Ventilatory responses to cooling the ventrolateral medullary surface of awake and anesthetized goats

1995 ◽  
Vol 78 (1) ◽  
pp. 247-257 ◽  
Author(s):  
P. J. Ohtake ◽  
H. V. Forster ◽  
L. G. Pan ◽  
T. F. Lowry ◽  
M. J. Korducki ◽  
...  
Keyword(s):  
Pulmonary Ventilation ◽  
Respiratory Rhythm ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Arterial Pco2 ◽  
Respiratory Rhythmogenesis ◽  
Ventilatory Responses ◽  
Anesthesia Breathing ◽  
A Site ◽  
Caudal Area

The ventrolateral medulla (VLM) has been reported to be important as a source of tonic facilitation of dorsal respiratory neurons and as a site critical for respiratory rhythmogenesis. We investigated these theories in awake and anesthetized goats (n = 13) by using chronically implanted thermodes to create reversible neuronal dysfunction at superficial VLM sites between the first hypoglossal rootlet and the pontomedullary junction (area M (rostral) and area S). During halothane anesthesia (arterial PCO2 = 57.4 +/- 4.5 Torr), bilateral cooling (thermode temperature = 20 degrees C) of 60–100% of areas M and S for 30 s produced a sustained apnea (46 +/- 4 s) that lasted beyond the period of cooling. While the animals were awake (arterial PCO2 = 36.0 +/- 1.9 Torr), cooling the identical region in the same goats resulted in a decrease (approximately 50%) in pulmonary ventilation, with a brief apnea seen only in one goat. Reductions in both tidal volume and frequency were observed. Qualitatively similar responses were obtained when cooling caudal area M-rostral area S and rostral area M, but the responses were less pronounced. Minimal effects were seen in response to cooling caudal area S. During anesthesia, breathing is critically dependent on superficial VLM neurons, whereas in the awake state these neurons are not essential for the maintenance of respiratory rhythm. Our data are consistent with these superficial VLM neuronal regions providing tonic facilitation to more dorsal respiratory neurons in both the anesthetized and awake states.

Spatiotemporal Activity Patterns During Respiratory Rhythmogenesis in the Rat Ventrolateral Medulla

2006 ◽  
Vol 95 (3) ◽  
pp. 1982-1991 ◽  
Author(s):  
Jonathan A. N. Fisher ◽  
Vitaliy A. Marchenko ◽  
Arjun G. Yodh ◽  
Robert F. Rogers
Keyword(s):  
Optical Imaging ◽  
High Speed ◽  
Spatial Organization ◽  
Imaging Techniques ◽  
Respiratory Rhythm ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Respiratory Rhythmogenesis ◽  
In Situ Preparation

One of the most important brain rhythms is that which generates involuntary breathing movements. The lower brain stem contains neural circuitry for respiratory rhythm generation in mammals. To date, microsectioning and selective lesioning studies have revealed anatomical regions necessary for respiratory rhythmogenesis. Although respiratory neurons distributed within these regions can be identified by their firing patterns in different phases of the respiratory cycle, conventional electrophysiology techniques have limited the study of spatial organization within this network. Optical imaging techniques offer the potential for monitoring the spatiotemporal activity of large groups of neurons simultaneously. Using high-speed voltage-sensitive dye imaging and spatial correlation analysis in an arterially perfused in situ preparation of the juvenile rat, we determined the spatial distribution of respiratory neuronal activity in a region of the ventrolateral respiratory group containing the pre-Bötzinger complex (pBC) during spontaneous eupneic breathing. While distinctly pre- and postinspiratory-related responses were spatially localizable on length scales less than 100 μm, we found the studied area on whole exhibited a spatial mixture of phase-spanning and postinspiratory-related activity. Additionally, optical recordings revealed significant widespread hyperpolarization, suggesting inhibition in the same region during expiration. This finding is consistent with the hypothesis that inhibitory neurons play a crucial role in the inspiration-expiration phase transition in the pBC. To our knowledge this is the first optical imaging of a near fully intact in situ preparation that exhibits both eupneic respiratory activity and functional reflexes.

scholarly journals Maturation of the Mammalian Respiratory System

1999 ◽  
Vol 79 (2) ◽  
pp. 325-360 ◽  
Author(s):  
Gérard Hilaire ◽  
Bernard Duron
Keyword(s):  
Respiratory Activity ◽  
Respiratory Rhythm ◽  
Ventrolateral Medulla ◽  
Pacemaker Neurons ◽  
Inhibitory Processes ◽  
Respiratory Rhythmogenesis ◽  
Respiratory Network ◽  
Network Functions

