scholarly journals The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time

2018 ◽  
Vol 41 (1) ◽  
pp. 475-499 ◽  
Author(s):  
Jan-Marino Ramirez ◽  
Nathan A. Baertsch
Keyword(s):  
Coupled Oscillators ◽  
Respiratory Rhythm ◽  
Control Of Breathing ◽  
Lessons Learned ◽  
Rhythm Generation ◽  
Glutamatergic Transmission ◽  
Neuronal Control ◽  
Respiratory Network ◽  
Three Phase ◽  
The Brain

Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: ( a) glutamatergic transmission, which is amplified by ( b) intrinsic bursting and opposed by ( c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time.

scholarly journals Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a μ-opioid receptor agonist

2017 ◽  
Vol 312 (5) ◽  
pp. R727-R738 ◽  
Author(s):  
Peter M. Lalley ◽  
Steve W. Mifflin
Keyword(s):  
Spike Train ◽  
Brain Stem ◽  
Opioid Receptor ◽  
Respiratory Rhythm ◽  
Opioid Receptor Agonist ◽  
Respiratory Network ◽  
Three Phase ◽  
Μ Opioid Receptor ◽  
Effective Doses ◽  
The Brain

μ-Opioid receptors are distributed widely in the brain stem respiratory network, and opioids with selectivity for μ-type receptors slow in vivo respiratory rhythm in lowest effective doses. Several studies have reported μ-opioid receptor effects on the three-phase rhythm of respiratory neurons, but there are until now no reports of opioid effects on oscillatory activity within respiratory discharges. In this study, effects of the μ-opioid receptor agonist fentanyl on spike train discharge properties of several different types of rhythm-modulating medullary respiratory neuron discharges were analyzed. Doses of fentanyl that were just sufficient for prolongation of discharges and slowing of the three-phase respiratory rhythm also produced pronounced enhancement of spike train properties. Oscillation and burst patterns detected by autocorrelation measurements were greatly enhanced, and interspike intervals were prolonged. Spike train properties under control conditions and after fentanyl were uniform within each experiment, but varied considerably between experiments, which might be related to variability in acid-base balance in the brain stem extracellular fluid. Discharge threshold was shifted to more negative levels of membrane potential. The effects on threshold are postulated to result from opioid-mediated disinhibition and postsynaptic enhancement of N-methyl-d- aspartate receptor current. Lowering of firing threshold, enhancement of spike train oscillations and bursts and prolongation of discharges by lowest effective doses of fentanyl could represent compensatory adjustments in the brain stem respiratory network to override opioid blunting of CO2/pH chemosensitivity.

A network model of respiratory rhythmogenesis

1992 ◽  
Vol 263 (4) ◽  
pp. R962-R975 ◽  
Author(s):  
M. D. Ogilvie ◽  
A. Gottschalk ◽  
K. Anders ◽  
D. W. Richter ◽  
A. I. Pack
Keyword(s):  
Reasonable Agreement ◽  
Respiratory Rhythm ◽  
Superior Laryngeal Nerve ◽  
Laryngeal Nerve ◽  
Phase Resetting ◽  
Phase Singularity ◽  
Respiratory Rhythmogenesis ◽  
Respiratory Network ◽  
Three Phase ◽  
Model Predictions

A mathematical model of the three-phase respiratory network proposed by Richter et al. (News Physiol. Sci. 1: 109-112, 1986) is developed and its properties are examined. The model reproduces the experimentally determined trajectories of membrane potential for the five physiologically distinct types of neurons included. Stepwise parameter changes can produce a respiratory rhythm with only two separate electrophysiological phases, result in apnea, or produce more complex patterns of firing. The phase-resetting behavior of the model was obtained with perturbing stimuli and is comparable to experimentally determined phase-resetting data. There is reasonable agreement between model predictions and experimental results. In the model, the properties of the phase singularity make termination of the respiratory rhythm by an appropriately timed perturbation virtually impossible, which is in agreement with experimental observations. The rhythm can be stopped by alterations that simulate the effect of input from the superior laryngeal nerve; the rhythm is locked in the postinspiratory phase. We conclude that our results are consistent with the concept of a network oscillator as the source of the respiratory rhythm.

Norepinephrine Differentially Modulates Different Types of Respiratory Pacemaker and Nonpacemaker Neurons

2006 ◽  
Vol 95 (4) ◽  
pp. 2070-2082 ◽  
Author(s):  
Jean-Charles Viemari ◽  
Jan-Marino Ramirez
Keyword(s):  
Frequency Modulation ◽  
Respiratory Rhythm ◽  
Network Activity ◽  
Flufenamic Acid ◽  
Pacemaker Activity ◽  
Rhythm Generation ◽  
Burst Frequency ◽  
Pacemaker Neurons ◽  
Respiratory Network ◽  
Different Types

