Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker–network model

Smith, Jeffrey C.; Butera, Robert J.; Koshiya, Naohiro; Negro, Christopher Del; Wilson, Christopher G.; Johnson, Stephen E.

doi:10.1016/s0034-5687(00)00155-9

Cited by 250 publications

(261 citation statements)

References 44 publications

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“…A detailed understanding of the cellular mechanisms underlying rhythm and pattern generation with the ventrolateral medulla remains to be elucidated. However, there are data to support a pacemakernetwork hypothesis, which states that the kernel for rhythm generation consists of a population of neurons with intrinsic pacemaker properties that are embedded within, and modulated by, a neuronal network (Rekling and Feldman, 1998;Smith et al, 2000). It has been postulated that the pacemaker properties arise from intrinsic voltage-dependent conductances that confer increases in burst frequency at depolarized membrane potentials and decreases, to the point of inhibiting rhythmic bursting, at hyperpolarized membrane potentials Butera et al, 1999a,b).…”

Section: Discussionmentioning

confidence: 99%

Absence ofNdn, Encoding the Prader-Willi Syndrome-Deleted Genenecdin, Results in Congenital Deficiency of Central Respiratory Drive in Neonatal Mice

et al. 2003

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necdin (Ndn) is one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome. necdin is upregulated during neuronal differentiation and is thought to play a role in cell cycle arrest in terminally differentiated neurons. Most necdin-deficient Ndn tm2Stw mutant pups carrying a targeted replacement of Ndn with a lacZ reporter gene die in the neonatal period of apparent respiratory insufficiency. We now demonstrate that the defect can be explained by abnormal neuronal activity within the putative respiratory rhythm-generating center, the pre-Bötzinger complex. Specifically, the rhythm is unstable with prolonged periods of depression of respiratory rhythmogenesis. These observations suggest that the developing respiratory center is particularly sensitive to loss of necdin activity and may reflect abnormalities of respiratory rhythm-generating neurons or conditioning neuromodulatory drive. We propose that necdin deficiency may contribute to observed respiratory abnormalities in individuals with Prader-Willi syndrome through a similar suppression of central respiratory drive.

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Section: Discussionmentioning

confidence: 99%

Absence ofNdn, Encoding the Prader-Willi Syndrome-Deleted Genenecdin, Results in Congenital Deficiency of Central Respiratory Drive in Neonatal Mice

et al. 2003

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“…The data presented in this study suggest that endogenously released 5-HT acting on the 5-HT 2A receptor modulates the transient and the persistent sodium current in PBC neurons. This is particularly interesting because the activation of the persistent sodium current in respiratory neurons has been implicated in the generation of the respiratory rhythm (Butera et al, 1999;Smith et al, 2000).…”

Section: Abstract: Respiratory Rhythm; Endogenous Serotonin; Pre-bö mentioning

confidence: 99%

“…Because of their potential role in generating the respiratory rhythm (Rekling and Feldman, 1998;Butera et al, 1999;McCrimmon et al, 2000;Smith et al, 2000), we examined the effects of 5-HT 2A antagonists on this pacemaker activity. Pacemaker neurons were synaptically isolated by applying the mixture containing CPP, CNQX, bicuculline, and strychnine as described above plus a gap-junction blocker (50 M 18␤-glycyrrhetinic acid).…”

Section: -Ht 2a Antagonists Differently Affect Cadmiuminsensitive Anmentioning

confidence: 99%

“…A slowly inactivating persistent sodium current has been demonstrated in pacemaker neurons Del Negro et al, 2002) and is postulated to underlie pacemaker activity in pre-Bötzinger neurons (Butera et al, 1999;Smith et al, 2000;Del Negro et al, 2002). Indeed, all pacemaker neurons in the PBC cease to generate pacemaker activity in the presence of TTX (Thoby-Brisson and Ramirez, 2001).…”

Section: Role Of Sodium-dependent Burst Activity In Respiratory Rhythmmentioning

confidence: 99%

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Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

2002

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Endogenous amines and peptides continuously modulate the activity of neuronal networks and are required even for their normal operation. The respiratory rhythm generator, localized in the pre-Bö tzinger complex, is not an exception. This network is modulated by various neurotransmitters, including serotonin (5-HT). In this study, we isolated the respiratory network in brainstem slices and demonstrate that the endogenous activation of 5-HT 2A is required for the generation of the respiratory rhythm in vitro. At the network level, activation of 5-HT 2A receptors with 4-iodo-2,5-dimethoxyamphetamine or the 5-HT uptake blocker alaproclate increased the frequency of respiratory activity. Blockade of endogenously activated 5-HT 2A receptors with three different antagonists decreased the frequency, amplitude, and regularity of respiratory population activity, an effect that was blocked by protein kinase C (PKC) activators. At the cellular level, blockade of 5-HT 2A receptors reduced the action potential discharge in all examined respiratory neurons, which was associated with a reduction in the fast and the persistent sodium current. Continuous application of 5-HT 2A -receptor antagonists differentially affected pacemaker neurons. Pacemaker activity was eliminated in cadmiuminsensitive pacemaker neurons. In cadmium-sensitive pacemaker neurons, the frequency of pacemaker activity was unaffected and the amplitude of pacemaker bursts was enhanced. It is assumed that cadmium-insensitive pacemakers rely on the persistent sodium current, whereas cadmium-sensitive pacemakers depend on the activation of calcium currents. We conclude that endogenously activated 5-HT 2A receptors are required for maintaining fictive respiratory activity in the brainstem slice by modulating sodium conductances via a PKC pathway.