In this review, the maturational changes occurring in the mammalian respiratory network from fetal to adult ages are analyzed. Most of the data presented were obtained on rodents using in vitro approaches. In gestational day 18 (E18) fetuses, this network functions but is not yet able to sustain a stable respiratory activity, and most of the neonatal modulatory processes are not yet efficient. Respiratory motoneurons undergo relatively little cell death, and even if not yet fully mature at E18, they are capable of firing sustained bursts of potentials. Endogenous serotonin exerts a potent facilitation on the network and appears to be necessary for the respiratory rhythm to be expressed. In E20 fetuses and neonates, the respiratory activity has become quite stable. Inhibitory processes are not yet necessary for respiratory rhythmogenesis, and the rostral ventrolateral medulla (RVLM) contains inspiratory bursting pacemaker neurons that seem to constitute the kernel of the network. The activity of the network depends on CO2 and pH levels, via cholinergic relays, as well as being modulated at both the RVLM and motoneuronal levels by endogenous serotonin, substance P, and catecholamine mechanisms. In adults, the inhibitory processes become more important, but the RVLM is still a crucial area. The neonatal modulatory processes are likely to continue during adulthood, but they are difficult to investigate in vivo. In conclusion, 1) serotonin, which greatly facilitates the activity of the respiratory network at all developmental ages, may at least partly define its maturation; 2) the RVLM bursting pacemaker neurons may be the kernel of the network from E20 to adulthood, but their existence and their role in vivo need to be further confirmed in both neonatal and adult mammals.

Effects on breathing of ventrolateral medullary cooling in awake goats

1995 ◽  
Vol 78 (1) ◽  
pp. 258-265 ◽  
Author(s):  
H. V. Forster ◽  
P. J. Ohtake ◽  
L. G. Pan ◽  
T. F. Lowry ◽  
M. J. Korducki ◽  
...  
Keyword(s):  
Pulmonary Ventilation ◽  
Control Level ◽  
Control Of Breathing ◽  
Ventrolateral Medulla ◽  
Neuronal Dysfunction ◽  
Subsequent Increase ◽  
Initial Decrease ◽  
Caudal Area ◽  
Stimulation Of

Our objective was to investigate the role of the ventrolateral medulla (VLM) in the control of breathing during the awake state. In 17 awake adult goats, chronically implanted thermodes were used to cool the VLM and thereby cause reversible neuronal dysfunction in all or portions of the area between the first hypoglossal rootlet and the ponto-medullary junction (so-called area M (rostral) and area S). Within 5 s after the initiation of cooling, 60–100% of areas M and S, pulmonary ventilation (VE) decreased uniformly over conditions of eucapnia, hypercapnia, hypoxia, and exercise (P < 0.05). Between 10 and 20 s of cooling, the reduction in VE was approximately 10% greater during eucapnia and hypercapnia than during hypoxia and exercise (P < 0.05). For the remaining 10 s of cooling and for about 1 min after cooling, VE increased to and above control level. Cooling only rostral area M or only caudal area M-rostral area S affected breathing qualitatively in the same manner as when 60–100% of areas M and S were cooled. However, cooling caudal area S had effects that differed significantly (P < 0.05) from more rostral cooling in that the initial decrease in VE was attenuated and the subsequent increase was accentuated. The initial uniform decreased VE during cooling suggests that superficial VLM nonchemoreceptor neurons facilitate breathing. The subsequent relatively greater effect of cooling during eucapnia and hypercapnia probably reflects dysfunction of chemoreceptor-related neurons that normally stimulate breathing. The stimulation of breathing during the later stages and after cooling may suggest that some VLM neurons inhibit breathing.

scholarly journals Imaging of respiratory-related population activity with single-cell resolution

2007 ◽  
Vol 292 (1) ◽  
pp. C508-C516 ◽  
Author(s):  
Frank Funke ◽  
Mathias Dutschmann ◽  
Michael Müller
Keyword(s):  
Single Cell ◽  
Neuronal Activity ◽  
Single Cells ◽  
Activity Patterns ◽  
Respiratory Rhythm ◽  
Network Activity ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Population Activity ◽  
Respiratory Network

