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。一种广泛研究的呼吸系统形式 运动可塑性是长期设施（PLTF），急性后长时间的运动输出增加 间歇性缺氧（AIH）。多种不同的细胞机制有助于AIH诱导的PLTF。很遗憾， 我们对如何调节这些机制的理解是有限的。 AIH引起的两个不同的机制 伪运动设施（PMF）被称为Q和S途径。 Q途径需要phrenic电机 神经元5-HT2受体激活，而S途径是由Phrenic运动神经元5-HT7受体引发的。 Q和S途径共同激活会引起强大的串扰抑制；实际上，等于Q和S途径激活 取消PMF表达。与现代AIH（MAIH）一起，Q路径占主导地位，但受S途径的约束 抑制; S途径抑制作用释放了这种“制动”，使MAIH诱导的PLTF加倍。 重复的AIH（RAIH）预处理通过未知机制增强了MAIH诱导的PLTF。这 财产对于利用Raih的转化努力至关重要，以改善人们的呼吸 颈椎损伤或神经肌肉疾病。该提议的基本目标是了解如何 这些累积的raih益处会产生。我们的中心假设是RAIH最小化Q-S途径串扰 相互作用，使得两者都可以促进AIH引起的运动可塑性。 AIH诱导的Phrenial运动可塑性表现出深远的年龄依赖性性二态性。但是，我们 基本上不知道年龄和性别如何改变对PMF机制的影响，或 对RAIH预处理的反应。那就是我们将比较年轻（3个月）的Q和S途径相互作用 中年（12个月）与雄性大鼠（当性二态性最大时）。我们还将调查 差异RAIH对隔膜LTF的差异性预处理在未经麻醉的年轻和中年女性中 雄鼠。对正常大鼠的年龄和性别影响的了解增加将建立“基本规则” 转化为困扰着不同年龄的男人和女人的临床疾病。 我们提出了基于文献和令人兴奋的初步的RAIH增强PLTF的工作蜂窝模型 数据。基于此模型，我们提出了四个特定的目的，以测试Raih预处理的假设：1） 减少Q和S途径串扰抑制，从而从两者中贡献（AIM 1）； 2）优势 通过增加关键途径分子的表达来通往PMF的Q途径（AIM 2）。由于AIH诱导的PLTF 表现出深远的年龄依赖性二态性，我们将测试以下假设：1）Q和S途径 PMF受年龄和Estrus循环女性大鼠的影响不同（AIM 3）； 2）年龄和性是关键 RAIH增强diaphragm运动可塑性的决定因素（AIM 4）。这些研究将大大推动我们的 了解RAIH增强的浮力运动可塑性，并加快利用Raih的能力 治疗灾难性临床疾病的治疗方式，损害呼吸并威胁生命本身。