Biomedical subjects

Irene C Solomon

Publications and source records attributed to Irene C Solomon.

13 recordsLinked to original sources

PubMed2005

Chemical activation of pre-Bötzinger complex in vivo reduces respiratory network complexity.

In the in vivo anesthetized adult cat model, multiple patterns of inspiratory motor discharge have been recorded in response to chemical stimulation and focal hypoxia of the pre-Bötzinger complex (pre-BötC), suggesting that this region may participate in the generation of complex respiratory dynamics. The complexity of a signal can be quantified using approximate entropy (ApEn) and multiscale entropy (MSEn) methods, both of which measure the regularity (orderliness) in a time series, with the latter method taking into consideration temporal fluctuations in the underlying dynamics. The current investigation was undertaken to examine the effects of pre-BötC-induced excitation of phasic phrenic nerve discharge, which is characterized by high-amplitude, rapid-rate-of-rise, short-duration bursts, on the complexity of the central inspiratory neural controller in the vagotomized, chloralose-anesthetized adult cat model. To assess inspiratory neural network complexity, we calculated the ApEn and MSEn of phrenic nerve bursts during eupneic (basal) discharge and during pre-BötC-induced excitation of phasic inspiratory bursts. Chemical stimulation of the pre-BötC using DL-homocysteic acid (DLH; 10 mM; 10-20 nl; n=10) significantly reduced the ApEn from 0.982+/-0.066 (mean+/-SE) to 0.664+/-0.067 (P<0.001) followed by recovery ( approximately 1-2 min after DLH) of the ApEn to 1.014+/-0.067; a slightly enhanced magnitude reduction in MSEn was observed. Focal pre-BötC hypoxia (induced by sodium cyanide; NaCN; 1 mM; 20 nl; n=2) also elicited a reduction in both ApEn and MSEn, similar to those observed for the DLH-induced response. These observations demonstrate that activation of the pre-BötC reduces inspiratory network complexity, suggesting a role for the pre-BötC in regulation of complex respiratory dynamics.

Animals↗

PubMed2004

Glutamate neurotransmission is not required for, but may modulate, hypoxic sensitivity of pre-Bötzinger complex in vivo.

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.

Action Potentials↗

PubMed2004

Time-frequency representation of inspiratory motor output in anesthetized C57BL/6 mice in vivo.

Inspiratory motor discharges, in addition to long-time-scale rhythmic oscillatory bursting, exhibit short-time-scale rhythmic oscillations that have been identified, and subsequently characterized, using power spectral analyses [predominantly fast-Fourier transforms (FFT)]. These analyses assume that the signal being analyzed is stationary; however, this is not the case for most biological signals, which exhibit varying degrees of nonstationarity. To overcome this limitation, time-frequency methods, which provide not only the frequency content but also information regarding the timing of these fast rhythmic oscillations (i.e., dynamics of spectral activity), should be used. Thus this study was performed to investigate the dynamic or time-varying features of spectral activity in inspiratory motor output. Both conventional time-invariant and time-frequency (time-varying) spectral analysis methods were performed on recordings of diaphragm EMG, phrenic nerve, and hypoglossal nerve discharges obtained from spontaneously breathing urethan-anesthetized adult C57BL/6 mice. Conventional time-invariant spectral analysis using a FFT algorithm revealed three dominant peaks in the power spectrum, which were located at 1) 20-46, 2) 83-149, and 3) 177-227 Hz. Time-frequency spectral analysis using a generalized time-frequency representation (TFR) with the smoothed pseudo-Wigner-Ville distribution (SPWD) kernel confirmed the general location of these spectral peaks, identified additional spectral peaks within the frequency ranges described above, and revealed a time-dependent expression of spectral activity within the inspiratory burst for each of the frequency ranges. Furthermore, this method revealed that 1) little or no spectral activity occurs during the initial portion of the inspiratory burst in any of the frequency ranges identified, 2) transient oscillations in the magnitude of spectral power exist where spectral activity occurs, and 3) total spectral power exhibits an augmenting pattern over the course of the inspiratory burst. These data, which provide the first description of spectral content in inspiratory motor discharges in adult mice, show that both time-invariant and time-varying spectral analysis methods are capable of identifying short-time-scale rhythmic oscillations in inspiratory motor discharge (as expected); however, the dynamic (i.e., timing) features of this oscillatory activity can only be obtained using the time-frequency method. We suggest that time-frequency methods, such as the SPWD, should be used in future studies examining short-time-scale (fast) rhythmic oscillations in inspiratory motor discharges, because additional insight into the neural control mechanisms that participate in inspiratory-phase neuronal and motoneuronal synchronization may be obtained.