The pre-Bötzinger complex (PBC) in the rostral ventrolateral medulla contains a kernel involved in respiratory rhythm generation. So far, its respiratory activity has been analyzed predominantly by electrophysiological approaches. Recent advances in fluorescence imaging now allow for the visualization of neuronal population activity in rhythmogenic networks. In the respiratory network, voltage-sensitive dyes have been used mainly, so far, but their low sensitivity prevents an analysis of activity patterns of single neurons during rhythmogenesis. We now have succeeded in using more sensitive Ca2+ imaging to study respiratory neurons in rhythmically active brain stem slices of neonatal rats. For the visualization of neuronal activity, fluo-3 was suited best in terms of neuronal specificity, minimized background fluorescence, and response magnitude. The tissue penetration of fluo-3 was improved by hyperosmolar treatment (100 mM mannitol) during dye loading. Rhythmic population activity was imaged with single-cell resolution using a sensitive charge-coupled device camera and a ×20 objective, and it was correlated with extracellularly recorded mass activity of the contralateral PBC. Correlated optical neuronal activity was obvious online in 29% of slices. Rhythmic neurons located deeper became detectable during offline image processing. Based on their activity patterns, 74% of rhythmic neurons were classified as inspiratory and 26% as expiratory neurons. Our approach is well suited to visualize and correlate the activity of several single cells with respiratory network activity. We demonstrate that neuronal synchronization and possibly even network configurations can be analyzed in a noninvasive approach with single-cell resolution and at frame rates currently not reached by most scanning-based imaging techniques.

scholarly journals Inspiratory Off-Switch Mediated by Optogenetic Activation of Inhibitory Neurons in the preBötzinger Complex In Vivo

2021 ◽  
Vol 22 (4) ◽  
pp. 2019
Author(s):  
Swen Hülsmann ◽  
Liya Hagos ◽  
Volker Eulenburg ◽  
Johannes Hirrlinger
Keyword(s):  
Respiratory Rate ◽  
Respiratory Rhythm ◽  
Inhibitory Neurons ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Transgenic Mouse Line ◽  
Respiratory Network ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

The role of inhibitory neurons in the respiratory network is a matter of ongoing debate. Conflicting and contradicting results are manifold and the question whether inhibitory neurons are essential for the generation of the respiratory rhythm as such is controversial. Inhibitory neurons are required in pulmonary reflexes for adapting the activity of the central respiratory network to the status of the lung and it is hypothesized that glycinergic neurons mediate the inspiratory off-switch. Over the years, optogenetic tools have been developed that allow for cell-specific activation of subsets of neurons in vitro and in vivo. In this study, we aimed to identify the effect of activation of inhibitory neurons in vivo. Here, we used a conditional transgenic mouse line that expresses Channelrhodopsin 2 in inhibitory neurons. A 200 µm multimode optical fiber ferrule was implanted in adult mice using stereotaxic surgery, allowing us to stimulate inhibitory, respiratory neurons within the core excitatory network in the preBötzinger complex of the ventrolateral medulla. We show that, in anesthetized mice, activation of inhibitory neurons by blue light (470 nm) continuously or with stimulation frequencies above 10 Hz results in a significant reduction of the respiratory rate, in some cases leading to complete cessation of breathing. However, a lower stimulation frequency (4–5 Hz) could induce a significant increase in the respiratory rate. This phenomenon can be explained by the resetting of the respiratory cycle, since stimulation during inspiration shortened the associated breath and thereby increased the respiratory rate, while stimulation during the expiratory interval reduced the respiratory rate. Taken together, these results support the concept that activation of inhibitory neurons mediates phase-switching by inhibiting excitatory rhythmogenic neurons in the preBötzinger complex.

Nitric oxide and respiratory rhythm in mammals: a new modulator of phase transition?

2007 ◽  
Vol 35 (5) ◽  
pp. 1258-1263 ◽  
Author(s):  
O. Pierrefiche ◽  
A.P.L. Abdala ◽  
J.F.R. Paton
Keyword(s):  
Nitric Oxide ◽  
Phase Transition ◽  
Soluble Guanylate Cyclase ◽  
Respiratory Rhythm ◽  
Central Pattern Generators ◽  
Cellular Level ◽  
Respiratory Neurons ◽  
No Donor ◽  
Respiratory Rhythmogenesis ◽  
Pattern Generators

