Characterization of lumbar plasticity and remote injury mechanisms after SCI

描述（由申请人提供）：人类脊髓损伤（SCI）导致永久性功能障碍。丧失行动能力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枢模式发生器（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，因为活动依赖性可塑性在脊髓中是丰富的。通过训练，脊髓神经元重新学习启动运动的组成部分，尽管失去了下行驱动。为了诱导SCI后最强大的学习和恢复，我们假设训练必须尽早进行，以利用CNS可塑性的峰值。不幸的是，过早提供的训练干预未能产生功能改善，甚至破坏震中的神经血管完整性。直接的细胞障碍仍然不清楚，因为SCI的后遗症是复杂的，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损伤部位越来越远的地方。很明显，神经胶质反应性和细胞因子的产生是SCI后继发性发病机制的核心。这些过程对运动CPGs区域内运动再学习的影响尚未得到研究。SCI是否诱导了阻止运动再学习的早期微环境？在损伤部位的早期病理学的有效介质是基质金属蛋白酶-9（MMP-9）。在中心，MMP-9促进白细胞浸润并切割许多细胞因子和趋化因子。在这个建议中，我们提出了第一个证据，MMP-9的活性远离损伤的腰髓在急性期。我们打算检验这一假设，即挫伤性SCI导致MMP-9的早期远程生产，防止保留诱导的可塑性和运动再学习。我们的策略包括操纵MMP-9的远程活动与SCI后早期跑步机训练相结合。使用一种新的脊髓学习范例，我们将研究腰骶段的孤立能力，以确定可塑性的运动CPGs。在我们的实验过程中，我们将确定运动再学习的最佳环境。我们的初步数据表明，MMP-9的去除减弱了远程炎症，并与早期TM训练相结合，促进适应性可塑性和强大的运动恢复。我们的研究结果将提供一个单独的治疗腰髓损伤结合早期TM训练的治疗潜力。 公共卫生相关性：脊髓损伤（SCI）导致贯穿神经轴的双重和相互冲突的机制。迄今为止，远距离损伤级联的功能影响仍然知之甚少。我们以前发现激活的小胶质细胞和细胞因子的表达10节段的损伤部位在腰髓。远端神经胶质病变的发现可能表明突触稳态的破坏。我们认为，脊髓损伤后早期腰椎增大的远端机制导致训练无效。MMP-9是一种有效的调节剂， 在急性损伤阶段的炎症过程。在这里，我们提出，远程生产的MMP-9阻碍突触功能和它的抑制将创造一个宽容的环境，为节省诱导和活动依赖性可塑性。我们概述了新的实验来阐明SCI后远程损伤反应的功能意义。

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.