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性特征。一种良好的呼吸形式 运动可塑性是长期设施（PLTF），急性触发的phrenic活性长期增加 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 低氧发作的严重程度。而Q途径需要5-HT2受体在Phrenic Motor上激活 神经元，S途径需要腺苷2A受体激活。这些独特的细胞内信号传导 途径通过强大的串扰抑制作用相互作用；确实，并发途径激活实际上取消了PLTF 尽管我们已经了解了有关AIH诱导的细胞内信号传导机制的大量知识 PLTF，我们对细胞间信号传导的作用一无所知。最近的报道表明，神经胶质调节 多种神经元系统（包括小胶质细胞）的神经可塑性，中枢神经系统的先天免疫球。自从 实际上，关于小胶质细胞在调节AIH诱导的运动可塑性中的作用的几乎没有什么知道的 主要目标是探索正常大鼠和全身性炎症大鼠中的知识差距。 基本的假设指导我们的提议，小胶质细胞对竞争的调节不同 现代与重度AIH引起的PLTF机制（AIM 1）。我们提出了一个统一的模型来解释 AIH诱导的PLTF的这种差异小胶质细胞调节。在严重缺氧期间，我们提出 运动神经元释放Fractalkine（神经元独有的趋化因子），激活小胶质细胞分子受体 （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）。使用现代AIH，细胞间分子碱和腺苷信号传导允许表达式 血清素依赖性PLTF（即Q途径），但具有持久的腺苷约束（AIM 3）。我们进一步 提议即使轻度全身性炎症也会增强中等AIH期间的小胶质细胞腺苷释放， 增加跨对抑制和抑制PLTF表达（AIM 4）。最后，由于AIH诱导的PLTF 表现出深远的年龄依赖性二态性，我们将检验以下假设。 小胶质细胞相互作用受女性与雄性大鼠年龄的影响不同（AIM 5）。 该项目将是第一次尝试在任何形式的呼吸运动中确定小胶质细胞的特定作用 可塑性，大大增加了我们关于细胞间信号的重要性的机械理解 在呼吸运动可塑性中。由于重复的AIH正在作为一种新型的治疗干预措施来恢复 呼吸（和其他运动），患有障碍症患者，例如颈脊柱损伤或ALS， 对调节AIH引起的可塑性的因素的更多了解将有助于优化AIH协议并改善 成功翻译这种承诺的治疗方式的机会。对年龄和年龄的了解增加 性影响将建立“基本规则”，以转化为遭受男性和女性的临床疾病。