The modulation and regulation of episodic breathing in mammals
Creators: name: Zimmer, Mary Elizabeth
Publisher: name: University of British Columbia
Year: 2009

description: Within mammals, episodic breathing is commonly observed in marine mammals which spend a large proportion of their time under water, some species of hibernating mammals where body temperature and metabolism are extremely reduced, hypothermic neonatal rat pups in which body temperature and metabolism are also reduced, and even in isolated rat brainstem-spinal cord preparations at reduced temperatures. Current models of mammalian respiratory neural control can not explain how these patterns are produced, and therefore do not adequately explain respiratory control in general. This thesis was designed to test hypotheses concerning the generation and modulation of episodic breathing in various species, under various conditions, and provide new insights into basic mechanisms of respiratory control in mammals. During entrance into hibernation, the breathing pattern of some mammals waxes and wanes and an episodic pattern forms during deep hibernation. I found that the episodic breathing pattern changed as a function of temperature in the golden mantled ground squirrel during steady state hibernation at different temperatures. Breathing pattern changed in conjunction with temperature dependent changes in metabolism, while total ventilation remained unchanged (over a 5-14°C temperature range). This supports other data that showed elevated air convection requirements during hibernation, and implicates factors other than metabolism in regulating the level of total ventilation during the hibernation state (Chapter 2). In order to determine the effect of temperature, independent of changes in arousal state on breathing pattern, hypothermia was experimentally induced in the same species during the summer. Reductions in body temperature and metabolic rate also led to the formation of episodic breathing patterns at very low temperatures (5°C), demonstrating that hibernation associated changes and changes in state are not necessary for production of episodic breathing (Chapter 3). Furthermore, changes in the chemosensitivity to hypercapnia and hypoxia during hypothermia were examined to determine the effect of temperature independent of hibernation influences. I found that the chemosensitivity to hypercapnia was retained during hypothermia. This may be unique to hibernators and play a stronger role in the regulation of breathing during hibernation. The response to hypoxia was abolished during hypothermia, however, indicating that something unique to the hibernation state may be involved in maintaining hypoxic sensitivity during hibernation (Chapter 3). Cooling isolated brainstem spinal cord preparations revealed that episodic breathing patterns of respiratory motor discharge originate from neural centers in the medulla in both hibernating species (hamsters; Chapter 5) and non-hibernating species (rats; Chapter 4). One possible neural mechanism underlying the switch from continuous to episodic breathing involves the blockade of GABAA receptors in the medulla (Chapter 6). Whether this is the same mechanism that initiates episodic breathing during reduced temperatures, in vivo and in vitro, remains to be seen. From the data collected in this thesis concerning the modulation of episodic breathing, and the available literature on the neural control of breathing in mammals, I have proposed a new hypothesis about how respiratory rhythm generation arises; the segmental respiratory rhythm generator hypothesis (Chapter 7). My model consists of two anatomically and functionally distinct rhythm generators (a rostral rhythm generator, RRG, and a caudal rhythm generator, the pre- Bötzinger complex), which under appropriate conditions can produce either a regular, continuous pattern of neural discharge or an episodic pattern of motor discharge. Under "normal" conditions, the two networks are functionally connected, and although both networks produce activity, the I neurons from the pre-Bötzinger complex drive motor discharge. During reductions in temperature, metabolism, and state, the pre-I neurons from the RRG can "escape" from the control of the I neurons of the pre-Bötzinger complex, and putative intrinsic mechanisms now drive an episodic rhythm.