Pacemakers are found throughout the mammalian CNS. Yet, it remains largely unknown how these neurons contribute to network activity. Here we show that for the respiratory network isolated in transverse slices of mice, different functions can be assigned to different types of pacemakers and nonpacemakers. This difference becomes evident in response to norepinephrine (NE). Although NE depolarized 88% of synaptically isolated inspiratory neurons, this neuromodulator had differential effects on different neuron types. NE increased in cadmium-insensitive pacemakers burst frequency, not burst area and duration, and it increased in cadmium-sensitive pacemakers burst duration and area, but not frequency. NE also differentially modulated nonpacemakers. Two types of nonpacemakers were identified: “silent nonpacemakers” stop spiking, whereas “active nonpacemakers” spontaneously spike when isolated from the network. NE selectively induced cadmium-sensitive pacemaker properties in active, but not silent, nonpacemakers. Flufenamic acid (FFA), a blocker of ICAN, blocked the induction as well as modulation of cadmium-sensitive pacemaker activity, and blocked at the network level the NE-induced increase in burst area and duration of inspiratory network activity; the frequency modulation (FM) was unaffected. We therefore propose that modulation of cadmium-sensitive pacemaker activity contributes at the network level to changes in burst shape, not frequency. Riluzole blocked the FM of isolated cadmium-insensitive pacemakers. In the presence of riluzole, NE caused disorganized network activity, suggesting that cadmium-insensitive pacemakers are critical for rhythm generation. We conclude that different types of nonpacemaker and pacemaker neurons differentially control different aspects of the respiratory rhythm.

scholarly journals Spatial and Functional Architecture of the Mammalian Brain Stem Respiratory Network: A Hierarchy of Three Oscillatory Mechanisms

2007 ◽  
Vol 98 (6) ◽  
pp. 3370-3387 ◽  
Author(s):  
J. C. Smith ◽  
A. P. L. Abdala ◽  
H. Koizumi ◽  
I. A. Rybak ◽  
J. F. R. Paton
Keyword(s):  
Brain Stem ◽  
Sodium Current ◽  
Respiratory Rhythm ◽  
Central Pattern Generators ◽  
Respiratory Neurons ◽  
Mammalian Brain ◽  
Two Phase ◽  
Respiratory Network ◽  
Three Phase ◽  
The One

Mammalian central pattern generators (CPGs) producing rhythmic movements exhibit extremely robust and flexible behavior. Network architectures that enable these features are not well understood. Here we studied organization of the brain stem respiratory CPG. By sequential rostral to caudal transections through the pontine-medullary respiratory network within an in situ perfused rat brain stem–spinal cord preparation, we showed that network dynamics reorganized and new rhythmogenic mechanisms emerged. The normal three-phase respiratory rhythm transformed to a two-phase and then to a one-phase rhythm as the network was reduced. Expression of the three-phase rhythm required the presence of the pons, generation of the two-phase rhythm depended on the integrity of Bötzinger and pre-Bötzinger complexes and interactions between them, and the one-phase rhythm was generated within the pre-Bötzinger complex. Transformation from the three-phase to a two-phase pattern also occurred in intact preparations when chloride-mediated synaptic inhibition was reduced. In contrast to the three-phase and two-phase rhythms, the one-phase rhythm was abolished by blockade of persistent sodium current ( INaP). A model of the respiratory network was developed to reproduce and explain these observations. The model incorporated interacting populations of respiratory neurons within spatially organized brain stem compartments. Our simulations reproduced the respiratory patterns recorded from intact and sequentially reduced preparations. Our results suggest that the three-phase and two-phase rhythms involve inhibitory network interactions, whereas the one-phase rhythm depends on INaP. We conclude that the respiratory network has rhythmogenic capabilities at multiple levels of network organization, allowing expression of motor patterns specific for various physiological and pathophysiological respiratory behaviors.

scholarly journals Neurogenic hypertension and the secrets of respiration

2017 ◽  
Vol 312 (6) ◽  
pp. R864-R872 ◽  
Author(s):  
Benedito H. Machado ◽  
Daniel B. Zoccal ◽  
Davi J. A. Moraes
Keyword(s):  
Brain Stem ◽  
Neural Control ◽  
Respiratory Rhythm ◽  
Sympathetic Outflow ◽  
Neurogenic Hypertension ◽  
Electrophysiological Properties ◽  
Respiratory Network ◽  
Rhythm Pattern ◽  
Contraction And Relaxation ◽  
The Brain

Despite recent advances in the knowledge of the neural control of cardiovascular function, the cause of sympathetic overactivity in neurogenic hypertension remains unknown. Studies from our laboratory point out that rats submitted to chronic intermittent hypoxia (CIH), an experimental model of neurogenic hypertension, present changes in the central respiratory network that impact the pattern of sympathetic discharge and the levels of arterial pressure. In addition to the fine coordination of respiratory muscle contraction and relaxation, which is essential for O2 and CO2 pulmonary exchanges, neurons of the respiratory network are connected precisely to the neurons controlling the sympathetic activity in the brain stem. This respiratory-sympathetic neuronal interaction provides adjustments in the sympathetic outflow to the heart and vasculature during each respiratory phase according to the metabolic demands. Herein, we report that CIH-induced sympathetic over activity and mild hypertension are associated with increased frequency discharge of ventral medullary presympathetic neurons. We also describe that their increased frequency discharge is dependent on synaptic inputs, mostly from neurons of the brain stem respiratory network, rather than changes in their intrinsic electrophysiological properties. In perspective, we are taking into consideration the possibility that changes in the central respiratory rhythm/pattern generator contribute to increased sympathetic outflow and the development of neurogenic hypertension. Our experimental evidence provides support for the hypothesis that changes in the coupling of respiratory and sympathetic networks might be one of the unrevealed secrets of neurogenic hypertension in rats.

