Mechanisms of inactivity-induced respiratory plasticity

项目概要/摘要 指导该提议的基本假设是减少呼吸系统的突触输入 运动神经元引起补偿可塑性，将呼吸运动输出保持在一定范围内 与生活兼容。我们在当前项目期间的具体目标是研究细胞 引起不活动诱导膈运动促进（iPMF）的机制，这是一种持久的 膈神经活动长期减少后膈爆发幅度增加。 将在麻醉大鼠中研究两种减少膈活动的不同方法：一种是 减少呼吸网络的整体活动（低碳酸血症），另一个特别是 减少膈运动神经元的脊髓突触输入（C2 轴突传导阻滞）。的 这些方法引发的 iPMF 表现出惊人的相似性，但也可能存在重要差异。 低碳酸血症和 C2 传导阻滞都会引起 iPMF（即振幅增加），但仅 低碳酸血症引起膈爆发频率促进，提示 iPMF 的可能性 由多种机制引起，具体取决于神经活动是否局部减少 与全球相比。在这个项目中，我们将重点关注导致 iPMF 的脊柱机制。我们的 工作模型是减少膈运动神经元的突触输入刺激 TNF 释放 在膈运动核中（目标 1），激活膈内或附近的非典型 PKC (aPKC) 同工型 产生 iPMF 的运动神经元（目标 2 和 3）。我们进一步建议 iPMF 须遵守 监管限制，类似于其他形式的神经可塑性。通过对独特的调查 斯普拉格道利大鼠亚种，我们将获得有关机制的重要见解 限制 iPMF。具体来说，我们假设更大的组成型 NMDA-谷氨酸 受体活性限制了该大鼠亚品系中的 iPMF（目标 4），可能是由于遗传或 表观遗传因素。由于未能引发 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气脱机失败 支持，组成型 NMDA 受体活性的差异可能会区分以下患者： 与那些没有成功摆脱通气支持的人相比。详细了解 产生 iPMF 的细胞级联对于了解其生理作用至关重要 高度新颖的可塑性形式，并且重要的是确定有希望的治疗靶点 治疗呼吸控制疾病的药物干预。

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.