Algorithms↗

PubMed2003

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

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.

Animals↗

PubMed2003

Connexin36 distribution in putative CO2-chemosensitive brainstem regions in rat.

Recent work from our laboratory has demonstrated that the gap junction proteins connexin26 (Cx26) and connexin32 (Cx32) are expressed in neurons in putative CO2-chemosensitive brainstem regions in both neonatal and adult rats. Whether the recently identified neuron-specific gap junction protein connexin36 (Cx36) is also present in these brainstem regions remains to be determined. Therefore, in the current experiments, immunoblot and immunohistochemical protocols were used to investigate the regional distribution and cellular localization of Cx36 in putative CO2-chemosensitive brainstem regions in both neonatal and adult rats. Immunoblot analyses revealed Cx36 expression in putative CO2-chemosensitive brainstem regions in each of the age groups examined, although both regional and developmental differences in the relative expression levels were detected. Immunohistochemical analyses confirmed Cx36 expression in neurons in each of the putative CO2-chemosensitive brainstem regions and revealed both somal and dendritic labeling patterns. These findings provide additional morphological evidence supporting the potential for gap junctional communication in these regions in both neonatal and adult rats. We propose that the gap junction protein Cx36 also contributes to the neuroanatomical substrate for gap junctional communication, which is hypothesized to play a role in central CO2 chemoreception.

Aging↗

PubMed2003

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

Microinjection of dl-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 CO(2)/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 CO(2)/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 microM) or MZ (50 microM) 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 CO(2)/H(+) chemosensitivity in this region. Furthermore, these findings suggest that focal increases in pre-BötC CO(2)/H(+) may have contributed to the modulation of the DLH-induced responses previously observed during systemic hypercapnia.

Acidosis↗

PubMed2003

CO2 transduction in avian intrapulmonary chemoreceptors is critically dependent on transmembrane Na+/H+ exchange.

Avian intrapulmonary chemoreceptors (IPC) are vagal respiratory afferents that are inhibited by high lung Pco(2) and excited by low lung Pco(2). Previous work suggests that increased CO(2) inhibits IPC by acidifying intracellular pH (pH(i)) and that pH(i) is determined by a kinetic balance between the rate of intracellular carbonic anhydrase-catalyzed CO(2) hydration/dehydration and transmembrane extrusion of acids and/or bases by various exchangers. Here, the role of amiloride-sensitive Na(+)/H(+) exchange (NHE) in the IPC CO(2) response was tested by recording single-unit action potentials from IPC in anesthetized ducks, Anas platyrhynchos. For each of the IPC tested, blockade of the NHE using dimethyl amiloride (DMA) elicited a marked (>50%) dose-dependent decrease in mean IPC discharge (P < 0.05), suggesting that NHE is important for pH(i) regulation and CO(2) transduction in IPC. In addition, activation of the NHE using 12-O-tetradecanoylphorbol 13-acetate stimulated six of the seven IPC tested, although the overall effect was not statistically significantly (P = 0.07). Taken together, these findings suggest that CO(2) transduction in IPC is dependent on transmembrane NHE although it is likely to be much slower than carbonic anhydrase-catalyzed hydration-dehydration of CO(2).

Amiloride↗

PubMed2003

Influence of respiratory network drive on phrenic motor output evoked by activation of cat pre-Botzinger complex.

