Transient, reversible apnoea following ablation of the pre‐Bötzinger complex in rats

Abstract

The rhythmic alterations of cranial and spinal nerves which are characteristic of eupnoeic ventilatory activity are dependent upon two interrelated processes. Neuronal mechanisms within the pontile and medullary brainstem are responsible for generating the eupnoeic rhythm. For this rhythm to be expressed in activities of cranial and spinal nerves, a level of tonic neuronal input is required (e.g. Euler, 1986;St-John, 1998a). Thus, eupnoea could be eliminated following ablation of neurons which are responsible for its neurogenesis andÏor which provide for a tonic input. The necessity of a tonic input for eupnoea to be manifested is inherent in the concept of an 'apnoeic threshold' for arterial partial pressures of carbon dioxide. Hence, apnoea can be induced by hyperventilation of anaesthetized or decerebrate preparations (see Cherniack et al. 1979;Euler, 1986 for discussion). The apnoea which follows a blockade of neuronal activities in extensive regions on or near the ventrolateral medullary surface is likewise considered to result from the elimination of a tonic input (see St-John, 1998a for review). As opposed to a tonic input, neuronal activities within a rostral medullary pre-B otzinger complex have been hypothesized to be an exclusive mechanism for generating the eupnoeic rhythm (Smith et al. 1990(Smith et al. , 1991Rekling & Feldman, 1998). This hypothesis was based upon the finding that ablation of neurons in this region eliminates the rhythmic activity of an in vitro brainstem-spinal cord preparation of the neonatal rat. Yet, this rhythmic activity differs markedly from eupnoea in vivo but appears identical with gasping (St-John, 1996;1998a). Ablation of the pre-B otzinger complex in vivo has led to inconsistent findings. In anaesthetized or decerebrate adult cats, eupnoea continued following the placement of multiple lesions which, in sum, destroyed the entire pre-B otzinger complex (Speck & Feldman, 1982;Speck & Beck, 1989). In decerebrate newborn rats, unilateral injections of the neurotoxin kainic acid into the pre-B otzinger complex did not eliminate eupnoea (Huang et al. 1997). In anaesthetized adult rats, apnoea is reported following bilateral injections of the GABA agonist muscimol into the rostral ventrolateral medulla (Koshiya et al. 1993;Koshiya & Guyenet, 1996). Recently, Ramirez et al. 1998 reported that injections of reversible blockers of synaptic activity into the pre-B otzinger complex of anaesthetized adult cats caused transient reductions of phrenic activity. At some, but not all of these effective sites, bilateral injections of

Atropine microdialysis within or near the pre-Bötzinger Complex increases breathing frequency more during wakefulness than during NREM sleep

“…These data led to the conclusion that the neurogenesis of eupnea is within rostral pontine nuclei (53). This conclusion is supported by data showing that chemical destruction of the preBötC in vivo only transiently eliminated respiratory rhythm (51). Moreover, data from other studies have shown that a pontine-medullary circuit is necessary for the three-phase eupneic respiratory rhythm and that the medulla in isolation is only capable of generating the gasping rhythm (48,52,53).…”

“…Likewise, based on data from carbachol-induced rapid-eye-movement (REM) sleep and in vitro studies, it has been hypothesized that direct and indirect excitatory M 2 receptor modulation of hypoglossal motoneurons maintains a patent upper airway during REM sleep (4,5). Furthermore, strong support for a role for mAChRs in respiratory rhythmogenesis comes from studies using a medullary slice preparation from neonatal rats that found that local application of ACh excites 88% of inspiratory neurons within the pre-Bötzinger Complex (preBötC), a site critical for respiratory rhythm generation in some (55,57), but not all (51,53), studies. These preBötC responses to ACh were blocked by atropine and by specific blockers of M 3 receptors, but not by specific blockers of M 1 , M 2 , or M 5 receptors, leading to the conclusion that ACh is excitatory to preBötC neurons (45,46), likely through the activation of postsynaptic M 3 receptors.…”

Dichlorvos-induced central apnea: Effects of selective brainstem exposure in the rat

“…There is substantial evidence pointing to the importance of specific neuronal groups within the ventral medulla. The pre-Bötzinger complex (preBötC) contains cholinergic neurons[10] and is integral to normal respiratory function[11]. Other sites in the ventral region of the medulla are involved in respiratory control and contain cholinergic synapses, including the ventral surface of the medulla[12], the nucleus ambiguus[13] and the retrotrapezoid nucleus[14].…”

Noeud vital for breathing in the brainstem: gasping—yes, eupnoea—doubtful

“…Thus, the return of eupnoea was not due to actions of remnants, if any, of the pre-Bö tzinger complex but rather to a reorganization of the pontomedullary neuronal circuit for eupnoea. Importantly, gasping was eliminated irreversibly following these perturbations of the pre-Bö tzinger complex (St Jacques & St John 1999).…”