The role of serotonin in central sleep apnea, sympathoexcitation, and heart failure in spinalcord injured mice.

项目摘要 睡眠呼吸暂停，影响2-4%的一般人群和8-10%的退伍军人人口，是15倍 在脊髓损伤（SCI）患者中更常见。睡眠呼吸暂停与心血管并发症有关， 包括高血压、冠状动脉疾病（CAD）、中风和心房纤颤，沿着自主神经， 代谢和认知共病。有三种神经调节机制决定了 呼吸暂停事件的频率和持续时间：上呼吸道通透性、唤醒和化学反射反应 缺氧和高碳酸血症我们的工作揭示了对缺氧的唤醒和化学反射反应， 在中枢神经系统（TPH 2-/-）中缺乏5-羟色胺（5-HT）的小鼠中，高碳酸血症的作用减弱。 此外，我们还发现SCI导致野生型大鼠中枢神经系统5-HT的耗竭， 小鼠（TPH 2 +/+），再加上对缺氧和高碳酸血症的唤醒和化学反射反应的钝化。我们 假设对低氧和高碳酸血症的唤醒和化学反射反应的钝化导致 呼吸暂停频率和持续时间增加。除了这些修改，我们建议， TPH 2-/-小鼠中枢神经系统中的5-HT伴随着左心室几何形状的改变 交感神经系统活动（SNSA）增加，可能导致心力衰竭。我们的初步 研究显示TPH 2-/-小鼠的左心室肥大是明显的，这可以通过保守的射血来证明。 分数和左心室质量增加。同样，在TPH 2-/-小鼠中SNSA增加是明显的。 我们假设在TPH 2-/-小鼠中观察到的这些变化在TPH 2 +/+小鼠中也是明显的， SCI.我们认为，我们的研究结果提供了一个潜在的统一机制，可以解释这种联系 中枢性睡眠和心力衰竭之间的联系研究结果还将为以下方面提供依据： 治疗性调节5-HT水平及其受体亚型以减轻中枢调节的呼吸暂停事件 脊髓完整或损伤的退伍军人的心脏功能障碍。

Project Summary Sleep apnea, which affects 2-4% of the general population and 8-10% in the veteran population, is 15 times more prevalent in patients with spinal cord injury (SCI). Sleep apnea is linked to cardiovascular co-morbidities, including hypertension, coronary artery disease (CAD), stroke, and atrial fibrillation, along with autonomic, metabolic, and cognitive co-morbidities. There are three neurally regulated mechanisms that determine the frequency and duration of apneic events: upper airway collapsibility and the arousal and chemoreflex response to hypoxia and hypercapnia. Our work revealed that the arousal and chemoreflex response to hypoxia and hypercapnia are blunted in mice with a deficiency of serotonin (5-HT) in the central nervous system (TPH2-/-). Additionally, we also uncovered that SCI leads to depletion of 5-HT in the central nervous system in wild-type mice (TPH2+/+), coupled to blunting of the arousal and chemoreflex response to hypoxia and hypercapnia. We hypothesize that blunting of the arousal and chemoreflex response to hypoxia and hypercapnia leads to increases in apnea frequency and duration. In addition to these modifications, we propose that the depletion of 5-HT in the central nervous system is accompanied by alterations in left ventricular geometry in TPH2-/- mice and increases in sympathetic nervous system activity (SNSA) that could lead to heart failure. Our preliminary work revealed left ventricular hypertrophy was evident in TPH2-/- mice, as evidenced by a conserved ejection fraction and an increase in left ventricular mass. Likewise, increased SNSA was evident in the TPH2-/- mice. We hypothesize that these changes observed in TPH2-/- mice will also be evident in TPH2+/+ mice following SCI. We propose that our results provide an underlying unifying mechanism that could explain the link between central sleep and heart failure in SCI mammals. The results will also provide the rationale to therapeutically modulates 5-HT levels and its receptor sub-types to mitigate centrally modulated apneic events and cardiac dysfunction in Veterans with intact or injured spinal cord.