Characterization of lumbar plasticity and remote injury mechanisms after SCI

描述(申请人提供)：人类脊髓损伤(SCI)导致永久性功能损害。机动性的丧失是最明显和最令人衰弱的后果之一。基于活动的跑步机(TM)训练试图通过向脊髓中央模式生成器(CPG)提供传入感觉输入来促进步行的恢复。这种方法显示出巨大的潜力，因为脊髓中存在丰富的依赖活动的可塑性。通过训练，脊髓神经元重新学习启动运动组件，尽管失去了下行驱动。为了诱导脊髓损伤后最强健的学习和恢复，我们假设训练必须及早进行，以利用中枢神经系统的可塑性高峰。不幸的是，过早提供的训练干预无法改善功能，甚至破坏了震中神经血管的完整性。直接的细胞障碍仍不清楚，因为脊髓损伤的后遗症很复杂，并导致一系列功能障碍。重要的是，炎症机制在损伤后迅速扩散到离病变部位越来越远的地方。很明显，胶质细胞的反应性和细胞因子的产生是脊髓损伤后继发性发病的核心。这些过程对运动CPG区域内运动再学习的影响仍未得到检验。脊髓损伤是否诱导了阻止运动再学习的早期微环境？基质金属蛋白酶-9(MMP9)是损伤部位早期病理的一个强有力的中介。在震中，基质金属蛋白酶-9促进白细胞的渗透，并裂解一些细胞因子和趋化因子。在这项建议中，我们提出了第一个证据表明，在急性期，基质金属蛋白酶-9活性远离损伤的腰髓。我们打算检验这一假说，即挫伤脊髓损伤会导致早期远程产生基质金属蛋白酶-9，从而防止节制诱导的可塑性和运动再学习。我们的策略包括操纵基质金属蛋白酶-9的远程活动，并结合脊髓损伤后的早期跑步机训练。使用一种新的脊髓学习范式，我们将检查腰椎节段的孤立容量来确定运动CPG的可塑性。在我们的实验过程中，我们将确定一个最佳的运动再学习环境。我们的初步数据表明，去除基质金属蛋白酶-9可减轻远端炎症，结合早期TM训练可促进适应性可塑性和强健的运动恢复。我们的研究结果将为腰髓损伤的单独治疗结合早期TM训练提供治疗潜力。 公共卫生相关性：脊髓损伤(SCI)导致整个神经轴的双重和相互冲突的机制。到目前为止，远距离损伤级联反应的功能影响仍然知之甚少。我们之前在腰髓损伤部位发现了激活的小胶质细胞和细胞因子表达的10个节段。远端神经胶质病的发现可能表明突触内稳态被破坏。我们认为腰椎膨大的远距离机制是脊髓损伤后早期训练无效的原因。基质金属蛋白酶-9是早期的一种强有力的调节因子 损伤急性期的炎症过程。在这里，我们认为，远距离产生的基质金属蛋白酶-9阻碍突触功能，它的抑制将创造一个允许的环境，既有节制诱导的可塑性，也有活性依赖的可塑性。我们概述了新的实验，以阐明脊髓损伤后远程损伤反应的功能含义。

DESCRIPTION (provided by applicant): Human spinal cord injury (SCI) results in permanent functional impairments. A loss in mobility is one of the most noticeable and debilitating consequences. Activity-based treadmill (TM) training attempts to promote recovery of walking by providing afferent sensory input to spinal central pattern generators (CPGs). This approach shows great potential, as activity-dependent plasticity is abundant in the spinal cord. With training, spinal neurons relearn to initiate components of locomotion despite lost descending drive. To induce the most robust learning and recovery after SCI, we hypothesize that training must occur early to take advantage of peak CNS plasticity. Unfortunately, training interventions that are delivered too early fail to produce functional improvement and even disrupt neurovascular integrity at the epicenter. Direct cellular impediments remain unclear, as the sequela of SCI is complex and leads to a host of dysfunction. Importantly, inflammatory mechanisms spread to progressively greater distances from the lesion site acutely after injury. It is clear that glial reactivity and cytokine production are central to secondary pathogenesis after SCI. The influence of these processes on motor relearning within regions of locomotor CPGs remains unexamined. Does SCI induce an early microenvironment that prevents motor relearning? A potent mediator of early pathology at the injury site is matrix metalloproteinase-9 (MMP-9). At the epicenter, MMP-9 facilitates leukocyte infiltration and cleaves a number of cytokines and chemokines. In this proposal, we present the first evidence of MMP-9 activity away from the injury in the lumbar cord during acute stages. We intend to test the hypothesis that contusive SCI results in early remote production of MMP-9 that prevents sparing-induced plasticity and motor re-learning. Our strategy involves manipulating remote activity of MMP-9 in conjunction with early treadmill training after SCI. Using a novel spinal learning paradigm; we will examine the isolated capacity of lumbosacral segments to determine plasticity of locomotor CPGs. Over the course of our experiments, we will identify an optimal environment for motor relearning. Our preliminary data suggests that removal of MMP-9 attenuates remote inflammation and in combination with early TM training promotes adaptive plasticity and robust locomotor recovery. Findings from our work will provide therapeutic potential for an isolated treatment to the lumbar cord injury in conjunction with early TM training. PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) results in dual and conflicting mechanisms throughout the neuraxis. To date, functional implications of distant injury cascades remain poorly understood. We previously found activated microglia and cytokine expression 10 segments from the site of injury in the lumbar cord. Findings of remote gliopathy may indicate a disruption of synaptic homeostasis. We suggest that distant mechanisms in the lumbar enlargement contribute to training inefficacy early after SCI. MMP-9 is a potent regulator of early inflammatory processes during acute stages of injury. Here, we propose that remote production of MMP-9 impedes synaptic function and its inhibition will create a permissive environment for both sparing-induced and activity-dependent plasticity. We outline novel experiments to elucidate functional implications of the remote injury response after SCI.