""""""""Automatic"""""""" breathing movements, which occur without conscious effort, are generated within the pontile and medullary portions of the brainstem. Eupnea is normal breathing. In eupnea, sufficient oxygen is supplied to the body and carbon dioxide is removed to meet the metabolic demands. If eupnea ceases, hypoxia will develop. Severe hypoxia recruits gasping, which is a mechanism for """"""""autoresuscitation."""""""" We have proposed that fundamentally different mechanisms generate eupnea and gasping. Eupnea reflects the output of a pontomedullary neuronal circuit whereas gasping is generated by the discharge of medullary pacemakers. During eupnea, these pacemaker mechanisms are suppressed. Studies will evaluate multiple hypotheses concerning the neurophysiological mechanisms by which respiratory rhythms are generated. Included will be an evaluation that medullary neurons, with discharge characteristics consonant with generating the gasp, will continue rhythmic bursts following a blockade of synaptic transmission. Hence, these bursts are considered to represent a """"""""pacemaker discharge."""""""" The studies require the reversible alteration from eupnea to gasping. Both extracellular and intracellular recordings of neuronal activities will be obtained continuously. Agents will be applied to block synaptic transmission. The in situ preparations of the """"""""neonatal"""""""" and """"""""juvenile"""""""" rats are uniquely suited for these studies. Hypoxia-induced gasping can be reversibly induced, viability is maintained following administration of pharmacological agents to block synaptic transmission, and the minimal movements of the brainstem make possible the extracellular and intracellular recordings of neuronal activities. Results of these studies will provide significant and unique information as to the mechanisms by which normal breathing is generated. Such information might provide insights into dysfunctions of the control of ventilation in humans, such as in """"""""sleep apnea"""""""" or the """"""""sudden infant death syndrome."""""""" ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL026091-23A2
Application #
7140802
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Golden, AL
Project Start
1982-01-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
23
Fiscal Year
2006
Total Cost
$330,455
Indirect Cost
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
St-John, Walter M; Li, Aihua; Leiter, J C (2009) Genesis of gasping is independent of levels of serotonin in the Pet-1 knockout mouse. J Appl Physiol (1985) 107:679-85
St-John, Walter M; Stornetta, Ruth L; Guyenet, Patrice G et al. (2009) Location and properties of respiratory neurones with putative intrinsic bursting properties in the rat in situ. J Physiol 587:3175-88
St-John, Walter M (2008) Eupnea of in situ rats persists following blockers of in vitro pacemaker burster activities. Respir Physiol Neurobiol 160:353-6
St-John, Walter M; Leiter, J C (2008) Maintenance of gasping and restoration of eupnea after hypoxia is impaired following blockers of alpha1-adrenergic receptors and serotonin 5-HT2 receptors. J Appl Physiol 104:665-73
St-John, Walter M; Waki, Hidefumi; Dutschmann, Mathias et al. (2007) Maintenance of eupnea of in situ and in vivo rats following riluzole: a blocker of persistent sodium channels. Respir Physiol Neurobiol 155:97-100
Toppin, Veronica A L; Harris, Michael B; Kober, Anna M et al. (2007) Persistence of eupnea and gasping following blockade of both serotonin type 1 and 2 receptors in the in situ juvenile rat preparation. J Appl Physiol 103:220-7
Harris, Michael B; St-John, Walter M (2005) Phasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation. Am J Physiol Regul Integr Comp Physiol 289:R450-R455
Pierrefiche, Olivier; Shevtsova, Natalia A; St-John, Walter M et al. (2004) Ionic currents and endogenous rhythm generation in the pre-Botzinger complex: modelling and in vitro studies. Adv Exp Med Biol 551:121-6
St-John, Walter M; Leiter, J C (2003) High-frequency oscillations of phrenic activity in eupnea and gasping of in situ rat: influence of temperature. Am J Physiol Regul Integr Comp Physiol 285:R404-12
Harris, Michael B; St -John, Walter M (2003) Tonic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation. Am J Physiol Regul Integr Comp Physiol 285:R215-21

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