The overall objective of this project is to further our understanding of basic processes involved in the control of breathing. The proposed experiments are designed to investigate interactions between exercise and factors that affect ventilation at rest. In accordance with the requirements of gas exchange, the ventilatory response to exercise is enhanced or attenuated when resting ventilation and blood gases are changed by various chronic treatments, regulating the arterial carbon dioxide tension with the same precision in exercise regardless of its initial value. it is hypothesized that changes in resting ventilatory drive elicit a common mechanism that actively modulates the ventilatory response to exercise. The objective of these experiments is to test this hypothesis and to further investigate the nature of this postulated mechanism. Awake goats trained to wear a respiratory mask and run on a treadmill will be used as an experimental model. To assess the generality of the postulated mechanism which modulates exercise hyperpnea to match the requirements of gas exchange, ventilatory and blood gas responses to exercise will be monitored with a variety of acute treatments that alter resting ventilation and blood gases with varied mechanisms of action. Specific attention will be devoted to hypoxia/exercise interactions using an experimental preparation that allows perfusion of the carotid body chemoreceptors to be isolated from the systemic circulation an awake exercising animal. To further investigate the role of chemoreceptors, experiments will be conducted after carotid body denervation and by using an additional treatment that increases resting ventilation but that changes blood gases int he reverse direction from normal. The role of pulmonary afferents in modulating the ventilatory response to exercise will be investigated via chronic hilar nerve denervation. Finally, the role of chest wall afferents in modulating the ventilatory response to exercise will be investigated via chronic thoracic dorsal rhizotomy. These experiments will further our understanding of interactions between resting ventilatory drive and ventilatory control in exercise. An understanding of these basic processes is fundamental to understanding the effects of many disease states or therapeutic treatments that alter resting ventilation and blood gases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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University of Wisconsin Madison
Schools of Veterinary Medicine
United States
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Mitchell, G S; Turner, D L; Henderson, D R et al. (2008) Spinal serotonin receptor activation modulates the exercise ventilatory response with increased dead space in goats. Respir Physiol Neurobiol 161:230-8
Rhodes, Justin S; van Praag, Henriette; Jeffrey, Susan et al. (2003) Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behav Neurosci 117:1006-16
Johnson, Rebecca A; Mitchell, Gordon S (2003) Exercise-induced changes in hippocampal brain-derived neurotrophic factor and neurotrophin-3: effects of rat strain. Brain Res 983:108-14
Johnson, R A; Rhodes, J S; Jeffrey, S L et al. (2003) Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience 121:1-7
Fuller, David D; Johnson, Stephen M; Johnson, Rebecca A et al. (2002) Chronic cervical spinal sensory denervation reveals ineffective spinal pathways to phrenic motoneurons in the rat. Neurosci Lett 323:25-8
Zabka, A G; Behan, M; Mitchell, G S (2001) Long term facilitation of respiratory motor output decreases with age in male rats. J Physiol 531:509-14
Mitchell, G S; Baker, T L; Nanda, S A et al. (2001) Invited review: Intermittent hypoxia and respiratory plasticity. J Appl Physiol 90:2466-75
Rhodes, J S; Hosack, G R; Girard, I et al. (2001) Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior. Psychopharmacology (Berl) 158:120-31
Mitchell, G S; Powell, F L; Hopkins, S R et al. (2001) Time domains of the hypoxic ventilatory response in awake ducks: episodic and continuous hypoxia. Respir Physiol 124:117-28
Johnson, S M; Wilkerson, J E; Henderson, D R et al. (2001) Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro. J Appl Physiol 91:2703-12

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