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的 缺氧发作或慢性间歇性缺氧（CIH），这反过来又引起缺氧后相关变化 伴随呼吸驱动的长时程易化（LTF）和交感神经流出增加。CIH的影响 通过颈动脉体和孤束核（NTS）的二级神经元传递， 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收来自NTS的输入。其中的一个亚群 神经元投射到延髓头端腹外侧区（RVLM）和中线5-羟色胺 （5-HT）-产生神经元，在膈神经和舌下神经的调节中起重要作用的位点 球脊髓交感兴奋神经元的放电和活动。我的项目是基于中央 假设CIH通过下调对PVN的GABA能抑制性输入，将导致过度兴奋 后叶加压素和/或催产素的PVN神经元，通过中线多巴胺能和RVLM 交感神经能神经元增强舌下神经和膈神经运动神经元的反应， 交感兴奋性节前神经元的新的缺氧暴露。研究将在两个 阶段。在指导阶段，我将发展与研究计划相关的实验技能， 表征CIH对GABA能抑制性输入至PVN的影响（目的1：研究1-3）。在 独立期，我将确定PVN在CIH诱导的中线含5-HT细胞LTF中的作用 影响膈神经和舌下神经的活动（目的1：研究4和目的2）。另外，我会调查 加压素和/或催产素信号通路在CIH诱导的交感神经元上调中的作用 活动（目标3）。研究将在停止给药后24小时在对照和实验大鼠中进行。 最后一次暴露于七天或四周的CIH。我将定义GABA能抑制性输入到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，使用 免疫组化、分子方法（真实的时间PCR、Western印迹分析、HPLC和受体配体） 结合测定）和生理学实验（神经传递阻断和神经记录）。 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，并帮助设计特定的治疗方案， 与反复缺氧有关获得这个奖项将使我独立， 我的职业目标是研究室旁核在调节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.