CO2/H+ chemoreception in the cat pre-Bötzinger complex in vivo

2000 ◽  
Vol 88 (6) ◽  
pp. 1996-2007 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Marvin H. O'Neal
Keyword(s):  
Phrenic Nerve ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Rhythm Generation ◽  
Bötzinger Complex ◽  
Tissue Acidosis ◽  
Respiratory Rhythm Generation ◽  
Additional Support ◽  
Nerve Discharge

We examined the effects of focal tissue acidosis in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10–20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 μM) or methazolamide (MZ; 50 μM). Microinjection of AZ and MZ into 14 sites in the pre-BötC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5–15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO2/H+ brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-BötC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-BötC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO2/H+ and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.

Pre-Bötzinger Complex Functions as a Central Hypoxia Chemosensor for Respiration In Vivo

2000 ◽  
Vol 83 (5) ◽  
pp. 2854-2868 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Judith A. Neubauer
Keyword(s):  
Short Duration ◽  
Phrenic Nerve ◽  
Excitatory Amino Acid ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Unique Region ◽  
Homocysteic Acid ◽  
Bötzinger Complex ◽  
Nerve Discharge

Recently, we identified a region located in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) in which activation of ionotropic excitatory amino acid receptors usingdl-homocysteic acid (DLH) elicits a variety of excitatory responses in the phrenic neurogram, ranging from tonic firing to a rapid series of high-amplitude, rapid rate of rise, short-duration inspiratory bursts that are indistinguishable from gasps produced by severe systemic hypoxia. Therefore we hypothesized that this unique region is chemosensitive to hypoxia. To test this hypothesis, we examined the response to unilateral microinjection of sodium cyanide (NaCN) into the pre-BötC in chloralose- or chloralose/urethan-anesthetized vagotomized, paralyzed, mechanically ventilated cats. In all experiments, sites in the pre-BötC were functionally identified using DLH (10 mM, 21 nl) as we have previously described. All sites were histologically confirmed to be in the pre-BötC after completion of the experiment. Unilateral microinjection of NaCN (1 mM, 21 nl) into the pre-BötC produced excitation of phrenic nerve discharge in 49 of the 81 sites examined. This augmentation of inspiratory output exhibited one of the following changes in cycle timing and/or pattern: 1) a series of high-amplitude, short-duration bursts in the phrenic neurogram (a discharge similar to a gasp), 2) a tonic excitation of phrenic neurogram output, 3) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a gasplike burst), or 4) an increase in frequency of phrenic bursts accompanied by small increases or decreases in the amplitude of integrated phrenic nerve discharge. Our findings identify a locus in the brain stem in which focal hypoxia augments respiratory output. We propose that the respiratory rhythm generator in the pre-BötC has intrinsic hypoxic chemosensitivity that may play a role in hypoxia-induced gasping.

Medullary regions for neurogenesis of gasping: noeud vital or noeuds vitals?

1996 ◽  
Vol 81 (5) ◽  
pp. 1865-1877 ◽  
Author(s):  
Walter M. St. John
Keyword(s):  
Mammalian Species ◽  
Respiratory Rhythm ◽  
Rhythmic Activity ◽  
Neonatal Rat ◽  
Rhythm Generation ◽  
Bötzinger Complex ◽  
Per Se ◽  
Respiratory Rhythm Generation

St. John, Walter M. Medullary regions for neurogenesis of gasping: noeud vital or noeuds vitals? J. Appl. Physiol. 81(5): 1865–1877, 1996.—Gasping is a critical mechanism for survival in that it serves as a mechanism for autoresuscitation when eupnea fails. Eupnea and gasping are separable patterns of automatic ventilatory activity in all mammalian species from the day of birth. The neurogenesis of the gasp is dependent on the discharge of neurons in the rostroventral medulla. This gasping center overlaps a region termed “the pre-Bötzinger complex.” Neuronal activities of this complex, characterized in an in vitro brain stem spinal cord preparation of the neonatal rat, have been hypothesized to underlie respiratory rhythm generation. Yet, the rhythmic activity of this in vitro preparation is markedly different from eupnea but identical with gasping in vivo. In eupnea, medullary neuronal activities generating the gasp and the identical rhythm of the in vitro preparation are incorporated into a portion of the pontomedullary circuit defining eupneic ventilatory activity. However, these medullary neuronal activities do not appear critical for the neurogenesis of eupnea, per se.

