Plasticity and Repair in the Phrenic Motor System

膈运动系统的可塑性和修复

• 批准号: 8297157
• 负责人: Paul J Reier
• 金额: $ 34.62万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297157
• 关键词: Ablation; Address; Air; Animal Model; Animals; Attention; Attenuated; Axon; Behavior; Brain Stem; Breathing; Cell Nucleus; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Communication; Complex; Complication; Contralateral; Contusions; Development; Environmental air flow; Excitotoxic lesion; Exhibits; External Intercostal Muscle; Fiber; Functional disorder; Funding; Human; Hypercapnia; Impairment; Injury; Interneurons; Interruption; Investigation; Ipsilateral; Laboratory Study; Lead; Lesion; Life; Masks; Measurement; Methods; Modeling; Monitor; Motor; Motor Neurons; Muscle; Neck; Nerve Fibers; Neurobiology; Neuronal Plasticity; Neurons; Outcome; Output; Paralysed; Pathology; Patients; Phrenic Motor System; Physiological; Plethysmography; Publishing; Rattus; Recovery; Regulation; Research; Respiratory Diaphragm; Respiratory Muscles; Respiratory physiology; Role; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Injuries; Spinal cord injury; System; Testing; Therapeutic; Tissues; awake; axon growth; base; central gray matter; clinically relevant; functional outcomes; gray matter; improved; injured; injury and repair; neural circuit; neuron loss; neurophysiology; relating to nervous system; repaired; research study; respiratory; response; short-term potentiation; spinal cord repair; transmission process; white matter; white matter injury

DESCRIPTION (provided by applicant): Respiratory impairment is a potentially life-threatening complication of mid-to upper cervical spinal cord injury (SCI). The majority of experimental studies addressing this problem have employed a high cervical (C2) injury model that interrupts transmission of respiratory signals between brainstem centers and spinal circuits involved in the regulation of respiratory muscle activity. One of the more prominent spinal respiratory networks is the phrenic motor system, which is comprised of neurons (phrenic motoneurons, PhMNs) that innervate the diaphragm -- the main respiratory muscle -- and spinal pre-phrenic interneurons which may regulate PhMN activity under specific physiological conditions. While C2 injuries have yielded valuable information about the potential for spontaneous recovery (neuroplasticity) and approaches to improve breathing post-injury, they do not reproduce the complex pathobiology of more frequently occurring mid-cervical SCIs. Such injuries result in damage to descending respiratory axons, as well as a focal loss of PhMNs and pre-phrenic interneurons (i.e., white and gray matter injury, respectively). As with other functions, the impact of white matter disruption on respiratory outcomes is well recognized. In contrast, the contribution of gray matter damage is poorly understood and possibly masked by the deficits attributed to axonal compromise. Therefore, a need exists to determine the impact of neuronal loss on respiratory deficits and neuroplasticity potential in order to guide the development of effective therapeutic strategies. In that regard, this proposal i based on the view that optimal spinal cord repair is not only dependent on restoring communication across the site of injury by promoting axonal growth, but also re-establishment of neural circuitry that in the intact spinal cord is vital to PhMN activity and ultimately diaphram function. The present proposal will employ a lateralized, mid-cervical contusion injury model to test the central hypothesis that PhMN and/or interneuronal loss impairs diaphragm function under specific respiratory conditions and thereby triggers neuroplastic changes to maintain adequate ventilation. Aim I will investigate the effect of contusion on neurophysiological activity of spared PhMNs and the contribution of PhMN loss to changes in diaphragm function. Subsequent experiments will test whether discrete pharmacological lesions of central gray matter (i.e., interneuron deletion) in the absence of either white matter or motoneuron damage results in respiratory deficits similar to those seen after contusion. Aim II will address the contribution of two forms of respiratory plasticity in spared contralateral phrenic and non-phrenic motor systems (e.g. intercostal) to breathing behavior by simultaneous monitoring of inspiratory muscle activity and ventilation in awake animals. A battery of neuroanatomical tracing approaches will be then used to define changes the underlying neural substrate that could be associated with this plasticity. These studies of an anatomically and functionally defined spinal network are likely to have significant implications leading to a more comprehensive understanding of white vs. gray matter contributions to other SCI-related functional outcomes. PUBLIC HEALTH RELEVANCE: Many spinal cord injuries (SCIs) occur in the neck region (cervical spinal cord) and result in impaired breathing due to disruption of nerve cells and fibers that control activity of the diaphragm (the primary muscle of inspiration). To obtain greater definition of therapeutic opportunities requires an understanding of how tissue damage and loss contribute to deficits in breathing and what opportunities exist for promoting repair and lasting recovery. Using an animal model of cervical SCI that emulates the basic pathology and weakened breathing capacity seen in patients with similar injuries, the proposed research will address these important issues.

