Appropriate breathing requires 1) feedback concerning the level of CO2 from central chemoreceptors, and 2) a tonic 'drive', partly from CO2, and partly from other sources including the rostral ventrolateral medulla (RVLM). Recent work established that 1) central chemoreception is present at many brainstem locations, and 2) the retrotrapezoid nucleus (RTN) is a key RVLM site that provides both chemoreception and a tonic drive to breathe. We ask: Why are there so many central chemoreceptor sites? How do they work? What is the physiological role of the RTN in the control of breathing? We will evaluate chemoreceptor and RTN function during sleep and wakefulness in a chronic unanesthetized rat model using a microdialysis probe to deliver substances to the RTN (or other site). The probe tip is 1 mm in length and 240 mum in diameter, a volume of 45 nl. It allows repeated application of neuroactive substances at the same site in the same animal with continuous measurement of ventilation and oxygen consumption (whole body plethysmograph), arousal state (EEG, nuchal EMG), body temperature and blood pressure (telemetry), and, in some cases, blood gases and pH. Approximately 2/3 of the experiments use this model; 1/3 an anesthetized, ventilated rat with phrenic activity as the measure of respiratory output. For studies of chemoreception physiology, we produce focal tissue acidosis by CO2 microdialysis in both models. For studies of mechanism, we alter neural function by injection/dialysis within the focal region of acidosis in the anesthetized rat. For studies of the RTN, we inhibit neurons reversibly by dialysis with muscimol, a GABA-A receptor agonist, in the chronic model. Central chemoreceptor physiology is significant; CO2 is a key component of the respiratory control system and CO2 retention in disease causes morbidity. Chemoreception and RTN function vary with arousal state, and thus are likely to be important in sleep disordered breathing, and the RTN is hypothesized to be an animal homologue for the arcuate nucleus, described as abnormal in SIDS victims.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL028066-22
Application #
6536806
Study Section
Special Emphasis Panel (ZRG2-GMA-2 (01))
Program Officer
Twery, Michael
Project Start
1981-12-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
22
Fiscal Year
2002
Total Cost
$359,780
Indirect Cost
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
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
Nattie, Eugene; Li, Aihua (2012) Respiration and autonomic regulation and orexin. Prog Brain Res 198:25-46
Nattie, Eugene; Li, Aihua (2012) Central chemoreceptors: locations and functions. Compr Physiol 2:221-54
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; 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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