Repairing maladaptive corticospinal tract development

描述(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损伤可能比成熟阶段的类似损伤具有更复杂的影响，这是因为发育中的CST轴突与脊髓运动神经回路建立连接的强烈活动依赖竞争。在建立脊髓连接时，较活跃的CST神经元比较不活跃的CST神经元更具竞争力。CST与脊髓运动回路的连接丢失会导致运动障碍或丧失。新的CST连接通过脊髓内反应性轴突萌发而竞争获得，导致新的、潜在的适应不良的功能。在人类中，发育过程中的CST损伤会产生脑性瘫痪，这是一种常见的破坏性发育运动障碍。脑性瘫痪的痉挛、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的CST连接产生的。有待检验的总体假设是，在发育过程中，单侧CST损伤使对侧CST轴突免于进一步丢失。备用的CST轴突在建立其对侧连接方面竞争力较弱，因为它们在激活脊髓运动神经回路方面不如正常。我们认为，这种竞争劣势会恶化，因为来自非受累大脑半球的完整的CST发展出健壮的同侧脊髓连接，加强和竞争受损的CST。我们进一步提出，完整的脑干通路也施加了竞争压力。我们的目标是修复受损的CST连接并恢复运动功能，方法是通过直接激活使备用的CST轴突在建立脊髓连接方面更具竞争力，或者通过去激活和停用来降低未受损的系统的竞争力。目的1直接验证这一假说，即大脑两侧发育中的CST之间的活动依赖竞争的不平衡造成恶性循环：发育早期受损的CST逐渐失去驱动对侧脊髓运动神经回路的能力，而未受损的CST发展新的双侧连接和双侧运动控制功能。我们的目标是通过改变依赖活动的竞争的方向来中断这个循环，以恢复受损一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性和功能的变化。这一新方法将允许实时评估发育可塑性，并使测试假设在阶段性、急性实验中是不可能的。目的2用一种新的双侧CST和镜像运动的小鼠模型来验证这一假说，就像脑瘫一样。与其他模型不同，双侧CST和异常控制不是通过对损伤或不活动的反应，而是通过有条件地切除EphA4受体基因而产生的CST轴突引导缺陷。反应性模型在临床上是相关的，但不能区分同侧CST是因为异常连接而适应性不良，还是因为它的竞争优势超过了对侧CST，从而使其连接和功能丧失。使用这个新的模型，我们分离了这些替代方案，并利用活动依赖的竞争来促进更大的对侧CST功能。AIM 3测试了发育中的皮质脊髓和脑干系统之间的一种新的依赖活动的竞争。我们将检验这一假设，即发育中的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会导致CST脊椎连接异常和运动障碍，这将使RST/REST在脊髓连接方面胜过CST。虽然这可以帮助恢复功能，但由于与CST相比，RST和REST的功能有限，运动技能仍然受损。我们认为，更强大的脑干系统意味着CST的削弱。

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.