We have previously demonstrated that microinjection of dl-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce either phasic or tonic excitation of phrenic nerve discharge during hyperoxic normocapnia. Breathing, however, is influenced by input from both central and peripheral chemoreceptor activation. This influence of increased respiratory network drive on pre-BötC-induced modulation of phrenic motor output is unclear. Therefore, these experiments were designed to examine the effects of chemical stimulation of neurons (DLH; 10 mM; 10-20 nl) in the pre-BötC during hyperoxic modulation of CO2 (i.e., hypercapnia and hypocapnia) and during normocapnic hypoxia in chloralose-anesthetized, vagotomized, mechanically ventilated cats. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-BötC during baseline conditions of hyperoxic normocapnia [arterial PCO2 (PaCO2) = 37-43 mmHg; n = 22] produced a tonic (nonphasic) excitation of phrenic nerve discharge. During hypercapnia (PaCO2 = 59.7 +/- 2.8 mmHg; n = 17), similar microinjection produced excitation in which phasic respiratory bursts were superimposed on varying levels of tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency (P < 0.01). In contrast, during hypocapnia (PaCO2 = 29.4 +/- 1.5 mmHg; n = 11), microinjection of DLH produced nonphasic tonic excitation of phrenic nerve discharge that was less robust than the initial (normocapnic) response (i.e., decreased amplitude). During normocapnic hypoxia (PaCO2 = 38.5 +/- 3.7; arterial Po2 = 38.4 +/- 4.4; n = 8) microinjection of DLH produced phrenic excitation similar to that seen during hypercapnia (i.e., increased frequency of phasic respiratory bursts superimposed on tonic discharge). These findings demonstrate that phrenic motor activity evoked by chemical stimulation of the pre-BötC is influenced by and integrates with modulation of respiratory network drive mediated by input from central and peripheral chemoreceptors.

Acid-Base Equilibrium↗

PubMed2003

Blockade of brain stem gap junctions increases phrenic burst frequency and reduces phrenic burst synchronization in adult rat.

Recent investigations have examined the influence of gap junctional communication on generation and modulation of respiratory rhythm and inspiratory motoneuron synchronization in vitro using transverse medullary slice and en bloc brain stem-spinal cord preparations obtained from neonatal (1-5 days postnatal) mice. Gap junction proteins, however, have been identified in both neurons and glia in brain stem regions implicated in respiratory control in both neonatal and adult rodents. Here, we used an in vitro arterially perfused rat preparation to examine the role of gap junctional communication on generation and modulation of respiratory rhythm and inspiratory motoneuron synchronization in adult rodents. We recorded rhythmic inspiratory motor activity from one or both phrenic nerves before and during pharmacological blockade (i.e., uncoupling) of brain stem gap junctions using carbenoxolone (100 microM), 18alpha-glycyrrhetinic acid (25-100 microM), 18beta-glycyrrhetinic acid (25-100 microM), octanol (200-300 microM), or heptanol (200 microM). During perfusion with a gap junction uncoupling agent, we observed an increase in the frequency of phrenic bursts (~95% above baseline frequency; P < 0.001) and a decrease in peak amplitude of integrated phrenic nerve discharge (P < 0.001). The increase in frequency of phrenic bursts resulted from a decrease in both T(I) (P < 0.01) and T(E) (P < 0.01). In addition, the pattern of phrenic nerve discharge shifted from an augmenting discharge pattern to a "bell-shaped" or square-wave discharge pattern in most experiments. Spectral analyses using a fast Fourier transform (FFT) algorithm revealed a reduction in the peak power of both the 40- to 50-Hz peak (corresponding to the MFO) and 90- to 110-Hz peak (corresponding to the HFO) although spurious higher frequency activity (> or =130 Hz) was observed, suggesting an overall loss or reduction in inspiratory-phase synchronization. Although additional experiments are required to identify the specific brain stem regions and cell types (i.e., neurons, glia) mediating the observed modulations in phrenic motor output, these findings suggest that gap junction communication modulates generation of respiratory rhythm and inspiratory motoneuron synchronization in adult rodents in vitro.

Age Factors↗

PubMed2002

Gap junctions in CO(2)-chemoreception and respiratory control.

Recent evidence indicates that gap junctions play a more prominent role in normal functioning of the mammalian central nervous system (CNS) than was once believed. Accumulating evidence from both neonatal and adult rodents indicates that gap junctions participate in multiple aspects of respiratory control, including central CO(2) chemoreception, respiratory rhythmogenesis, and respiratory motoneuron output. This review provides an overview of gap junction neurobiology in the mammalian CNS and presents the anatomical and electrophysiological evidence for gap junctions in CO(2) chemoreception and respiratory control.

