Contributions of the pre-Bötzinger complex and the Kölliker-fuse nuclei to respiratory rhythm and pattern generation in awake and sleeping goats.

We investigated in three groups of awake and sleeping goats whether there are differences in ventilatory responses after injections of Ibotenic acid (IA, glutamate receptor agonist and neurotoxin) into the pre-Bötzinger complex (preBötC), lateral parabrachial (LPBN), medial (MPBN) parabrachial, or Kölliker-Fuse nuclei (KFN). In one group, within minutes after bilateral injection of 10µl IA (50mM) into the preBötC, there was a 10-fold increase in breathing frequency, but 1.5h later, the goats succumbed to terminal apnea. These data are consistent with findings in reduced preparations that the preBötC is critical to sustaining normal breathing. In a second group, increasing volumes (0.5-10µl) of IA injected at weekly intervals into the preBötC elicited a near-dose-dependent tachypnea and irregular breathing that lasted at least 5h. There were apneas restricted to wakefulness, but none were terminal. Postmortem histology revealed that the preBötC was 90% destroyed, but there was a 25-40% above normal number of neurons in the presumed parafacial respiratory group that may have contributed to maintenance of arterial blood gas homeostasis. In a third group, bilateral injections (1 and 10µl) of IA into the LPBN, MPBN, or KFN did not significantly increase breathing in any group, and there were no terminal apneas. However, 3-5h after the injections into the KFN, breathing frequency was decreased and the three-phase eupneic breathing pattern was eliminated. Between 10 and 15h after the injections, the eupneic breathing pattern was not consistently restored to normal, breathing frequency remained attenuated, and there were apneas during wakefulness. Our findings during wakefulness and NREM sleep warrant concluding that (a) the preBötC is a primary site of respiratory rhythm generation; (b) the preBötC and the KFN are determinants of respiratory pattern generation; (c) after IA-induced lesions, there is time-dependent plasticity within the respiratory control network; and (d) ventilatory control mechanisms are state dependent.

Plasticity of respiratory rhythm-generating mechanisms in adult goats.

Abrupt destruction of >70% of the pre-Bötzinger complex (preBötzC) in awake goats results in terminal apnea (Wenninger et al. 2004b). Herein we report data on awake and sleeping goats in which the preBötzC was incrementally destroyed by injection of ibotenic acid (IBO) in increasing volumes at weekly intervals. All injections resulted in an acute tachypnea and dysrhythmia featuring apneas and increased variation in breathing. In studies at night, 10-15 hours after the injections, apneas were nearly all central and occurred during the awake state and variation in breathing was greater while awake than during NREM sleep. However, one week after the final IBO injection, the breathing pattern, breath-to-breath variation, and arterial blood gases were unchanged from baseline, indicating recovery. Histology revealed more than 90% destruction of the preBötzC region, and greater than 80% destruction of the surrounding area. We conclude: (1) the dysrhythmic effects on breathing acutely after the injection are state-dependent, and (2) after incremental, near-complete destruction of the preBötzC region, time-dependent plasticity within the respiratory network provides a normal respiratory rhythm that sustains normal arterial blood gases.

The carotid chemoreceptors are a major determinant of ventilatory CO2 sensitivity and of PaCO2 during eupneic breathing.

Both carotid and intracranial chemoreceptors are critical to a normal ventilatory CO2-H+ chemosensitivity. At low levels of hypercapnia, the carotid contribution is probably greater than the central contribution but, at high levels, the intracranial chemoreceptors are dominant. The carotid chemoreceptors are also critical to maintaining a stable and normal eupneic PaCO2, but lesion-induced attenuation of intracranial CO2-H+ chemosensitivity does not consistently alter eupneic PaCO2. A major unanswered question is why do intracranial chemoreceptors in carotid body denervation (CBD) animals tolerate an acidosis during eupnea which prior to CBD elicits a marked increase in breathing.