描述（由申请人提供）：呼吸障碍是中上颈脊髓损伤（SCI）的一种潜在危及生命的并发症。大多数解决这个问题的实验研究都采用了高位颈椎（C2）损伤模型，该模型会中断参与调节呼吸肌活动的脑干中心和脊髓回路之间的呼吸信号传输。更重要的脊髓呼吸网络之一是膈运动系统，它由支配膈肌（主要呼吸肌）的神经元（膈运动神经元，PhMN）和脊髓前膈中间神经元组成，可以在特定的条件下调节 PhMN 活动。生理条件。虽然 C2 损伤提供了有关自发恢复潜力（神经可塑性）和改善损伤后呼吸的方法的宝贵信息，但它们并没有重现更频繁发生的颈中部 SCI 的复杂病理学。这种损伤会导致呼吸下行轴突损伤，以及 PhMN 和膈前中间神经元的局灶性丢失（即分别为白质和灰质损伤）。与其他功能一样，白质破坏对呼吸系统结果的影响已得到广泛认可。相比之下，人们对灰质损伤的贡献知之甚少，并且可能被轴突损害造成的缺陷所掩盖。因此，需要确定神经元损失对呼吸缺陷和神经可塑性潜力的影响，以指导有效治疗策略的开发。在这方面，该提议基于这样的观点：最佳的脊髓修复不仅依赖于通过促进轴突生长来恢复损伤部位的通讯，而且还依赖于重建完整脊髓中的神经回路，这对于恢复完整的脊髓至关重要。 PhMN 活性和最终膈肌功能。目前的提案将采用侧化、中颈挫伤损伤模型来测试中心假设，即 PhMN 和/或中间神经元损失会损害特定呼吸条件下的膈肌功能，从而引发神经可塑性变化以维持足够的通气。目标 我将研究挫伤对神经生理活动的影响 幸存的 PhMN 的数量以及 PhMN 损失对膈肌功能变化的贡献。随后的实验将测试在没有白质或运动神经元损伤的情况下，中央灰质的离散药理学损伤（即中间神经元缺失）是否会导致类似于挫伤后所见的呼吸缺陷。目标 II 将解决两种形式的呼吸可塑性对幸存的对侧膈肌和非膈肌的贡献 通过同时监测清醒动物的吸气肌活动和通气来评估运动系统（例如肋间）对呼吸行为的影响。然后将使用一系列神经解剖学追踪方法来定义可能与这种可塑性相关的潜在神经基质的变化。这些对解剖学和功能上定义的脊柱网络的研究可能具有重大意义，有助于更全面地了解白质与灰质对其他 SCI 相关功能结果的贡献。 公共卫生相关性：许多脊髓损伤 (SCI) 发生在颈部（颈脊髓），并因神经细胞和纤维破坏而导致呼吸受损 控制膈肌（吸气的主要肌肉）的活动。为了更好地定义治疗机会，需要了解组织损伤和损失如何导致呼吸缺陷，以及存在哪些促进修复和持久恢复的机会。拟议的研究将使用颈椎 SCI 动物模型来模拟类似损伤患者的基本病理学和呼吸能力减弱，从而解决这些重要问题。