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

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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.