Central chemoreception refers to the reflex regulation of breathing determined by the detection at many hindbrain sites of brain interstitial fluid (ISF) pH, which monitors the balance of three key processes, alveolar ventilation (via arterial PCO2), cerebral blood flow, and brain tissue metabolism. We hypothesize that three sites (and neurons), the retrotrapezoid nucleus (RTN: glutamatergic, Phox2b- expressing neurons), the medullary raphe (MR: serotonergic neurons), and the lateral hypothalamus (LH: orexinergic neurons) are of particular importance in sleep-related control of breathing, the upper airway and arousal. We propose that in wakefulness, the orexin neurons of the LH excite serotonergic neurons of the MR and both contribute to chemoreception via effects at the RTN. In sleep, orexinergic and medullary serotonergic neurons are less active and ventilatory chemosensitivity is reduced. In rats studied in wakefulness and sleep during both the active and quiet parts of their diurnal cycle, we manipulate these sites alone or in combination by cell specific lesions via orexin receptor-saporin conjugates, by focal dialysis of neuroactive agents, e.g., an OX1R antagonist, and by oral administration of a novel antagonist to both the OX1R and OX2R. We measure breathing as well as the electromyogram (EMG) of the major 'pump'muscle, the diaphragm, and a representative upper airway muscle, the genioglossus, in response to steady-state CO2 stimulation tests and to a newly applied dynamic CO2 test that evaluates the detection threshold at more physiological levels of CO2 elevation. We will also measure ISF pH at RTN and MR in these same conditions. This project continues our long-term focus on central chemoreception as a complex system function-not simply as a single site reflex-and focuses on chemoreceptor sites active in sleep vs wakefulness.
Central chemoreception, which involves detection of brain pH at many locations, provides critical chemical feed-back for the normal regulation of breathing in a breath-to-breath manner. Chemoreception is of particular importance in the stimulation of breathing and arousal during obstructive sleep apnea and in the breathing instability that may follow. We focus on the function in sleep and wakefulness of arousal neurons, orexin and serotonin, that sense pH and affect breathing via a third pH sensing structure, the retrotrapezoid nucleus. Abnormal central chemoreception is a key defect in the congenital central hypoventilation syndrome and is hypothesized to play a role in the Sudden Infant Death Syndrome.
|Barrett, Karlene T; Dosumu-Johnson, Ryan T; Daubenspeck, J Andrew et al. (2016) Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development. J Neurosci 36:3943-53|
|Li, Aihua; Roy, Sarah H; Nattie, Eugene E (2016) An augmented CO2 chemoreflex and overactive orexin system are linked with hypertension in young and adult spontaneously hypertensive rats. J Physiol 594:4967-80|
|Li, Aihua; Nattie, Eugene (2014) Orexin, cardio-respiratory function, and hypertension. Front Neurosci 8:22|
|Ma, Tian; Lopez-Aguiar, Alexandra G N; Li, Aihua et al. (2014) Mice lacking G0S2 are lean and cold-tolerant. Cancer Biol Ther 15:643-50|
|Li, Ningjing; Nattie, Eugene; Li, Aihua (2014) The role of melanin concentrating hormone (MCH) in the central chemoreflex: a knockdown study by siRNA in the lateral hypothalamus in rats. PLoS One 9:e103585|
|Cummings, Kevin J; Commons, Kathryn G; Trachtenberg, Felicia L et al. (2013) Caffeine improves the ability of serotonin-deficient (Pet-1-/-) mice to survive episodic asphyxia. Pediatr Res 73:38-45|
|Li, Ningjing; Li, Aihua; Nattie, Eugene (2013) Focal microdialysis of COýýý in the perifornical-hypothalamic area increases ventilation during wakefulness but not NREM sleep. Respir Physiol Neurobiol 185:349-55|
|Li, Aihua; Hindmarch, Charles C T; Nattie, Eugene E et al. (2013) Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. J Physiol 591:4237-48|
|Ray, Russell S; Corcoran, Andrea E; Brust, Rachael D et al. (2013) Egr2-neurons control the adult respiratory response to hypercapnia. Brain Res 1511:115-25|
|Nattie, Eugene; Li, Aihua (2012) Respiration and autonomic regulation and orexin. Prog Brain Res 198:25-46|
Showing the most recent 10 out of 87 publications