Role of the PVN in Chronic Intermittent Hypoxia-Induced Cardiorespiratory Changes

阻塞性睡眠呼吸暂停、夜间哮喘和心血管疾病与反复发作有关 低氧发作或慢性间歇性低氧(CIH)，继而导致低氧后相关的变化 呼吸驱动的长期易化(LTF)和交感神经流出增加。CIH的影响 通过颈动脉小体和孤束核(NTS)的二级神经元传递到 脑干、呼吸和心血管调节部位。然而，下丘脑室旁核(PVN) 含有加压素和/或催产素的神经元也接受来自NTS的输入。这些人中的一小部分 神经元投射到延髓头端腹外侧区和中线5-羟色胺 产生5-羟色胺的神经元，在膈神经和舌下神经的调节中起重要作用的部位 球脊髓交感兴奋性神经元的放电和活动。我的项目是基于中环 假设CIH通过下调下丘脑室旁核的GABA能抑制输入，将导致过度兴奋 中线5-羟色胺能和RVLM对含加压素和/或催产素的PVN神经元的影响 谷氨酸能神经元增强舌下运动神经元和膈运动神经元的反应 交感神经兴奋性节前神经元对新的低氧暴露。研究将分两个阶段进行 阶段。在指导阶段，我将发展与研究计划相关的实验技能，并 描述CIH对下丘脑室旁核GABA能抑制输入的影响(目标1：研究1-3)。在 独立期，我将确定PVN在CIH诱导的中线5-羟色胺细胞LTF中的作用 影响膈神经和舌下神经的活动(目标1：研究4和目标2)。另外，我还会调查 加压素和/或催产素信号通路在CIH诱导交感神经上调中的作用 活动(目标3)。研究将在对照组和试验组大鼠停止服药24小时后进行 最后一次接触七天或四周的CIH。我将确定GABA能抑制输入对PVN的作用 血管加压素和催产素神经元在CIH诱导的呼吸和心血管变化中的作用 免疫组织化学、分子方法(实时聚合酶链式反应、蛋白印迹分析、高效液相和受体配体 结合实验)和生理实验(阻断神经传递和神经记录)。 这些研究将有助于更好地理解CIH诱导的神经机制。 心肺变化，并协助设计治疗疾病的特定治疗方案 与反复缺氧有关。获得这个奖项将使我在未来的日子里更加独立. 追求我的职业目标，研究下丘脑室旁核在调节与压力相关的自主神经紊乱中的作用。

Obstructive sleep apnea, nocturnal asthma, and cardiovascular disorders are associated with repeated hypoxic episodes or chronic intermittent hypoxia (CIH), that In turn, cause post-hypoxic changes associated with long-term facilitation (LTF) of respiratory drive and increased sympathetic outflow. The effects of CIH are transmitted through carotid bodies and second order neurons of the nucleus tractus solitarius (NTS), to brainstem respiratory and cardiovascular regulating sites. However, hypothalamic paraventricular (PVN) neurons containing vasopressin and/or oxytocin, also receive inputs from the NTS. A subpopulatlon of these neurons projects to the rostral ventrolateral region of the medulla oblongata (RVLM) and midline serotonin (5-HT)-producing neurons, sites that play an important role in regulation of phrenic and hypoglossal nerve discharge and activity of bulbospinal sympathoexcitatory neurons. My project is based on the central hypothesis that CIH, via downregulation of GABAergic inhibitory inputs to the PVN, will lead to overexcitation of vasopressin- and/or oxytocin-containing PVN neurons that through midline serotonergic and RVLM glutamatergic neurons enhance the responses of hypoglossal and phrenic motoneurons and of sympathoexcitatory preganglionic neurons to a new hypoxic exposure. Studies will be carried out in two phases. In the Mentored phase, I will develop my experimental skills pertinent to the research plan and characterize the effects of CIH on GABAergic Inhibitory inputs to the PVN (Aim 1: Studies 1-3). In the Independent phase, I will determine the role of the PVN in CIH-induced LTF of midline 5-HT-containing cells affecting activity of phrenic and hypoglossal nerves (Aim 1: Study 4 and Aim 2). In addition, I will investigate the role of vasopressin and/or oxytocin signaling pathways in CIH-induced upregulation of sympathetic activity (Aim 3). Studies will be performed in control and experimental rats at 24 hours after cessation of their last exposure to seven days or four weeks of CIH. I will define the role of GABAergic inhibitory Inputs to PVN vasopressin- and oxytocin-containing neurons in CIH-induced respiratory and cardiovascular changes, using immunohistochemistry, molecular approaches (real time PCR, Western blot analysis, HPLC and receptorligand binding assay), and physiological experiments (blockade of neural transmission and nerve recording). These studies will contribute to better understanding of neuronal mechanisms involved in CIH-induced cardiorespiratory changes, and aid in designing specific therapeutic regimes in treatment of conditions associated with repeated oxygen deprivation. The attainment of this award will make me independent In pursuing my career goal to study the role of the PVN In mediating stress-related autonomic disturbances.