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 运动可塑性是膈神经长时程易化（pLTF），即急性运动后膈神经运动输出的延长增加。 间歇性缺氧（AIH）。多种不同的细胞机制有助于AIH诱导的pLTF。不幸的是， 我们对这些机制是如何调节的理解是有限的。AIH诱导的两种不同机制 膈运动促进（pMF）被称为Q和S途径。Q通路需要膈神经运动 神经元5-HT 2受体激活，而S途径由膈运动神经元5-HT 7受体启动。 Q和S途径共激活增强了强有力的串扰抑制;事实上， 取消pMF表达。中度AIH（mAIH）以Q通路为主，但受到S通路的限制 抑制; S途径抑制释放这种“制动”，使mAIH诱导的pLTF加倍。 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作为改善人们呼吸的治疗方法的转化努力中， 颈椎损伤或神经肌肉疾病。本提案的基本目标是了解如何 这些累积的rAIH益处出现。我们的中心假设是，rAIH最小化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的两性异形。但我们 我基本上不知道年龄和性别如何改变对pMF机制的影响，或者它们对pMF机制的影响。 对rAIH预处理的反应。因此，我们将比较Q和S途径的相互作用，在年轻（3个月）和 中年（12个月）雌性大鼠与雄性大鼠（性二态性最大时）。我们亦会研究 不同的rAIH预处理对未麻醉的年轻和中年女性与 雄性大鼠增加对正常大鼠年龄和性别影响的了解将建立以下“基本规则”： 转化为临床疾病，折磨不同年龄的男性和女性。 我们提出了一个工作细胞模型的rAIH增强pLTF的基础上，文献和令人兴奋的初步 数据在此基础上，我们提出了四个具体的目标来检验rAIH预处理的假设：1） 降低Q和S通路串扰抑制，使两者都能做出贡献（目标1）;和2）加强 通过增加关键途径分子的表达，将Q途径转化为pMF（目的2）。由于AIH诱导的pLTF 表现出深刻的年龄依赖性的两性异形，我们将测试的假设，1）Q和S途径 对pMF的影响受年龄和发情周期雌性大鼠的影响不同（目的3）; 2）年龄和性别是关键 rAIH增强膈肌运动可塑性的决定因素（目的4）。这些研究将大大促进我们的 了解rAIH增强的膈运动可塑性，并加速我们利用rAIH作为一种 治疗危害呼吸和威胁生命本身的破坏性临床疾病的治疗方式。

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.