scholarly journals Effects of persistent sodium current blockade in respiratory circuits depend on the pharmacological mechanism of action and network dynamics

2019 ◽  
Author(s):  
Ryan S. Phillips ◽  
Jonathan E. Rubin
Keyword(s):  
Experimental Data ◽  
Sodium Current ◽  
Respiratory Rhythm ◽  
Experimental Results ◽  
Respiratory Neurons ◽  
Persistent Sodium Current ◽  
Rhythm Generation ◽  
Respiratory Network ◽  
Respiratory Rhythm Generation

AbstractThe mechanism(s) of action of most commonly used pharmacological blockers of voltage-gated ion channels are well understood; however, this knowledge is rarely considered when interpreting experimental data. Effects of blockade are often assumed to be equivalent, regardless of the mechanism of the blocker involved. Using computer simulations, we demonstrate that this assumption may not always be correct. We simulate the blockade of a persistent sodium current (INaP), proposed to underlie rhythm generation in pre-Bötzinger complex (pre-BötC) respiratory neurons, via two distinct pharmacological mechanisms: (1) pore obstruction mediated by tetrodotoxin and (2) altered inactivation dynamics mediated by riluzole. The reported effects of experimental application of tetrodotoxin and riluzole in respiratory circuits are diverse and seemingly contradictory and have led to considerable debate within the field as to the specific role ofINaPin respiratory circuits. The results of our simulations match a wide array of experimental data spanning from the level of isolated pre-BötC neurons to the level of the intact respiratory network and also generate a series of experimentally testable predictions. Specifically, in this study we: (1) provide a mechanistic explanation for seemingly contradictory experimental results from in vitro studies ofINaPblock, (2) show that the effects ofINaPblock in in vitro preparations are not necessarily equivalent to those in more intact preparations, (3) demonstrate and explain why riluzole application may fail to effectively blockINaPin the intact respiratory network, and (4) derive the prediction that effective block ofINaPby low concentration tetrodotoxin will stop respiratory rhythm generation in the intact respiratory network. These simulations support a critical role forINaPin respiratory rhythmogenesis in vivo and illustrate the importance of considering mechanism when interpreting and simulating data relating to pharmacological blockade.Author summaryThe application of pharmacological agents that affect transmembrane ionic currents in neurons is a commonly used experimental technique. A simplistic interpretation of experiments involving these agents suggests that antagonist application removes the impacted current and that subsequently observed changes in activity are attributable to the loss of that current’s effects. The more complex reality, however, is that different drugs may have distinct mechanisms of action, some corresponding not to a removal of a current but rather to a changing of its properties. We use computational modeling to explore the implications of the distinct mechanisms associated with two drugs, riluzole and tetrodotoxin, that are often characterized as sodium channel blockers. Through this approach, we offer potential explanations for disparate findings observed in experiments on neural respiratory circuits and show that the experimental results are consistent with a key role for the persistent sodium current in respiratory rhythm generation.

Lessons Learned From Coaching Postsecondary Students With Traumatic Brain Injury

2020 ◽  
Vol 5 (1) ◽  
pp. 88-96
Author(s):  
Mary R. T. Kennedy
Keyword(s):  
College Students ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Sense Of Self ◽  
Scientific Evidence ◽  
Sudden Onset ◽  
Lessons Learned ◽  
Speech Language Pathologists ◽  
The Brain ◽  
Exhaustive List

Purpose The purpose of this clinical focus article is to provide speech-language pathologists with a brief update of the evidence that provides possible explanations for our experiences while coaching college students with traumatic brain injury (TBI). Method The narrative text provides readers with lessons we learned as speech-language pathologists functioning as cognitive coaches to college students with TBI. This is not meant to be an exhaustive list, but rather to consider the recent scientific evidence that will help our understanding of how best to coach these college students. Conclusion Four lessons are described. Lesson 1 focuses on the value of self-reported responses to surveys, questionnaires, and interviews. Lesson 2 addresses the use of immediate/proximal goals as leverage for students to update their sense of self and how their abilities and disabilities may alter their more distal goals. Lesson 3 reminds us that teamwork is necessary to address the complex issues facing these students, which include their developmental stage, the sudden onset of trauma to the brain, and having to navigate going to college with a TBI. Lesson 4 focuses on the need for college students with TBI to learn how to self-advocate with instructors, family, and peers.

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