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: 8514958
• 负责人: Christopher N. Hansen
• 金额: $ 2.6万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514958
• 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.

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。

项目成果

Lumbar Myeloid Cell Trafficking into Locomotor Networks after Thoracic Spinal Cord Injury.

胸部脊髓损伤后，腰部髓样细胞运输到运动网络中。

• DOI: 10.1016/j.expneurol.2016.05.019
• 发表时间: 2016-08
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Hansen CN;Norden DM;Faw TD;Deibert R;Wohleb ES;Sheridan JF;Godbout JP;Basso DM
• 通讯作者: Basso DM

Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury.

• DOI: 10.3389/fncir.2016.00011
• 发表时间: 2016
• 期刊: Frontiers in neural circuits
• 影响因子: 3.5
• 作者: Hansen CN;Faw TD;White S;Buford JA;Grau JW;Basso DM
• 通讯作者: Basso DM