The role of the pre-Botzinger complex in respiratory rhythmogenesis and chemosensitivity during physiologic conditions.

摘要

The pre-Botzinger Complex (preBotzC), located within the ventral respiratory group, has been shown to be critical in generating the normal respiratory rhythm, and has also been implicated in respiratory chemosensitivity. However, many of the studies examining the role of the preBotzC have been performed in reduced or anesthetized preparations, and the role of the preBotzC during different physiologic conditions is relatively unknown. Therefore, the aims of this dissertation were to examine the preBotzC in the adult, conscious animal, including (1) the effects on breathing during a microdialysis-induced focal acidosis of the preBotzC, (2) the effects of respiratory rhythm and pattern when the preBotzC is depressed with opioids, and (3) the effects of respiratory rhythm and blood gas homeostasis during both sleep and wakefulness when the preBotzC is destroyed incrementally. To examine these aims, microtubules were bilaterally implanted into the preBotzC of adult goats, allowing for the microdialysis of mock cerebral spinal fluid (mCSF) equilibrated with different levels of CO2, as well as injection of both reversible and irreversible receptor agonists. A unilateral, but not bilateral acidosis created with dialysis of mCSF equilibrated with 25 and 50% increased inspiratory flow (VI), as a function of increased respiratory frequency (f), by a maximum of 10%, whereas dialysis of 80% CO2 caused disruptions in both respiratory rhythm and pattern. These findings support the conclusions that the preBotzC does contribute to the total respiratory chemosensitive response, and that high levels of CO2 presumably damages rhythmogenic neurons, manifested by irregularities in breathing. Injection of a mu-opioid receptor agonist did not disrupt breathing during eupneic breathing conditions, but did depress breathing during both hypoxia and hypercapnia. These findings support the conclusions that the preBotzC may have a condition-dependent role in respiratory rhythmogenesis. Incremental destruction of the preBotzC with a neurotoxin that binds irreversibly to glutamate receptors resulted in an immediate and profound tachypnia, as well as disruption in both respiratory rhythm and pattern. However, full recovery occurred by the following day, and one week after the final injection, when on average, 84% of the total preBotzC was destroyed, all eupneic breathing variables and blood gases were unchanged from the pre-injection baseline. These findings are in striking contrast with a previous study that demonstrated that an abrupt destruction lesioning 70% of preBotzC results in terminal apnea, and suggest that plasticity within the respiratory network is occurring to maintain blood gas homeostasis. Finally, examining respiratory rhythm and pattern during sleep 10 hours and 5 days after neurotoxin injection, demonstrated that the variability in breathing is greater during wakefulness than sleep, and the variability decreases over time. These findings are in contrast to a previous study that showed that destruction of the preBotzC in rats leads to progressive, increasing disturbances in first rapid eye movement sleep, and then days later, in the non-rapid eye movement sleep state and wakefulness, and that the loss of the preBotzC may result in sleep-disordered breathing (SDB). The findings of the current study suggest that the goat may not be a model for SDB, and also the preBotzC may also have a state-dependent role in respiratory rhythmogenesis.