Mechanisms of inactivity-induced respiratory plasticity

项目摘要/摘要 指导这一提议的基本假设是减少了对呼吸的突触输入 运动神经元引起代偿性可塑性，将呼吸运动输出保持在一定范围内 与生活相容。我们在目前项目期间的具体目标是研究细胞 导致静止诱导的膈运动促进(IPMF)的机制，持续性的 随着膈神经活动时间的延长，膈神经爆发的幅度增加。 将在麻醉大鼠身上研究两种不同的减少膈神经活动的方法：一种是 减少呼吸网络的整体活动(低碳酸血症)，以及另一个具体的 减少对膈运动神经元的脊髓突触输入(C2轴突传导阻滞)。这个 这些方法所诱发的iPMF表现出惊人的相似性，但也可能有重要的差异。 低碳酸血症和C2传导阻滞均可引起iPMF(即，幅度增加)，但仅 低碳酸血症引起的膈肌爆发频率易化提示iPMF的可能性 由多种机制引起，取决于神经活动是否局部减少 而不是全球。在本项目中，我们将重点研究导致iPMF的脊髓机制。我们的 工作模式是减少对膈运动神经元的突触输入，刺激肿瘤坏死因子的释放 在膈运动核(Aim 1)，激活非典型蛋白激酶C(APKC)亚型位于或靠近膈肌 产生iPMF的运动神经元(目标2和3)。我们进一步建议，iPMF必须遵守 调节约束，类似于其他形式的神经可塑性。通过对一个独一无二的 我们将获得有关以下机制的重要见解： 约束iPMF。具体地说，我们假设更大的构成NMDA-谷氨酸 受体活性限制了这个大鼠亚系(AIM 4)的iPMF，可能是由于遗传或 表观遗传因素。由于未能诱导iPMF可能会导致呼吸控制障碍 对人类健康的重要性，如长时间呼吸机后的呼吸机脱机失败 支持，组成NMDA受体活性的差异可能会区分 成功地摆脱对呼吸机支持的依赖比那些没有这样做的人。详细了解 导致iPMF的细胞级联对于理解iPMF的生理作用是必不可少的 非常新颖的可塑性形式，而且--重要的是--确定有希望的治疗靶点 治疗呼吸控制障碍的药物干预。

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.