Focal CO2/H+ alters phrenic motor output response to chemical stimulation of cat pre-Bötzinger complex in vivo

2003 ◽  
Vol 94 (6) ◽  
pp. 2151-2157 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Induced Response ◽  
Homocysteic Acid ◽  
Mechanically Ventilated ◽  
Bötzinger Complex ◽  
Tissue Acidosis ◽  
Tonic Excitation ◽  
Nerve Discharge

Microinjection ofdl-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce tonic excitation of phrenic nerve discharge. Although this DLH-induced tonic excitation can be modified by systemic hypercapnia, the role of focal increases in pre-BötC CO2/H+ in this modulation of the DLH-induced response remains to be determined. Therefore, we examined the effects of unilateral microinjection of DLH (10 mM; 10–20 nl) into the pre-BötC before and during increased focal pre-BötC CO2/H+ (i.e., focal tissue acidosis) in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Focal tissue acidosis was produced by blockade of carbonic anhydrase with either focal acetazolamide (AZ) or methazolamide (MZ) microinjection. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-BötC produced a nonphasic tonic excitation of phrenic nerve discharge ( n = 10). Microinjection of 10–20 nl AZ (50 μM) or MZ (50 μM) into these 10 sites in the pre-BötC increased the amplitude and/or frequency of eupneic phrenic bursts, as previously reported. Subsequent microinjection of DLH produced excitation in which phasic respiratory bursts were superimposed on tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency ( P < 0.05). These findings demonstrate that modulation of phrenic motor activity evoked by DLH-induced activation of the pre-BötC is influenced by focal CO2/H+chemosensitivity in this region. Furthermore, these findings suggest that focal increases in pre-BötC CO2/H+may have contributed to the modulation of the DLH-induced responses previously observed during systemic hypercapnia.

Glutamate Neurotransmission Is Not Required for, But May Modulate, Hypoxic Sensitivity of Pre-Bötzinger Complex In Vivo

2005 ◽  
Vol 93 (3) ◽  
pp. 1278-1284 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Excitatory Amino Acid ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Motor Output ◽  
Induced Response ◽  
Homocysteic Acid ◽  
Bötzinger Complex ◽  
Nerve Discharge

Focal hypoxia in the pre-Bötzinger complex (pre-BötC) in vivo elicits excitation of inspiratory motor output by modifying the patterning and timing of phrenic bursts. Hypoxia, however, has been reported to enhance glutamate release in some regions of the brain, including the medullary ventral respiratory column; thus the pre-BötC–mediated hypoxic respiratory excitation may result from, or be influenced by, hypoxia-induced activation of ionotropic glutamate [i.e., excitatory amino acid (EAA)] receptors. To test this possibility, the effects of focal pre-BötC hypoxia [induced by sodium cyanide (NaCN)] were examined before and after blockade of ionotropic EAA receptors [using kynurenic acid (KYN)] in this region in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Before blockade of ionotropic EAA receptors, unilateral microinjection of NaCN (1 mM; 10–20 nl) into the pre-BötC produced either phasic or tonic excitation of phrenic nerve discharge. Unilateral microinjection of KYN (50–100 mM; 40 nl) decreased the amplitude and frequency of basal phrenic nerve discharge; however, subsequent microinjection of NaCN, but not dl-homocysteic acid (DLH, a glutamate analog), still produced excitation of phrenic motor output. Under these conditions, the NaCN-induced excitation included frequency modulation (FM) of phasic phrenic bursts, and in many cases, augmented and/or fractionated phrenic bursts. These findings show that the hypoxia-sensing function of the in vivo pre-BötC, which produces excitation of phrenic nerve discharge, is not dependent on activation of ionotropic glutamate receptors, but ionotropic glutamate receptor activation may modify the expression of the focal hypoxia-induced response. Thus these findings provide additional support to the concept of intrinsic hypoxic sensitivity of the pre-BötC.

