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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL028066-32
Application #
8402588
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
1994-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
32
Fiscal Year
2013
Total Cost
$372,280
Indirect Cost
$136,660
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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
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
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
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
Nattie, Eugene (2011) Julius H. Comroe, Jr., distinguished lecture: central chemoreception: then ... and now. J Appl Physiol 110:1-8
Cummings, Kevin J; Hewitt, Julie C; Li, Aihua et al. (2011) Postnatal loss of brainstem serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia. J Physiol 589:5247-56
Penatti, Eliana M; Barina, Alexis E; Raju, Sharat et al. (2011) Maternal dietary tryptophan deficiency alters cardiorespiratory control in rat pups. J Appl Physiol 110:318-28
Ray, Russell S; Corcoran, Andrea E; Brust, Rachael D et al. (2011) Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 333:637-42
Penatti, Eliana; Barina, Alexis; Schram, Koren et al. (2011) Serotonin transporter null male mouse pups have lower ventilation in air and 5% CO2 at postnatal ages P15 and P25. Respir Physiol Neurobiol 177:61-5
Cummings, Kevin J; Li, Aihua; Nattie, Eugene E (2011) Brainstem serotonin deficiency in the neonatal period: autonomic dysregulation during mild cold stress. J Physiol 589:2055-64

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