Plasticity and Repair in the Phrenic Motor System

膈运动系统的可塑性和修复

• 批准号: 7341703
• 负责人: Paul J Reier
• 金额: $ 31.79万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341703
• 关键词: Acute; Adult; Alar; Axon; Behavior; Brain Stem; Breathing; Cell Nucleus; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chemicals; Complement; Condition; Contralateral; Data; Engraftment; Event; Goals; Hypercapnia; Hypoxia; Injury; Interneurons; Ipsilateral; Lead; Lesion; Measures; Mental Depression; Methods; Modification; Motor Neurons; Natural regeneration; Neuronal Plasticity; Neurons; Pathway interactions; Pattern; Phrenic Motor System; Physiological; Plastics; Population; Posterior Horn Cells; Process; Pseudorabies; Purpose; Range; Rate; Rattus; Recovery; Recovery of Function; Respiratory Diaphragm; Spinal; Spinal Cord; Spinal cord injury; Spinal hemilesion; Synapses; Testing; Therapeutic; Tissue Transplantation; Tissues; Transplantation; Transplanted tissue; Treatment Efficacy; axon growth; fetal; functional improvement; gray matter; hemiparesis; indexing; innovation; interdisciplinary approach; nerve stem cell; neural circuit; neurophysiology; novel; partial recovery; progenitor; receptor; relating to nervous system; repaired; research study; respiratory; response; response to injury; treatment effect

I Multiple forms of spontaneous respiratory neuroplasticity occur at spinal and brainstem levels in adult rats after lesions to the cervical spinal cord. The goal of this proposal is to enhance naturally occurring processes that can lead to partial improvement of phrenic motoneuron (PhMN) functions that were initially lost or modified after high cervical spinal cord injury (SCI) andto define underlying changes in the neural substrate. Current understanding of neuroplasticity in the phrenic motor system (PhMtrS) derives from studies of spinal hemilesions made above the phrenic nucleus (e.g., at C2). That injury abolishes descending inspiratory drive to ipsilateral PhMNs and renders the corresponding ipsilateral diaphragm (ipsiDIA) hemiparetic. We and others have recently described spontaneously emerging changes in PhMN function after C2 HMx - two of which are emphasized in the proposal. One entails a partial spontaneous recovery of ipsilateral diaphragm activity. The second involves a specific change in contralateral PhMN responses to elevated respiratory drive (hypercapnia). Aim 1will test the hypothesis that spontaneous, partial recovery of ipsiPhMN function following a C2 HMx entails neural circuit remodeling via the recruitment of interneurons. Aim 2 will test the hypothesis that stimulation of axonal growth by blockade of the Nogo- receptor (NgR), using the NgR antagonist, NEP1-40, will enhance spontaneously evolving ipsilateral PhMN functional recovery and possibly amplify the novel circuit to be defined in Aim 1, as well as contribute to modification of contralateral PhMN neuroplastic responses to respiratory challenge. The third Aim will test the hypothesis that introduction of a novel short propriospinal circuit via neural tissue transplantation can modify, alone or in combination with NEP1-40 delivery, ipsi- and contralateral PhMN neuroplastic responses following C2 HMx injury. We also will assess whether engraftment and therapeutic efficacy of FSC tissue can be complemented by NgR blockade. A multidisciplinary approach will be used involving transneuronal tracing, quantitative neurophysiological indices, and an innovative approach for obtaining repeated measures of breathing in freely-behaving rats. These aims identify with the long-range hypothesis that segmental gray matter repair and neural circuit remodeling provide an effective complement or alternative to long-tract regeneration via enhancement or modification of post-injury neuroplastic events.

我 成人脊髓和脑干水平发生多种形式的自发呼吸神经可塑性 颈脊髓损伤后的大鼠。该提案的目标是增强自然发生的 可以导致膈运动神经元（PhMN）功能部分改善的过程，这些功能最初是 高位颈脊髓损伤 (SCI) 后丢失或修改，并定义神经元的潜在变化 基材。目前对膈运动系统（PhMtrS）神经可塑性的理解源自 对膈核上方（例如 C2）的脊柱半侧研究。那个伤废了 下降吸气驱动至同侧 PhMN，并渲染相应的同侧膈肌 (ipsiDIA) 偏瘫。我们和其他人最近描述了 PhMN 自发出现的变化 C2 HMx 之后的功能 - 提案中强调了其中两个功能。一种需要部分自发的 同侧膈肌活动恢复。第二个涉及对侧 PhMN 的特定变化 对呼吸驱动力升高（高碳酸血症）的反应。目标 1 将检验自发假设， C2 HMx 后 ipsiPhMN 功能的部分恢复需要通过募集进行神经回路重塑 中间神经元。目标 2 将检验通过阻断 Nogo-刺激轴突生长的假设 受体（NgR），使用 NgR 拮抗剂 NEP1-40，将增强同侧 PhMN 的自发进化 功能恢复并可能放大目标 1 中定义的新颖电路，以及有助于 改变对侧 PhMN 神经可塑性对呼吸挑战的反应。第三个目标将测试 通过神经组织移植引入新型短本体脊髓回路的假设可以 单独或与 NEP1-40 递送联合改变同侧和对侧 PhMN 神经可塑性反应 C2 HMx 损伤后。我们还将评估 FSC 组织的植入和治疗效果 可以通过 NgR 阻断来补充。将使用涉及跨神经元的多学科方法 追踪、定量神经生理学指数以及获得重复测量的创新方法 自由行为的老鼠的呼吸。这些目标与分段灰色的长期假设一致 物质修复和神经回路重塑为长程治疗提供了有效的补充或替代 通过增强或改变损伤后神经塑性事件来再生。