| Summary: | 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.
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