Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity

间歇性缺氧引起的呼吸运动可塑性的调节

• 批准号: 10458511
• 负责人: Gordon S. Mitchell
• 金额: $ 59.4万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458511
• 关键词: Acute; Adenosine; Affect; Age; Basic Science; Biological; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Cell model; Cervical; Chemoreceptors; Clinical; Clinical Trials; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Disease; Estrus; Exhibits; Exposure to; Female; GTP-Binding Proteins; Goals; Hour; Hypoxia; Impairment; Knowledge; Larynx; Life; Literature; Mediator of activation protein; Modality; Modeling; Molecular; Motor; Motor Neurons; Motor output; Names; Neuromuscular Diseases; Neuronal Plasticity; Neurons; Outcome Study; Pathway interactions; Persons; Property; Rattus; Receptor Activation; Regulation; Respiratory Diaphragm; Sensory; Serotonin; Sex Differences; Spinal Injuries; Spinal cord injury; Stroke; System; Testing; Therapeutic; Translating; Translations; Woman; age related; base; improved; interdisciplinary approach; link protein; male; men; middle age; motor deficit; preconditioning; predictive modeling; receptor; relating to nervous system; respiratory; response; serotonin 7 receptor; sex; sexual dimorphism; young adult

ABSTRACT Plasticity is a hallmark of the neural system controlling breathing. One extensively studied form of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output after acute intermittent hypoxia (AIH). Multiple, distinct cellular mechanisms contribute to AIH-induced pLTF. Unfortunately, our understanding of how these mechanisms are regulated is limited. Two distinct mechanisms of AIH-induced phrenic motor facilitation (pMF) are known as the Q and S pathways. The Q pathway requires phrenic motor neuron 5-HT2 receptor activation, whereas the S pathway is initiated by phrenic motor neuron 5-HT7 receptors. Q and S pathway co-activation elicits powerful cross-talk inhibition; in fact, equal Q and S pathway activation cancels pMF expression. With moderate AIH (mAIH), the Q pathway dominates but is constrained by S pathway inhibition; S pathway inhibition releases this “brake,” doubling mAIH-induced pLTF. Repetitive AIH (rAIH) preconditioning enhances mAIH-induced pLTF through unknown mechanisms. This property is essential in our translational efforts to harness rAIH as a treatment to improve breathing in people with cervical spinal injury or neuromuscular disease. The fundamental goal of this proposal is to understand how these cumulative rAIH benefits arise. Our central hypothesis is that rAIH minimizes Q-S pathway cross-talk interactions, enabling both to contribute to AIH-induced phrenic motor plasticity. AIH-induced phrenic motor plasticity exhibits profound age-dependent sexual dimorphism. However, we know essentially nothing concerning how age and sex alter differentially affect pMF mechanisms, or their response to rAIH preconditioning. Thus, we will compare Q and S pathway interactions in young (3 month) and middle-aged (12 month) female vs male rats (when sexual dimorphisms are greatest). We will also investigate differential rAIH preconditioning effects on diaphragm LTF in unanesthetized young and middle-aged female vs male rats. Increased understanding of age and sex effects in normal rats will establish the “ground rules” for translation to clinical disorders that afflict men and women of different ages. We propose a working cellular model of rAIH-enhanced pLTF based on literature and exciting preliminary data. Based on this model, we propose four specific aims to test the hypotheses that rAIH preconditioning: 1) decreases Q and S pathway cross-talk inhibition, enabling contributions from both (Aim 1); and 2) strengthens the Q pathway to pMF by increasing the expression of key pathway molecules (Aim 2). Since AIH-induced pLTF exhibits profound age-dependent sexual dimorphisms, we will test the hypotheses that: 1) the Q and S pathways to pMF are differentially affected by age and the estrus cycle female rats (Aim 3); and 2) age and sex are key determinants of rAIH-enhanced diaphragm motor plasticity (Aim 4). These studies will greatly advance our understanding of rAIH-enhanced phrenic motor plasticity, and accelerate our ability to harness rAIH as a therapeutic modality to treat devastating clinical disorders that compromise breathing and threaten life itself.

抽象的 可塑性是控制呼吸的神经系统的标志。一种经过广泛研究的呼吸系统形式 运动可塑性是膈长期促进（pLTF），即急性刺激后膈运动输出的长期增加 间歇性缺氧（AIH）。多种不同的细胞机制导致 AIH 诱导的 pLTF。很遗憾， 我们对这些机制如何监管的理解是有限的。 AIH 诱发的两种不同机制 膈运动促进 (pMF) 被称为 Q 和 S 通路。 Q 通路需要膈运动 神经元 5-HT2 受体激活，而 S 途径由膈运动神经元 5-HT7 受体启动。 Q 和 S 通路共同激活可引发强大的串扰抑制；事实上，Q 和 S 通路激活相等 取消 pMF 表达。对于中度 AIH (mAIH)，Q 通路占主导地位，但受到 S 通路的限制 抑制; S 途径抑制会释放这种“刹车”，使 mAIH 诱导的 pLTF 倍增。 重复性 AIH (rAIH) 预处理通过未知机制增强 mAIH 诱导的 pLTF。这 在我们利用 rAIH 作为改善人类呼吸的治疗方法的转化努力中，财产至关重要 患有颈椎损伤或神经肌肉疾病。该提案的基本目标是了解如何 这些累积的 rAIH 益处就会出现。我们的中心假设是 rAIH 最大限度地减少 Q-S 通路串扰 相互作用，使两者都有助于 AIH 诱导的膈运动可塑性。 AIH 诱导的膈运动可塑性表现出深刻的年龄依赖性性别二态性。然而，我们 对于年龄和性别的变化如何不同地影响 pMF 机制或其它们基本上一无所知 对 rAIH 预处理的反应。因此，我们将比较年轻（3 个月）和 中年（12 个月）雌性与雄性大鼠（性别二态性最大时）。我们也会调查 rAIH 预处理对未麻醉青年和中年女性与膈肌 LTF 的差异影响 雄性大鼠。增加对正常大鼠的年龄和性别影响的了解将为以下方面建立“基本规则”： 转化为困扰不同年龄段男性和女性的临床疾病。 我们根据文献和令人兴奋的初步结果提出了 rAIH 增强 pLTF 的工作细胞模型 数据。基于该模型，我们提出了四个具体目标来检验 rAIH 预处理的假设：1) 降低 Q 和 S 通路串扰抑制，从而实现两者的贡献（目标 1）； 2) 加强 通过增加关键途径分子的表达来形成 pMF 的 Q 途径（目标 2）。由于 AIH 诱导的 pLTF 表现出深刻的年龄依赖性性别二态性，我们将测试以下假设：1）Q 和 S 途径 雌性大鼠的年龄和发情周期对 pMF 的影响不同（目标 3）； 2）年龄和性别是关键 rAIH 增强隔膜电机可塑性的决定因素（目标 4）。这些研究将极大地推动我们 了解 RAIH 增强的膈运动可塑性，并加快我们利用 RAIH 作为 治疗损害呼吸并威胁生命本身的破坏性临床疾病的治疗方式。