Unraveling the mechanism for respiratory rhythm generation

McCrimmon, Donald R.; Ramírez, Jan Marino; Alford, Simon; Zuperku, Edward J.

doi:10.1002/(sici)1521-1878(200001)22:1<6::aid-bies3>3.0.co;2-q

Cited by 43 publications

(15 citation statements)

References 26 publications

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“…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%

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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Section: -Ht 2a Antagonists Differently Affect Cadmiuminsensitive Anmentioning

confidence: 99%

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

2002

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“…Numerous studies and reviews have addressed the question of how the mammalian respiratory rhythm and motor pattern is generated, modulated, and transmitted to the respiratory muscles [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the growing knowledge in this field the models for respiratory rhythm generation are still being discussed controversially [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Reconfiguration of respiratory-related population activity in a rostrally tilted transversal slice preparation following blockade of inhibitory neurotransmission in neonatal rats

Funke

Müller

Dutschmann

2008

Pflugers Arch - Eur J Physiol

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Recent studies showed that respiratory rhythm generation depends on oscillators located in the pre-Bötzinger complex (pre-BötC) and the parafacial respiratory group (pFRG). To study inhibitory synaptic interactions between these two oscillators, we developed a rostrally tilted transversal slice preparation, which preserves these regions. The onset of rhythmic mass activity in the retrotrapezoid nucleus (RTN)/ pFRG preceded that of the pre-BötC. Blockade of glycinergic and gamma-aminobutyric acidic inhibition synchronized preBötC and RTN/pFRG activity and significantly increased preBötC burst frequency, amplitude, and duration. Population imaging revealed recruitment of inspiratory-like neurones, while expiratory-like neurones lost their phasic activity. The reconfiguration after disinhibition reveals: (1) synaptic inhibition of the pre-BötC arising from the RTN/pFRG, (2) excitatory drive from the RTN/pFRG that triggers the preBötC burst. Our findings support the view that these synaptic interactions in vitro relate to the initiation of the inspiratory phase or to the steering of the expiratory-inspiratory phase transition in vivo.

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“…Removal of only the PBC in the brain stem eliminated respiratory rhythm generation in neonatal rats (42). All six basic types of respiratory neurons were identified in the PBC (9, 42), and neurons with voltagedependent pacemaker-like properties were also found there (6,7,17,22,47). It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45).…”

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Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Liu

Wong‐Riley

2002

Journal of Applied Physiology

120

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Liu, Qiuli, and Margaret T. T. Wong-Riley. Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex. J Appl Physiol 92: 923-934, 2002; 10.1152/japplphysiol.00977.2001.-The preBötzinger complex (PBC) is postulated as the center of respiratory rhythmogenesis. Previously, we found a reduction or plateau of cytochrome oxidase (CO) activity in the PBC and other respiratory nuclei at postnatal days 3-4, despite a general increase of CO with age, suggesting a period of synaptic readjustment. The present study examined the expression of CO and a number of neurochemicals in the PBC at closer time intervals. At postnatal days 3-4 and, more prominently, at postnatal day 12, expression of CO, glutamate, and N-methyl-D-aspartate receptor subunit 1 was reduced, whereas expression of GABA, GABAB receptor, glycine receptor, and ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit 2 was increased. These findings are consistent with our hypothesis that decreased CO activity is associated with an increase in inhibitory drive (mediated by GABA and glycine, their receptors, and possibly blockage of Ca 2ϩ entry by glutamate receptor subunit 2) and a decrease in excitatory drive (mediated by glutamate and its receptors). Our findings point to two critical periods during postnatal development of the rat when their respiratory system may be more vulnerable to respiratory insults.N-methyl-D-aspartate receptor subunit 1; glutamate receptor subunit 2; GABAB receptor; neurokinin-1 receptor; glutamate THE MECHANISM OF RESPIRATORY rhythmogenesis is not fully understood, but cumulative evidence suggests that the pre-Bötzinger complex (PBC) may be the center or kernel of respiratory rhythm generation (12,37,38,42). The PBC is located at the rostroventrolateral medulla, ventral to the nucleus ambiguus (NA), and can be anatomically defined by the distribution of immunoreactive neurokinin-1 receptors (NK1R) (15). Removal of only the PBC in the brain stem eliminated respiratory rhythm generation in neonatal rats (42). All six basic types of respiratory neurons were identified in the PBC (9, 42), and neurons with voltagedependent pacemaker-like properties were also found there (6,7,17,22,47). It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45). The application of agonists and antagonists of some neurotransmitters and neuromodulators to the PBC can induce apparent changes in respiratory rhythm and pattern (8,21,34,41,43). However, very little is known about postnatal development of neurochemicals in the PBC when the system may be more vulnerable to respiratory distress.Cytochrome oxidase (CO) is the terminal enzyme of the mitochondrial respiratory chain and is considered to be a reliable marker of neurons' metabolic capacity and levels of functional activity (51). Previously, we found that the PBC and other respiratory nuclei in the rat exhibited a general increase in CO activity with postnatal development. However, there was a distin...

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Unraveling the mechanism for respiratory rhythm generation

Cited by 43 publications

References 26 publications

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

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

Reconfiguration of respiratory-related population activity in a rostrally tilted transversal slice preparation following blockade of inhibitory neurotransmission in neonatal rats

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

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