Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity

摘要 可塑性是控制呼吸的神经系统的标志。一种被广泛研究的呼吸道疾病 运动可塑性是指膈神经长期易化(PLTF)，即急性脑损伤后膈神经运动输出的持续增加。 间歇性缺氧(AIH)。多种不同的细胞机制参与了AIH诱导的pLTF。不幸的是， 我们对这些机制是如何监管的理解是有限的。AIH诱导的两种不同机制 膈肌运动促进(PMF)被称为Q通路和S通路。Q通路需要膈神经运动。 神经元5-HT2受体激活，而S通路是由膈运动神经元5-HT7受体启动的。 Q和S通路的共同激活引起强烈的串扰抑制；实际上，Q和S通路的激活等同于 取消PMF表达式。中度AIH时，Q通路占优势，但受S通路制约 抑制：抑制S通路释放了这一“刹车”，使MAIH诱导的pLTF加倍。 重复的AIH(RAIH)预适应通过未知的机制增强MAIH诱导的pLTF。这 在我们的翻译工作中，财产是必不可少的，我们利用RAH作为一种治疗方法来改善人们的呼吸 有颈椎损伤或神经肌肉疾病。这项建议的根本目标是了解如何 这些累积的Raih福利就产生了。我们的中心假设是，Raih最小化了Q-S通路的串扰 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明显的年龄依赖性的性二型性。然而，我们 基本上不知道年龄和性别的改变如何不同地影响PMF机制，或者他们的 对Raih预适应的反应。因此，我们将比较Q和S通路在杨氏(3月龄)和 中年(12月龄)雌性大鼠与雄性大鼠(性二型性最强时)。我们还将调查 不同程度的RAIH预适应对非麻醉中青年雌性VS大鼠横隔膜LTF的影响 雄鼠。增加对正常大鼠年龄和性别影响的了解将为 翻译为折磨不同年龄段的男性和女性的临床障碍。 在文献的基础上，我们初步提出了RAIH增强的pLTF的工作细胞模型。 数据。在这个模型的基础上，我们提出了四个具体的目标来检验RAIH预适应的假设：1) 减少Q和S途径的串扰抑制，使两者都有贡献(目标1)；和2)加强 Q通路通过增加关键通路分子的表达进入PMF(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，我们将检验以下假设：1)Q和S通路 对PMF的影响不同于年龄和发情周期的雌性大鼠(目标3)；2)年龄和性别是关键 RAIH增强的横隔膜运动可塑性的决定因素(目标4)。这些研究将极大地促进我们的 了解RAIH增强的膈运动可塑性，并加速我们将RAIH作为一种 治疗破坏性临床疾病的治疗方式，这些疾病危及呼吸并威胁生命本身。

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.