Models of Respiratory Rhythm Generation in the Pre-Bötzinger Complex. I. Bursting Pacemaker Neurons

1999 ◽  
Vol 82 (1) ◽  
pp. 382-397 ◽  
Author(s):  
Robert J. Butera ◽  
John Rinzel ◽  
Jeffrey C. Smith
Keyword(s):  
Membrane Potential ◽  
Respiratory Rhythm ◽  
Rhythm Generation ◽  
Minimal Models ◽  
Dynamic Features ◽  
Bursting Neurons ◽  
Wide Range ◽  
Bötzinger Complex ◽  
Voltage Dependent ◽  
Respiratory Rhythm Generation

A network of oscillatory bursting neurons with excitatory coupling is hypothesized to define the primary kernel for respiratory rhythm generation in the pre-Bötzinger complex (pre-BötC) in mammals. Two minimal models of these neurons are proposed. In model 1, bursting arises via fast activation and slow inactivation of a persistent Na+ current I NaP-h. In model 2, bursting arises via a fast-activating persistent Na+ current INaP and slow activation of a K+ current IKS. In both models, action potentials are generated via fast Na+ and K+currents. The two models have few differences in parameters to facilitate a rigorous comparison of the two different burst-generating mechanisms. Both models are consistent with many of the dynamic features of electrophysiological recordings from pre-BötC oscillatory bursting neurons in vitro, including voltage-dependent activity modes (silence, bursting, and beating), a voltage-dependent burst frequency that can vary from 0.05 to >1 Hz, and a decaying spike frequency during bursting. These results are robust and persist across a wide range of parameter values for both models. However, the dynamics of model 1 are more consistent with experimental data in that the burst duration decreases as the baseline membrane potential is depolarized and the model has a relatively flat membrane potential trajectory during the interburst interval. We propose several experimental tests to demonstrate the validity of either model and to differentiate between the two mechanisms.

Ionotropic excitatory amino acid receptors in pre-Bötzinger complex play a modulatory role in hypoxia-induced gasping in vivo

2004 ◽  
Vol 96 (5) ◽  
pp. 1643-1650 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Respiratory Rhythm ◽  
Receptor Activation ◽  
Induced Response ◽  
Brain Hypoxia ◽  
Bötzinger Complex ◽  
Before And After ◽  
Additional Support

Activation of ionotropic excitatory amino acid (EAA) receptors in pre-Bötzinger complex (pre-BötC) not only influences the eupneic pattern of phrenic motor output but also modifies hypoxia-induced gasping in vivo by increasing gasp frequency. Although ionotropic EAA receptor activation in this region appears to be required for the generation of eupneic breathing, it remains to be determined whether similar activation is necessary for the production and/or expression of hypoxia-induced gasping. Therefore, we examined the effects of severe brain hypoxia before and after blockade of ionotropic EAA receptors in the pre-BötC in eight chloralose-anesthetized, deafferented, mechanically ventilated cats. In each experiment, before blockade of ionotropic EAA receptors in the pre-BötC, severe brain hypoxia (6% O2 in a balance of N2 for 3-6 min) produced gasping. Although bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (20-100 mM; 40 nl) into the pre-BötC eliminated basal phrenic nerve discharge, severe brain hypoxia still produced gasping. Under these conditions, however, the onset latency to gasping was increased ( P < 0.05), the number of gasps was reduced for the same duration of hypoxic gas exposure ( P < 0.05), the duration of gasps was prolonged ( P < 0.05), and the duration between gasps was increased ( P < 0.05). These findings demonstrate that hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in the pre-BötC, but ionotropic EAA receptor activation in this region may modify the expression of the hypoxia-induced response. The present findings also provide additional support for the pre-BötC as the primary locus of respiratory rhythm generation.

