Mechanisms of inactivity-induced respiratory plasticity

不活动引起的呼吸可塑性机制

• 批准号: 8209201
• 负责人: Tracy L Baker
• 金额: $ 36.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209201
• 关键词: Automobile Driving; Axon; Birth; Brain Stem; Breathing; Cell Nucleus; Cessation of life; Clinical; Data; Disease; Employee Strikes; Ensure; Environmental air flow; Epigenetic Process; Exhibits; Failure; Frequencies; Genetic; Goals; Health; Human; Hypocapnia; Hypoxia; Intervention; Investigation; Life; Literature; Lung; Mammals; Mechanical ventilation; Methods; Modeling; Motor; Motor Neurons; Motor output; Muscle; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neuronal Plasticity; Neurons; Neurosciences; Patients; Physiological; Property; Protein Isoforms; Pump; Rattus; Receptor Activation; Reporting; Rivers; Role; Spinal; Spinal Cord Plasticity; Sprague-Dawley Rats; Study models; Synapses; TNF gene; Testing; Ventilator Weaning; Weaning; Work; base; disorder control; effective therapy; insight; novel; receptor; relating to nervous system; respiratory; therapeutic target

PROJECT SUMMARY/ABSTRACT The fundamental hypothesis guiding this proposal is that reduced synaptic inputs to respiratory motor neurons elicits compensatory plasticity, preserving respiratory motor output in a range compatible with life. Our specific goal in the present project period is to investigate cellular mechanisms giving rise to inactivity-induced phrenic motor facilitation (iPMF), a persistent increase in phrenic burst amplitude following prolonged decreases in phrenic neural activity. Two distinct methods of reducing phrenic activity will be studied in anesthetized rats: one that reduces overall activity in the respiratory network (hypocapnia) and another that specifically decreases spinal synaptic inputs to phrenic motor neurons (C2 axon conduction block). The iPMF evoked by these methods exhibits striking similarities, yet may have important differences. Hypocapnia and C2 conduction block both elicit iPMF (i.e., increased amplitude), but only hypocapnia elicits phrenic burst frequency facilitation suggesting the possibility of that iPMF arises from multiple mechanisms depending on whether neural activity was reduced localy versus globally. In this project, we will focus on spinal mechanisms leading to iPMF. Our working model is that reduced synaptic input to phrenic motor neurons stimulates TNF¿ release in the phrenic motor nucleus (Aim 1), activating atypical PKC (aPKC) isoforms in or near phrenic motor neurons that give rise to iPMF (Aims 2 and 3). We further propose that iPMF is subject to regulatory constraints, similar to other forms of neuroplasticity. By investigations of a unique sub-strain of Sprague Dawley rats, we will gain critical insights concerning mechanisms that constrain iPMF. In specific, we hypothesize that greater constitutive NMDA-glutamateric receptor activity constrains iPMF in this rat sub-strain (Aim 4), possibly due to genetic or epigenetic factors. Since failure to elicit iPMF may contribute to ventilatory control disorders of importance to human health, such as ventilatory weaning failure following prolonged ventilatory support, differences in constitutive NMDA receptor activity may diferentiate patients that successfully wean from ventilatory support versus those that do not. A detailed understanding of cellular cascades giving rise to iPMF is essential to understand the physiological role of this highly novel form of plasticity, and-importantly-to identify promising therapeutic targets for pharmacological interventions to treat respiratory control disorders.

项目摘要/摘要 指导该提议的基本假设是减少了突触输入到呼吸系统 运动神经元会引起补偿性可塑性，保留呼吸运动输出范围 与生活兼容。我们在当前项目期间的具体目标是研究细胞 导致无活动引起的伪运动设施（IPMF）的机制，持久 在神经活性延长下降后，腓骨突发放大器的增加。 在麻醉大鼠中将研究两种降低phrenic活性的不同方法：一种 降低呼吸网络（低核）的总体活动，而另一种则是专门的 降低对腓骨运动神经元（C2轴突传导块）的脊柱突触输入。这 这些方法引起的IPMF表现出惊人的相似性，但可能具有重要差异。 低碳酸盐和C2传导阻滞均引起IPMF（即增加放大器），但仅引起 低核心引起了phrenic爆发频率设施，提示了该IPMF的可能性 根据多种机制，具体取决于神经活动是否降低了局部 与全球。在这个项目中，我们将专注于导致IPMF的脊柱机制。我们的 工作模型是减少了对伪运动神经元的突触输入刺激TNF释放 在伪运动核中（AIM 1），激活非典型PKC（APKC）的同工型或附近 产生IPMF的运动神经元（目标2和3）。我们进一步建议IPMF受到 调节性约束，类似于其他形式的神经塑性。通过对独特的调查 Sprague Dawley Rats的子局部，我们将获得有关机制的关键见解 约束IPMF。具体而言，我们假设更大的本构nmda-glutamateric 受体活性限制了该大鼠亚策略中的IPMF（AIM 4），这可能是由于遗传或 表观遗传因素。由于未能引起IPMF可能会导致通气控制障碍 对人类健康的重要性，例如长时间通气后的通风故障 支持，组成型NMDA受体活性的差异可能会使患者区分 成功地从通气支持中与没有通风的支撑做断奶。对 引起IPMF的蜂窝级联对于了解这一点的身体作用至关重要 高新颖的可塑性形式，并且很大程度上可以确定有希望的治疗靶标的 治疗呼吸控制障碍的药理干预措施。