The objective of this proposal is to determine if intermittent hypoxia induces neural plasticity in the ventilatory control system. Specifically, the goal is to determine if repeated activation of the hypoxic ventilatory control system by exposure to chronic intermittent hypoxia induces a persistent functional enhancement of the system. Adult male rats will be exposed to chronic intermittent hypoxia (11 percent 02/air: 5-min/5-min, 12 h/day, 7 nights consecutively). Their previous data indicate a persistent and profound functional enhancement of the system after chronic intermittent hypoxia, including: 1) enhancement of phrenic and hypoglossal nerve responses to acute hypoxia, and 2) augmentation of long-term facilitation (a serotonin-dependent enhancement of respiratory activity that lasts for many minutes to hours after episodes of isocapnic hypoxia). In addition, the induced enhancement is primarily a central event (not carotid body) and requires serotonergic mechanisms. In this proposal, they plan to confirm these preliminary results, extend these observations to awake animals, investigate the effects of age on this enhancement and further define the exposure protocol. These objectives will be pursued by combining plethysmographic measurements of the hypoxic ventilatory response in awake rats with neurophysiological experiments in anesthetized rats. Five specific hypotheses will be tested: 1) chronic intermittent hypoxia causes prolonged enhancement of ventilatory responses to hypoxia; 2) chronic intermittent hypoxia enhances central integration of carotid chemoafferent inputs; 3) chronic intermittent hypoxia enhances carotid chemosensory transduction; 4) functional enhancement of the system following chronic intermittent hypoxia requires serotonergic mechanisms; and 5) chronic intermittent hypoxia during neonatal periods enhances hypoxic ventilatory responses in adult rats. These experiments imply that a fully developed, hypoxic ventilatory control system still exhibits an impressive degree of plasticity. The information derived from the proposed studies may contribute to our understanding the neural plasticity ventilatory control and may provide the rationale for therapies in some diseases.

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National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory and Applied Physiology Study Section (RAP)
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Brigham and Women's Hospital
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Cao, Ying; McGuire, Michelle; Liu, Chun et al. (2012) Phasic respiratory modulation of pharyngeal collapsibility via neuromuscular mechanisms in rats. J Appl Physiol 112:695-703
Liu, Chun; Cao, Ying; Malhotra, Atul et al. (2011) Sleep fragmentation attenuates the hypercapnic (but not hypoxic) ventilatory responses via adenosine A1 receptors in awake rats. Respir Physiol Neurobiol 175:29-36
Cao, Ying; Ling, Liming (2010) Urethane inhibits genioglossal long-term facilitation in un-paralyzed anesthetized rats. Neurosci Lett 477:124-8
Cao, Ying; Liu, Chun; Ling, Liming (2010) Glossopharyngeal long-term facilitation requires serotonin 5-HT2 and NMDA receptors in rats. Respir Physiol Neurobiol 170:164-72
McGuire, Michelle; Liu, Chun; Cao, Ying et al. (2008) Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats. J Appl Physiol 105:942-50
Ling, Liming (2008) Serotonin and NMDA receptors in respiratory long-term facilitation. Respir Physiol Neurobiol 164:233-41
McGuire, Michelle; Tartar, Jaime L; Cao, Ying et al. (2008) Sleep fragmentation impairs ventilatory long-term facilitation via adenosine A1 receptors. J Physiol 586:5215-29
McGuire, Michelle; Zhang, Yi; White, David P et al. (2005) Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats. J Physiol 567:599-611
McGuire, Michelle; Ling, Liming (2005) Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats. J Appl Physiol 98:1195-201
McGuire, Michelle; Zhang, Yi; White, David P et al. (2004) Serotonin receptor subtypes required for ventilatory long-term facilitation and its enhancement after chronic intermittent hypoxia in awake rats. Am J Physiol Regul Integr Comp Physiol 286:R334-41

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