Insights into the role of the pontine respiratory group in the control of breathing during physiologic conditions

My primary objective was to use an in vivo physiologic preparation to gain further insight into the role of the pontine respiratory group (PRG) in breathing and sleep. This dissertation is a culmination of three specific aims that examine the PRG in the adult animal under physiologic conditions.;Specific aim 1. For many years, acetylcholine has been known to contribute to the control of breathing and sleep. To probe further the contributions of cholinergic rostral pontine systems in breathing and sleep, this study was designed to microdialyze atropine, a competitive muscarinic receptor antagonist, into the pontine respiratory group during physiologic conditions in intact goats. I hypothesized microdialysis (MD) of atropine into the PRG would have site- and state-dependent effects on the control of breathing. In 16 goats, cannula were bilaterally implanted into either rostral pontine tegmental nuclei (RPTN, n=3), the lateral (LPBN, n=3) or medial (MPBN, n=4) parabrachial nuclei, or the Kolliker-fuse nucleus (KFN, n=6). Unilateral and bilateral nighttime MD of atropine into the KFN increased levels of NREM sleep by 63% (p>0.05) and 365% (p<0.01), respectively, via stabilization of sleep mechanisms. MD during the day or at night into the other 3 pontine sites had only minimal effects on any variable studied. Finally, bilateral MD of atropine decreased levels of acetylcholine and choline in the effluent mCSF. My hypothesis regarding site-specific effects was validated given the heterogeneous effects of MD at different pontine sites. My data support the concept that the KFN is a significant contributor to PRG cholinergically modulated control of breathing and sleep.;Specific aim 2. To probe further the contributions of the rostral pons to eupneic respiratory rhythm and pattern, I tested the hypothesis that ibotenic acid (IA) injections into the PRG would disrupt eupneic respiratory rhythm and pattern in a site- and state-specific manner. While awake and during NREM sleep 10--15 hours after the injections, there were increased numbers on apneas. However, there were no incidences of cessation of phasic diaphragm activity and/or terminal apneas. Breathing rhythm and pattern were normal 22 hours after the injections. Subsequent histological analysis of the PRG of lesioned goats showed a reduction in the area and number of neurons per respective target nucleus. These data do not support the concept that sites within the PRG are obligatory for respiratory rhythm generation, but rather that the KFN contributes particularly to eupneic rhythm and pattern.;Specific aim 3. The pontine respiratory group plays a role in numerous respiratory related functions, including regulation of the ventilatory response to hypercapnia and hypoxia. To probe further the contributions of the PRG to these responses, the objective of the present study was to test the hypothesis in my in vivo awake goat model that a perturbation/lesion would decrease the sensitivity to hypercapnia and hypoxia. The study reported herein was part of two larger studies where cholinergic modulation in the PRG was attenuated by MD of atropine, and IA injections neurotoxically lesioned the PRG. In 14 goats, cannula were bilaterally implanted into either the LPBN (n=4), MPBN (n=4), or KFN (n=6). Before and after cannula implantation, MD of atropine, and injection of IA, hypercapnic and hypoxic ventilatory sensitivities were assessed. Hypercapnic sensitivity was assessed by 3, 5 min periods at 3, 5, and 7% inspired CO2. CO2 sensitivity (DeltaV I/DeltaPaCO2) was unaffected (p>0.05) by any PRG perturbations/lesions. Hypoxic sensitivity was assessed with a 30 min period at 10.8% inspired O 2. The response to hypoxia was typically triphasic, with a 1° increase in VI, a 2° roll-off, and a 3° prolonged increase associated with shivering and increased metabolic rate and body temperature. Phase 1 of the hypoxic ventilatory responses was unaffected (p>0.05) by any PRG perturbations/lesions. However, phases 2 and 3 of the hypoxic response were altered by PRG perturbations/lesions. These effects were site-specific as the most consistent effects were with perturbations in the KFN. My findings support an integrative or modulatory role for the PRG, particularly the KFN, in the responses to hypoxia. (Abstract shortened by UMI.).