Plasticity and Repair in the Phrenic Motor System

膈运动系统的可塑性和修复

基本信息

批准号：
7162630
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
项目类别：
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/7162630
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

项目摘要

DESCRIPTION (provided by applicant): 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) and to 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 1 will 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.

描述（由申请人提供）：颈脊髓损伤后，成年大鼠的脊髓和脑干水平会发生多种形式的自发呼吸神经可塑性。该提案的目标是增强自然发生的过程，从而部分改善高位颈脊髓损伤（SCI）后最初丢失或改变的膈运动神经元（PhMN）功能，并定义神经基质的潜在变化。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）的脊髓半侧运动的研究。这种损伤消除了同侧 PhMN 的下降吸气动力，并导致相应的同侧膈肌 (ipsiDIA) 偏瘫。我们和其他人最近描述了 C2 HMx 后 PhMN 功能自发出现的变化——提案中强调了其中两个变化。一种需要同侧膈肌活动部分自发恢复。第二个涉及对侧 PhMN 对呼吸驱动力升高（高碳酸血症）反应的特定变化。目标 1 将检验以下假设：C2 HMx 后 ipsiPhMN 功能的自发、部分恢复需要通过招募中间神经元进行神经回路重塑。目标 2 将检验以下假设：使用 NgR 拮抗剂 NEP1-40 阻断 Nogo 受体 (NgR) 来刺激轴突生长，将增强自发进化的同侧 PhMN 功能恢复，并可能放大目标 1 中定义的新型回路，以及有助于改变对侧 PhMN 神经可塑性对呼吸挑战的反应。第三个目标将检验以下假设：通过神经组织移植引入新型短本体脊髓回路可以单独或与 NEP1-40 递送组合改变 C2 HMx 损伤后的同侧和对侧 PhMN 神经可塑性反应。我们还将评估 FSC 组织的移植和治疗效果是否可以通过 NgR 阻断来补充。将采用多学科方法，包括跨神经元追踪、定量神经生理学指数以及一种创新方法，用于获得自由行为大鼠的呼吸重复测量结果。这些目标与长期假设一致，即节段性灰质修复和神经回路重塑通过增强或改变损伤后神经可塑性事件，为长束再生提供有效的补充或替代。