NO (nitric oxide) modulates several central pattern generators, but its role in respiratory rhythmogenesis and its mode of action on medullary respiratory neurons during normoxia are unknown. We analysed the actions of NO on the mammalian respiratory network at the system and cellular levels. Given systemically, the NO donor diethylamine NONOate increased post-inspiratory duration in vagus, phrenic and hypoglossal nerves, whereas blockade of NO generation with L-NAME (NG-nitro-L-arginine methyl ester) produced the opposite response. At the cellular level, we pressure-ejected the NO donor on to respiratory neurons. NO had both inhibitory and excitatory effects on all types of respiratory neurons. Inhibitory effects involved soluble guanylate cyclase, as they were blocked with ODQ (1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one), whereas excitations were antagonized by uric acid and possibly mediated via peroxynitrite. Importantly, NO facilitated both GABA (γ-aminobutyric acid)- and NMDA (N-methyl-D-aspartate)-induced neuronal responses, but this was restricted to post-inspiratory and pre-inspiratory neurons; other neuron types showed additive effects only. Our results support NO as modulator of centrally generated respiratory activity and specifically of ligand-mediated responses in respiratory neuron types involved in respiratory phase transition.

Effect of body temperature on ventilatory control in the alligator

1982 ◽  
Vol 52 (1) ◽  
pp. 114-118 ◽  
Author(s):  
D. G. Davies ◽  
J. L. Thomas ◽  
E. N. Smith
Keyword(s):  
Body Temperature ◽  
Pulmonary Ventilation ◽  
Acid Base Balance ◽  
Acid Base ◽  
Arterial Pco2 ◽  
Ventilatory Responses ◽  
Arterial Blood ◽  
Base Balance ◽  
Alligator Mississipiensis ◽  
Induced Changes

Pulmonary ventilation and arterial blood acid-base balance were measured in six unanesthetized alligators, Alligator mississipiensis, at 15, 25, and 35 degree C. The animals exhibited pronounced ventilatory responses to hypercapnia at all temperatures studied. Arterial PCO2 increased and pH decreased with increases in body temperature during both normocapnia and hypercapnia. The fractional dissociation of imidazole (alpha Pr) remained constant with changes in body temperature during normocapnia, but increased with temperature during hypercapnia. Ventilatory sensitivity, defined as delta (VE/VO2/delta (alpha Pr), was independent of body temperature. We conclude that the control of breathing in the alligator is a physiological defense of alpha Pr and that ventilatory responses occur following nontemperature-induced changes in blood acid-base balance, which tend to return alpha Pr to a normal value.

Comparison of ventilatory responses to sustained reduction in arterial oxygen tension vs. content in awake ponies

1994 ◽  
Vol 76 (5) ◽  
pp. 2147-2153 ◽  
Author(s):  
T. F. Lowry ◽  
H. V. Forster ◽  
M. J. Korducki ◽  
A. L. Forster ◽  
M. A. Forster
Keyword(s):  
Pulmonary Ventilation ◽  
Control Level ◽  
Arterial Oxygen Tension ◽  
Hypoxic Hypoxia ◽  
Arterial Oxygen ◽  
Arterial Pco2 ◽  
Ventilatory Responses ◽  
Sustained Reduction ◽  
Breathing Room ◽  
Arterial Po2

To gain insight into central and peripheral contributions to changes in breathing during hypoxia, we compared effects on breathing of reducing inspired PO2 (hypoxic hypoxia) with reducing arterial O2 content (CaO2) through elevation of carboxy-hemoglobin (COHb) (CO hypoxia). Twelve awake ponies were studied during 1 h of breathing room air followed by 6 h when COHb was increased to 25% and CaO2 was decreased by 17%. When COHb was increased, arterial PCO2 (PaCO2) increased gradually to 1.3 Torr above (P < 0.05) control level between 30 and 45 min of CO exposure. Pulmonary ventilation (VE) decreased (P = 0.09) approximately 1 liter the first 30 min of CO exposure. After approximately 45 min, PaCO2 began to decrease, steadily reaching 1.5 Torr below (P < 0.05) control level by 4.5 h of CO hypoxia. VE did not change significantly after 30 min of elevated COHb. Eight ponies were also studied during 5 h of hypoxic hypoxia (arterial PO2 approximately 40 Torr). PaCO2 decreased 5 Torr (P < 0.05) within 5 min of hypoxia and decreased another 4 Torr (P < 0.05) between 30 min and 5 h of hypoxia consistent with hypoxic ventilatory acclimatization. VE increased (P < 0.05) within 3 min of hypoxic hypoxia but then decreased (P < 0.05; VE roll off) toward control and did not increase significantly with acclimatization. Because CO and hypoxic hypoxia both decrease brain oxygenation but only hypoxic hypoxia increases carotid chemoreceptor activity, we conclude that initial hypoventilation with CO hypoxia and VE roll off with hypoxic hypoxia are consistent with hypoxic ventilatory depression within the brain. In addition, hyperventilation with prolonged CO hypoxia is consistent with a central nervous system mechanism contributing to this phase of hypoxic ventilatory acclimatization in ponies.

