Delineating the acute, intermediate, and long-term effects of pituitary adenylate cyclase-activating peptide on breathing
Date
2014-09-24
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Abstract
Recent evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) is an important stress peptide, involved in the response to acute and chronic stress. Consistent with this function, we also know that PACAP plays a vital role in modulating breathing in neonatal mammals exposed to respiratory and temperature stress, though the exact mechanisms and locations of action are unknown. Likewise, while PACAP stimulates the adult carotid body acutely, the effect of PACAP on breathing in adult mammals over the intermediate term (days) and long term (months) has not been studied. Thus, the aim of the present work was to help delineate the acute, intermediate, and long-term roles of PACAP in modulating breathing in neonatal and adult mammals. In order to study the acute role of PACAP in a neonatal model, we first developed the in situ neonatal rat working heart-brainstem preparation and tested its efficacy using a known stimulant of neonatal respiration, theophylline. In using our newly developed preparation we were able to determine where theophylline acts to stimulate neonatal breathing and also make important comparisons between our semi-intact preparation and more reduced slice preparations (Chapter 2). We then used the in situ neonatal rat working heart-brainstem preparation to study the acute effects of exogenously applied PACAP (Chapter 3). We then studied the intermediate effects of PACAP on breathing by using a model of respiratory stress (chronic intermittent hypoxia) known to alter baseline ventilation as well as the acute hypoxic response (Chapter 4). Finally, we studied the effect of neonatal-maternal separation – a stress known to have long-term effects on breathing – and used quantitative RT-PCR to determine changes in PACAP gene expression in various breathing- and stress-related tissues. Important new findings from these studies include: 1) theophylline stimulates neonatal breathing independently of the carotid bodies, though adenosine receptors in the neonatal carotid body may play a role in mediating the hypoxic response; 2) exogenous PACAP potently stimulates and stabilizes neonatal breathing via carotid body-dependent and -independent mechanism, respectively; 3) PACAP is crucial in adult mice for surviving chronic intermittent hypoxia (a stress of intermediate duration often used to model sleep apnea; 4) chronic stress that has long-term effects on breathing does not change PACAP gene expression, but PACAP gene expression in stress-related tissues is sex-dependent. The experiments performed in this thesis thus help to elucidate the important role of PACAP in neonates and adults, and lead to the conclusion that the effects of PACAP on breathing may be intricately associated with the role of PACAP in stress responses.
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Neuroscience, Physiology
Citation
Mosca, E. V. (2014). Delineating the acute, intermediate, and long-term effects of pituitary adenylate cyclase-activating peptide on breathing (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25541