊髓运动回路的假设。限制皮质脊髓系统活动，导致CST异常的脊髓连接和运动障碍，将使RST/ReST在脊髓连接方面胜过CST。虽然这可能有助于恢复功能，但由于RST和ReST功能与CST相比有限，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。

项目成果

Motor Cortex Activity Organizes the Developing Rubrospinal System.

运动皮层活动组织发育中的红核脊髓系统。

• DOI: 10.1523/jneurosci.1719-15.2015
• 发表时间: 2015
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Williams,PrestonTJA;Martin,JohnH
• 通讯作者: Martin,JohnH