Hypoxia selectively excites vasomotor neurons of rostral ventrolateral medulla in rats

1994 ◽  
Vol 266 (1) ◽  
pp. R245-R256 ◽  
Author(s):  
M. K. Sun ◽  
D. J. Reis
Keyword(s):  
Sympathetic Nerves ◽  
Rostral Ventrolateral Medulla ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Cellular Mechanisms ◽  
Systemic Hypoxia ◽  
Adequate Stimulus ◽  
Central Oxygen ◽  
Cerebral Ischemic ◽  
Increased Activity

Systemic hypoxia [PaO2 27.3 +/- 1.8 (SE) mmHg] in anesthetized paralyzed rats reversibly increased within seconds the arterial pressure and activities of the sympathetic nerves and the reticulospinal vasomotor neurons of the rostral ventrolateral medulla (RVL). After peripheral chemodenervation, hypoxia also increased activity of the sympathetic nerves and doubled discharges of the vasomotor neurons while inhibiting a majority of the RVL respiratory neurons. Systemic hypercapnia was not effective in eliciting sympathoexcitatory responses. Iontophoresis of sodium cyanide stimulated the vasomotor and inhibited the respiratory neurons. In contrast, iontophoreses of H+, HCO3-, and lactate were without effects on activity of the vasomotor neurons. We conclude 1) hypoxia excites the vasomotor neurons by activating the arterial chemoreceptors and by activating intrinsic cellular mechanisms probably unrelated to accumulation of metabolic byproducts; 2) hypoxia may be the adequate stimulus exciting the RVL-spinal vasomotor and inhibiting the respiratory neurons during the cerebral ischemic response; and 3) these vasomotor neurons may be central oxygen detectors.

scholarly journals Site-specific effects on respiratory rhythm and pattern of ibotenic acid injections in the pontine respiratory group of goats

2010 ◽  
Vol 109 (1) ◽  
pp. 171-188 ◽  
Author(s):  
J. M. Bonis ◽  
S. E. Neumueller ◽  
K. L. Krause ◽  
T. Kiner ◽  
A. Smith ◽  
...  
Keyword(s):  
Pulmonary Ventilation ◽  
Respiratory Rhythm ◽  
Ibotenic Acid ◽  
Pattern Generation ◽  
Respiratory Pattern ◽  
Breathing Patterns ◽  
Site Specific ◽  
Specific Effects ◽  
Tegmental Nuclei ◽  
Pontine Respiratory Group

To probe further the contributions of the rostral pons to eupneic respiratory rhythm and pattern, we tested the hypothesis that ibotenic acid (IA) injections in the pontine respiratory group (PRG) would disrupt eupneic respiratory rhythm and pattern in a site- and state-specific manner. In 15 goats, cannulas were bilaterally implanted into the rostral pontine tegmental nuclei (RPTN; n = 3), the lateral (LPBN; n = 4) or medial parabrachial nuclei (MPBN; n = 4), or the Kölliker-Fuse nucleus (KFN; n = 4). After recovery from surgery, 1- and 10-μl injections (1 wk apart) of IA were made bilaterally through the implanted cannulas during the day. Over the first 5 h after the injections, there were site-specific ventilatory effects, with increased ( P < 0.05) breathing frequency in RPTN-injected goats, increased ( P < 0.05) pulmonary ventilation (V̇i) in LPBN-injected goats, no effect ( P < 0.05) in MPBN-injected goats, and a biphasic V̇i response ( P < 0.05) in KFN-injected goats. This biphasic response consisted of a hyperpnea for 30 min, followed by a prolonged hypopnea and hypoventilation with marked apneas, apneusis-like breathing patterns, and/or shifts in the temporal relationships between inspiratory flow and diaphragm activity. In the awake state, 10–15 h after the 1-μl injections, the number of apneas was greater ( P < 0.05) than during other studies at night. However, there were no incidences of terminal apneas. Breathing rhythm and pattern were normal 22 h after the injections. Subsequent histological analysis revealed that for goats with cannulas implanted into the KFN, there were nearly 50% fewer neurons ( P < 0.05) in all three PRG subnuclei than in control goats. We conclude that in awake goats, 1) IA injections into the PRG have site-specific effects on breathing, and 2) the KFN contributes to eupneic respiratory pattern generation.

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