Microglial regulation of intermittent hypoxia induced phrenic motor plasticity

小胶质细胞对间歇性缺氧诱导的膈运动可塑性的调节

• 批准号: 10323659
• 负责人: Gordon S. Mitchell
• 金额: $ 65.91万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323659
• 关键词: Acute; Adenosine; Affect; Age; Awareness; Breathing; CX3CL1 gene; CX3CR1 gene; Cells; Cervical; Clinical; Complement; Cyclic AMP; Data; Disease; Dose; Erythrocytes; Estrogens; Exhibits; Female; Fractalkine; Goals; Hour; Hypoxia; Immune; Impairment; Inflammation; Knowledge; Lipopolysaccharides; Macrophage Colony-Stimulating Factor; Microglia; Modality; Modeling; Motor; Motor Neurons; Motor output; Movement; Neuroglia; Neuromuscular Diseases; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Outcome; Pathway interactions; Persons; Protocols documentation; Rattus; Receptor Activation; Regulation; Reporting; Respiratory Diaphragm; Role; Serotonin; Severities; Signal Pathway; Signal Transduction; Spinal; Spinal Injuries; Spinal cord injury; System; Testing; Therapeutic; Therapeutic Intervention; Translations; Woman; age effect; age related; base; chemokine; experimental study; fractalkine receptor; improved; inhibitor; knock-down; male; men; middle age; novel therapeutic intervention; predictive modeling; receptor; relating to nervous system; respiratory; response; serotonin receptor; sex; sexual dimorphism; systemic inflammatory response; virtual; young adult

ABSTRACT Plasticity is a hallmark feature of the neural system controlling breathing. One well-studied form of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic activity triggered by acute intermittent hypoxia (AIH). Multiple distinct cellular mechanisms contribute to AIH-induced pLTF, depending on the severity of hypoxic episodes. Whereas the Q pathway requires 5-HT2 receptor activation on phrenic motor neurons, the S pathway requires adenosine 2A receptor activation. These distinct intra-cellular signaling pathways interact via powerful cross-talk inhibition; indeed, concurrent pathway activation actually cancels pLTF expression. Although we have learned a great deal about intra-cellular signaling mechanisms of AIH-induced pLTF, we know little concerning the role of inter-cellular signaling. Recent reports demonstrate that glia regulate neuroplasticity in multiple neural systems, including microglia, the innate immune cells of the CNS. Since virtually nothing is known concerning the role of microglia in regulating AIH-induced phrenic motor plasticity, our primary goal is to explore this knowledge gap in normal rats and in rats with systemic inflammation. The fundamental hypothesis guiding our proposal is that microglia differentially regulate competing pLTF mechanisms elicited by moderate versus severe AIH (Aim 1). We propose a unified model to explain such differential microglial regulation of AIH-induced pLTF. During severe hypoxia, we propose that phrenic motor neurons release Fractalkine (a chemokine unique to neurons), activating microglial Fractalkine receptors (unique to microglia) and triggering the microglial adenosine release necessary for severe AIH-induced pLTF (Aim 2). With moderate AIH, diminished inter-cellular Fractalkine and adenosine signaling permit the expression of serotonin-dependent pLTF (ie. Q pathway), but with a persistent adenosine constraint (Aim 3). We further propose that even mild systemic inflammation enhances microglial adenosine release during moderate AIH, increasing cross-talk inhibition and suppressing pLTF expression (Aim 4). Finally, since AIH-induced pLTF exhibits a profound age-dependent sexual dimorphism, we will test the hypothesis that phrenic motor neuron- microglia interactions are differentially affected by age in female versus male rats (Aim 5). This project will be the first attempt to identify a specific role of microglia in any form of respiratory motor plasticity, greatly increasing our mechanistic understanding concerning the importance of inter-cellular signaling in respiratory motor plasticity. Since repetitive AIH is emerging as a novel therapeutic intervention to restore breathing (and other movements) in people with debilitating disorders such as cervical spinal injury or ALS, greater understanding of factors regulating AIH-induced plasticity will help optimize AIH protocols and improve chances for successful translation of this promising therapeutic modality. Increased understanding of age and sex effects will establish “ground rules” for translation to clinical disorders that afflict both men and women.

抽象的 可塑性是控制呼吸的神经系统的标志特征。一种经过充分研究的呼吸形式 运动可塑性是膈长期促进（pLTF），即由急性刺激引起的膈活动的长期增加 间歇性缺氧（AIH）。多种不同的细胞机制有助于 AIH 诱导的 pLTF，具体取决于 缺氧事件的严重程度。而 Q 通路需要膈运动上的 5-HT2 受体激活 神经元中，S 通路需要腺苷 2A 受体激活。这些独特的细胞内信号传导 通路通过强大的串扰抑制相互作用；事实上，并发通路激活实际上取消了 pLTF 表达。尽管我们已经了解了大量关于 AIH 诱导的细胞内信号传导机制 pLTF，我们对细胞间信号传导的作用知之甚少。最近的报告表明神经胶质细胞调节 多个神经系统的神经可塑性，包括小胶质细胞，中枢神经系统的先天免疫细胞。自从 事实上，关于小胶质细胞在调节 AIH 诱导的膈运动可塑性中的作用，我们一无所知。 主要目标是探索正常大鼠和患有全身炎症的大鼠的这种知识差距。 指导我们建议的基本假设是小胶质细胞差异性地调节竞争 中度与重度 AIH 引发的 pLTF 机制（目标 1）。我们提出一个统一的模型来解释 AIH 诱导的 pLTF 的这种差异性小胶质细胞调节。严重缺氧时，我们建议膈 运动神经元释放 Fractalkine（神经元特有的趋化因子），激活小胶质细胞 Fractalkine 受体 （小胶质细胞独有）并触发严重 AIH 诱导的 pLTF 所需的小胶质细胞腺苷释放 （目标 2）。中度 AIH 时，细胞间 Fractalkine 和腺苷信号传导减弱，允许表达 血清素依赖性 pLTF（即 Q 途径），但具有持续的腺苷限制（目标 3）。我们进一步 提出即使是轻微的全身炎症也会增强中度 AIH 期间小胶质细胞腺苷的释放， 增加串扰抑制并抑制 pLTF 表达（目标 4）。最后，由于 AIH 诱导的 pLTF 表现出深刻的年龄依赖性性别二态性，我们将检验膈运动神经元的假设 雌性和雄性大鼠中小胶质细胞相互作用受年龄的影响不同（目标 5）。 该项目将是首次尝试确定小胶质细胞在任何形式的呼吸运动中的特定作用 可塑性，大大增加了我们对细胞间信号传导重要性的机制理解 呼吸运动可塑性。由于重复性 AIH 正在作为一种新的治疗干预措施出现，以恢复 患有颈椎损伤或 ALS 等衰弱性疾病的人的呼吸（和其他运动）， 更好地了解调节 AIH 诱导的可塑性的因素将有助于优化 AIH 方案并改善 成功转化这种有前景的治疗方式的机会。加深对年龄的了解 性别效应将为转化为困扰男性和女性的临床疾病建立“基本规则”。