Patterns of Phrenic Motor Output Evoked by Chemical Stimulation of Neurons Located in the Pre-Bötzinger Complex In Vivo

1999 ◽  
Vol 81 (3) ◽  
pp. 1150-1161 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Judith A. Neubauer
Keyword(s):  
Short Duration ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Chemical Stimulation ◽  
Arterial Blood ◽  
Bötzinger Complex ◽  
Tonic Excitation ◽  
Stimulation Of

Patterns of phrenic motor output evoked by chemical stimulation of neurons located in the pre-Bötzinger complex in vivo. The pre-Bötzinger complex (pre-BötC) has been proposed to be essential for respiratory rhythm generation from work in vitro. Much less, however, is known about its role in the generation and modulation of respiratory rhythm in vivo. Therefore we examined whether chemical stimulation of the in vivo pre-BötC manifests respiratory modulation consistent with a respiratory rhythm generator. In chloralose- or chloralose/urethan-anesthetized, vagotomized cats, we recorded phrenic nerve discharge and arterial blood pressure in response to chemical stimulation of neurons located in the pre-BötC with dl-homocysteic acid (DLH; 10 mM; 21 nl). In 115 of the 122 sites examined in the pre-BötC, unilateral microinjection of DLH produced an increase in phrenic nerve discharge that was characterized by one of the following changes in cycle timing and pattern: 1) a rapid series of high-amplitude, rapid rate of rise, short-duration bursts, 2) tonic excitation (with or without respiratory oscillations), 3) an integration of the first two types of responses (i.e., tonic excitation with high-amplitude, short-duration bursts superimposed), or 4) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a high-amplitude, short-duration burst). In 107 of these sites, the phrenic neurogram response was accompanied by an increase or decrease (≥10 mmHg) in arterial blood pressure. Thus increases in respiratory burst frequency and production of tonic discharge of inspiratory output, both of which have been seen in vitro, as well as modulation of burst pattern can be produced by local perturbations of excitatory amino acid neurotransmission in the pre-BötC in vivo. These findings are consistent with the proposed role of this region as the locus for respiratory rhythm generation.

Isolation of the Kernel for Respiratory Rhythm Generation in a Novel Preparation: The Pre-Bötzinger Complex “Island”

2001 ◽  
Vol 85 (4) ◽  
pp. 1772-1776 ◽  
Author(s):  
Shereé M. Johnson ◽  
Naohiro Koshiya ◽  
Jeffrey C. Smith
Keyword(s):  
Respiratory Rhythm ◽  
Fluorescent Imaging ◽  
Extracellular Potassium ◽  
Synaptic Inhibition ◽  
Rhythm Generation ◽  
Population Activity ◽  
Thin Slices ◽  
Bötzinger Complex ◽  
Population Burst ◽  
Respiratory Rhythm Generation

The pre-Bötzinger complex (pre-BötC), a bilaterally distributed network of rhythmogenic neurons within the ventrolateral medulla, has been proposed to be the critical locus for respiratory rhythm generation in mammals. To date, thin transverse medullary slice preparations that capture the pre-BötC have served as the optimal experimental model to study the region's inherent cellular and network properties. We have reduced the thin slices to isolated pre-BötC “islands” to further establish whether the pre-BötC has intrinsic rhythmicity and is the kernel for rhythmogenesis in the slice. We recorded neuron population activity locally in the pre-BötC with macroelectrodes and fluorescent imaging of Ca2+ activities with Calcium Green-1AM dye before and after excising the island. The isolated island remained rhythmically active with a population burst profile similar to the inspiratory burst in the slice. Rhythmic population activity persisted in islands after block of GABAAergic and glycinergic synaptic inhibition. The loci of pre-BötC Ca2+ activity imaged in thin slices and islands were similar, and imaged pre-BötC neurons exhibited synchronized flashing after blocking synaptic inhibition. Population burst frequency increased monotonically as extracellular potassium concentration was elevated, consistent with mathematical models consisting entirely of an excitatory network of synaptically coupled pacemaker neurons with heterogeneous, voltage-dependent bursting properties. Our results provide further evidence for a rhythmogenic kernel in the pre-BötC in vitro and demonstrate that the islands are ideal preparations for studying the kernel's intrinsic properties.

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