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“…(21) DEMONSTRATED in the in vitro neonatal rat brain stem preparation that elimination of the pre-Bötzinger complex (pre-BötzC) caused cessation of respiratory rhythm. Since then, results from many in vitro studies support the pre-BötzC as the site or "kernel" of respiratory rhythm generation (9,19,20,21). Furthermore, in in vivo studies on anesthetized cats and rats, injection of the glutamate receptor agonist DL-homocysteic acid into the pre-BötzC area increases tonic and/or phasic phrenic nerve output, whereas injections into other proximal or distal nuclei do not increase respiratory rhythm (1,15,22), thus providing a physiological definition of the preBötzC.…”

mentioning

confidence: 99%

Large lesions in the pre-Bötzinger complex area eliminate eupneic respiratory rhythm in awake goats

Wenninger

Pan

Klum

et al. 2004

Journal of Applied Physiology

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.-In awake goats, 29% bilateral destruction of neurokinin-1 receptorexpressing neurons in the pre-Bötzinger complex (pre-BötzC) area with saporin conjugated to substance P results in transient disruptions of the normal pattern of eupneic respiratory muscle activation (Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, Hodges MR, Feroah T, Davis S, and Forster HV. J Appl Physiol 97: 1620 -1628, 2004). Therefore, the purpose of these studies was to determine whether large or total lesioning in the pre-BötzC area of goats would eliminate phasic diaphragm activity and the eupneic breathing pattern. In awake goats that already had 29% bilateral destruction of neurokinin-1 receptor-expressing neurons in the pre-BötzC area, bilateral ibotenic acid (10 l, 50 mM) injection into the pre-BötzC area resulted in a tachypneic hyperpnea that reached a maximum (132 Ϯ 10.1 breaths/min) ϳ30 -90 min after bilateral injection. Thereafter, breathing frequency declined, central apneas resulted in arterial hypoxemia (arterial PO 2 ϳ40 Torr) and hypercapnia (arterial PCO2 ϳ60 Torr), and, 11 Ϯ 3 min after the peak tachypnea, respiratory failure was followed by cardiac arrest in three airway-intact goats. However, after the peak tachypnea in four tracheostomized goats, mechanical ventilation was initiated to maintain arterial blood gases at control levels, during which there was no phasic diaphragm or abdominal muscle activity. When briefly removed from the ventilator (ϳ90 s), these goats became hypoxemic and hypercapnic. During this time, minimal, passive inspiratory flow resulted from phasic abdominal muscle activity. We estimate that 70% of the neurons within the pre-BötzC area were lesioned in these goats. We conclude that, in the awake state, the pre-BötzC is critical for generating a diaphragm, eupneic respiratory rhythm, and that, in the absence of the pre-BötzC, spontaneous breathing reflects the activity of an expiratory rhythm generator. respiratory rhythm generator; terminal apnea; inspiratory and preinspiratory neurons SMITH ET AL. (21) DEMONSTRATED in the in vitro neonatal rat brain stem preparation that elimination of the pre-Bötzinger complex (pre-BötzC) caused cessation of respiratory rhythm. Since then, results from many in vitro studies support the pre-BötzC as the site or "kernel" of respiratory rhythm generation (9,19,20,21). Furthermore, in in vivo studies on anesthetized cats and rats, injection of the glutamate receptor agonist DL-homocysteic acid into the pre-BötzC area increases tonic and/or phasic phrenic nerve output, whereas injections into other proximal or distal nuclei do not increase respiratory rhythm (1,15,22), thus providing a physiological definition of the preBötzC. In addition, in vivo studies in anesthetized or decerebrate cats or rats demonstrate that lesioning of the pre-BötzC results in transient (24) or irreversible (7, 10, 18) elimination of eupneic respiratory activity. Further demonstrating the importance of the pre-BötzC in control of breathing was a study showing that Ͼ80% destruction o...

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Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker–network model

Cited by 250 publications

References 44 publications

Absence ofNdn, Encoding the Prader-Willi Syndrome-Deleted Genenecdin, Results in Congenital Deficiency of Central Respiratory Drive in Neonatal Mice

Absence ofNdn, Encoding the Prader-Willi Syndrome-Deleted Genenecdin, Results in Congenital Deficiency of Central Respiratory Drive in Neonatal Mice

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

Large lesions in the pre-Bötzinger complex area eliminate eupneic respiratory rhythm in awake goats

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