Animals↗

PubMed2002

Modulation of expiratory motor output evoked by chemical activation of pre-Bötzinger complex in vivo.

We have previously demonstrated that chemical stimulation of the pre-Bötzinger complex (pre-BötC) in the anesthetized cat produces either phasic or tonic excitation of phrenic nerve discharge. This region is characterized by a mixture of inspiratory-modulated, expiratory-modulated, and phase-spanning (including pre-inspiratory (pre-I)) neurons; however, its influence on expiratory motor output is unknown. We, therefore, examined the effects of chemical stimulation of the pre-BötC on expiratory motor output recorded from the caudal iliohypogastric (lumbar, L(2)) nerve. We found that unilateral microinjection of DL-homocysteic acid (DLH; 10 mM; 10-20 nl) into 16 sites in the pre-BötC enhanced lumbar nerve discharge, including changes in timing and patterning similar to those previously reported for phrenic motor output. Both increased peak amplitude and frequency of phasic lumbar bursts as well as tonic excitation of lumbar motor activity were observed. In some cases, evoked phasic lumbar nerve activity was synchronized in phase with phrenic nerve discharge. These findings demonstrate that chemical stimulation of the pre-BötC not only excites inspiratory motor activity but also excites expiratory motor output, suggesting a role for the pre-BötC in generation and modulation of inspiratory and expiratory rhythm and pattern.

Animals↗

PubMed2002

Role of gap junctions in CO(2) chemoreception and respiratory control.

Gap junctions are composed of connexins, which are organized into intercellular channels that form transmembrane pathways between neurons (cell-cell coupling), and in some cases, neurons and glia, for exchange of ions and small molecules (metabolic coupling) and ionic current (electrical coupling). Cell-cell coupling via gap junctions has been identified in brain stem neurons that function in CO(2)/H(+) chemoreception and respiratory rhythmogenesis; however, the exact roles of gap junctions in respiratory control are undetermined. Here we review the methods commonly used to study gap junctions in the mammalian brain stem under in vitro and in vivo conditions and briefly summarize the anatomical, pharmacological, and electrophysiological evidence to date supporting roles for cell-cell coupling in respiratory rhythmogenesis and central chemoreception. Specific research questions related to the role of gap junctions in respiratory control are suggested for future research.

Animals↗

PubMed2002

Modulation of gasp frequency by activation of pre-Bötzinger complex in vivo.

Under hyperoxic conditions, both chemical stimulation of neurons and focal hypoxia in the pre-Bötzinger complex (pre-BötC) in vivo modify the eupneic pattern of inspiratory motor output by eliciting changes in the patterning and timing of phrenic bursts, which includes both phasic and tonic excitation. The influence of this region on the gasping pattern of phrenic motor output produced during severe brain hypoxia is unknown. We therefore examined the effects of chemical stimulation of neurons (DL-homocysteic acid; DLH; 10 mM; < or =20 nl) and focal hypoxia (sodium cyanide; NaCN; 1 mM; < or =20 nl) in the pre-BötC on hypoxia-induced gasping in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Unilateral microinjection of DLH into the pre-BötC during hypoxia-induced gasping increased phrenic burst frequency by approximately 630% (P < 0.01) over baseline frequency due predominantly to a reduction in T(E) (from 28.9 +/- 6.2 to 5.2 +/- 1.8 s; mean +/- SE; P < 0.01). No significant changes in T(I) or rate of rise between hypoxia-induced gasps and the DLH-induced bursts were observed; the effects on peak amplitude of integrated phrenic nerve discharge were variable. Similar responses were evoked by unilateral microinjection of NaCN into the pre-BötC. These findings demonstrate that both activation of pre-BötC neurons and focal hypoxia in the pre-BötC not only influence the eupneic pattern of phrenic motor output but also modify the expression of hypoxia-induced gasping in vivo. These findings also provide additional support to the concept of intrinsic hypoxic chemosensitivity of the pre-BötC.

Animals↗