Characterization of lumbar plasticity and remote injury mechanisms after SCI

SCI 后腰椎可塑性和远程损伤机制的表征

• 批准号: 8398636
• 负责人: Christopher N. Hansen
• 金额: $ 3.64万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398636
• 关键词: Acute; Affect; Attention; Attenuated; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Chemosensitization; Chronic; Cleaved cell; Clinical; Complex; Conflict (Psychology); Contusions; Cytokine Activation; Data; Distant; Educational Intervention; Environment; Enzyme-Linked Immunosorbent Assay; Event; Excision; Fluorescence Resonance Energy Transfer; Functional disorder; Gelatin Zymography; Gelatinase B; Gelatinases; Hippocampus (Brain); Homeostasis; Human; Immunohistochemistry; In Situ; Infiltration; Inflammation; Inflammatory; Injury; Interneurons; Intervention; Intrathecal Injections; Knockout Mice; Knowledge; Learning; Lesion; Leukocytes; Locomotion; Locomotor Recovery; Long-Term Potentiation; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Microglia; Modeling; Morphology; Motor; N-Methylaspartate; Nature; Neuraxis; Neuroglia; Neuronal Plasticity; Neurons; Operant Conditioning; Oxidative Stress; Pathogenesis; Pathology; Pattern; Plastics; Process; Production; Proteins; Rattus; Recombinants; Recovery; Role; Secondary to; Sensory; Site; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Sprague-Dawley Rats; Staging; Synapses; Synapsin I; Synaptic plasticity; System; Testing; Therapeutic; Tissues; Training; Translating; Traumatic CNS injury; Up-Regulation; Walking; Work; base; central pattern generator; chemokine; cytokine; design; functional disability; functional improvement; inhibitor/antagonist; kinematics; novel; prevent; research study; response; response to injury; synaptic function

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.

描述（由申请人提供）：人类脊髓损伤（SCI）会导致永久性功能障碍。行动能力丧失是最明显、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恢复。这种方法显示出巨大的潜力，因为脊髓中具有丰富的活动依赖性可塑性。通过训练，尽管失去了下行驱动力，脊髓神经元仍能重新学习启动运动的组成部分。为了在 SCI 后诱导最强大的学习和恢复，我们假设训练必须尽早进行，以利用中枢神经系统可塑性的峰值。不幸的是，过早进行的训练干预无法产生功能改善，甚至破坏震中神经血管的完整性。直接的细胞障碍仍不清楚，因为 SCI 的后遗症很复杂，会导致一系列功能障碍。重要的是，损伤后炎症机制会迅速扩散到距病变部位更远的距离。很明显，神经胶质反应性和细胞因子的产生是 SCI 后继发发病机制的核心。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。 SCI 是否会诱发阻止运动再学习的早期微环境？损伤部位早期病理的有效介质是基质金属蛋白酶-9 (MMP-9)。在中心，MMP-9 促进白细胞浸润并裂解许多细胞因子和趋化因子。在这项提案中，我们提出了在急性期远离腰脊髓损伤的 MMP-9 活性的第一个证据。我们打算检验这样的假设：挫伤性 SCI 会导致 MMP-9 的早期远程产生，从而阻止保留引起的可塑性和运动再学习。我们的策略涉及操纵 MMP-9 的远程活动以及 SCI 后的早期跑步机训练。使用新颖的脊柱学习范例；我们将检查腰骶段的孤立能力，以确定运动 CPG 的可塑性。在我们的实验过程中，我们将确定运动重新学习的最佳环境。我们的初步数据表明，去除 MMP-9 可减轻远端炎症，并与早期 TM 训练相结合，可促进适应性可塑性和强大的运动恢复。我们的工作结果将为结合早期 TM 训练对腰脊髓损伤进行单独治疗提供治疗潜力。 公共卫生相关性：脊髓损伤 (SCI) 会导致整个神经轴出现双重且相互冲突的机制。迄今为止，人们对远处损伤级联的功能影响仍知之甚少。我们之前发现腰脊髓损伤部位的 10 个节段有激活的小胶质细胞和细胞因子表达。远程胶质病的发现可能表明突触稳态的破坏。我们认为，腰椎增大的远距离机制导致 SCI 后早期训练无效。 MMP-9 是早期的有效调节剂 损伤急性阶段的炎症过程。在这里，我们提出 MMP-9 的远程产生会阻碍突触功能，并且它的抑制将为保护诱导的可塑性和活动依赖性的可塑性创造一个宽松的环境。我们概述了新的实验来阐明 SCI 后远程损伤反应的功能影响。