Generation Of Breathing Rhythm Research Articles

Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation

Inspiration is the inexorable active phase of breathing. The brainstem pre-Bötzinger complex (preBötC) gives rise to inspiratory neural rhythm, but its underlying cellular and ionic bases remain unclear. The long-standing "pacemaker hypothesis" posits that the persistent Na+ current (INaP) that gives rise to bursting-pacemaker properties in preBötC interneurons is essential for rhythmogenesis. We tested the pacemaker hypothesis by conditionally knocking out and knocking down the Scn8a (Nav1.6 [voltage-gated sodium channel 1.6]) gene in core rhythmogenic preBötC neurons. Deleting Scn8a substantially decreases the INaP and abolishes bursting-pacemaker activity, which slows inspiratory rhythm invitro and negatively impacts the postnatal development of ventilation. Diminishing Scn8a via genetic interference has no impact on breathing in adult mice. We argue that the Scn8a-mediated INaP is not obligatory but that it influences the development andrhythmic function of the preBötC. The ubiquity of the INaP in respiratory brainstem interneurons could underlie breathing-related behaviors such as neonatal phonation or rhythmogenesis in different physiological conditions.

Dysregulation of breathing control through distinct molecular mechanisms of the brainstem cell population in neonatal sepsis

Introduction Neonatal sepsis is triggered by a dysregulated immune response leading to systemic inflammation and life-threatening organ dysfunction. The systemic alterations and activation of immune cells will impact the activity of neural circuits, neural and non-neuronal cell populations, including those in the brainstem involved in breathing rhythm generation and pattern. Elucidating the extent to which inflammation modulates the CNS control of breathing has eluded us due to the lack of appropriate physiological maneuvers capable of interrogating specific brainstem circuits in the neonatal period. We perform novel respiratory testing in newborn pups with unrestrained plethysmography using distinct TLR ligands to test the hypothesis that distinct forms of systemic inflammation modulate brainstem circuits in different ways. Our goal was to investigate how different systemic inflammatory insults at the neonatal period affect the brainstem by determining the contribution of neurons, astrocytes, and microglia in the breathing plasticity response. Methods CD1 mice were I.P. treated at postnatal day 5 (PD5) with LPS, or Pam3CSK4(PAM), or saline (control). Using a whole-body plethysmography system, we assessed brainstem arousal reflex. Briefly, unrestrained pups were placed inside of the chamber individually, and submitted to a room air (RA) exposure for 06 min, followed by 01 min of a gas mixture of 97%N2/3%CO2 (anoxia) repeated 05 times. Ultrasonic vocalization recordings, a measure of brainstem-spinal circuit prolonged-forced expiration, were obtained with the Avisoft SASLab Pro software. Bulk brainstem and gene expression analysis of isolated neurons, astrocytes, and microglia were performed with Clariom™ S Assay mouse and Affymetrix GeneChip Mouse Gene ST 2.0 arrays. Differential gene expression was analyzed using a cutoff of 2-fold change and P-value of 0.01 and t-test in comparison to the control. Results Respiratory frequency during the baseline phase was 176 BPM in the control group, while was founded lower in the LPS and PAM group. Tidal volume (TVb) and minute ventilation (MVb) were also diminished in both groups compared to the control. The gasp latency, or time to recover after each anoxic episode, was prolonged impairing the autoresuscitation, especially, in the PAM treated group. Vocalization function was also affected by inflammation presence resulting in a reduced number of calls per min. A robust gene modulation in the brainstem bulk of PD5 pups was caused in both inflammatory insults. The enrichment analysis showed activation of T helper cells whereas CIBERSORT analysis indicated enrichment of Treg and B cells memory. The molecular pathways activated in neurons, astrocytes, and microglia were founded distinct and specific to the TLR ligand while astrocytes exhibited a lack of responsiveness caused by PAM. Conclusions We conclude that TRLs ligands activate specific neural mechanisms that will detrimentally affect ventilatory response and the ability to autoresuscitate via a central mechanism in the course of neonatal sepsis.

The influence of opioids and nonopioid central nervous system active medications on central sleep apnea: a case-control study.

Opioids are known to contribute to central sleep apnea (CSA), but the influence of nonopioid central nervous system active medications (CNSAMs) on CSA remains unclear. In light of the hypothesized impact of nonopioid CNSAMs on respiration, we examined the relationships between the use of opioids only, nonopioid CNSAMs alone, and their combination with CSA. Among all adults who underwent polysomnography testing at the University of Michigan's sleep laboratory between 2013 and 2018 (n = 10,606), we identified 212 CSA cases and randomly selected 300 controls. Participants were classified into four groups based on their medication use: opioids alone, nonopioid CNSAMs only, their combination, and a reference group, including those who did not use any of these medications. We defined CSA as a binary outcome and as a continuous variable using central apnea index data. Logistic and linear regression were used to examine associations between medication use, CSA diagnosis, and central apnea index. Study participants included 58% men, and mean age was 50 (± 14 standard deviation years. Nearly half of the study participants did not use opioids or nonopioid CNSAMs, 6% used opioids alone, 27% nonopioid CNSAMs alone, and 16% used a combination of these medications. In adjusted analyses, opioids-only users had a nearly twofold increase in CSA odds, whereas those who used a combination of opioids and nonopioid CNSAMs had fivefold higher odds of CSA relative to the reference group. In contrast, the use of nonopioid CNSAMs alone had protective associations with CSA. This report showed increased odds of CSA, particularly among patients with sleep complaints who were prescribed opioids in combination with nonopioid CNSAMs compared with those who did not use any of these medications.

Clinical and experimental aspects of breathing modulation by inflammation.

Neuroinflammation is produced by local or systemic alterations and mediated mainly by glia, affecting the activity of various neural circuits including those involved in breathing rhythm generation and control. Several pathological conditions, such as sudden infant death syndrome, obstructive sleep apnea and asthma exert an inflammatory influence on breathing-related circuits. Consequently breathing (both resting and ventilatory responses to physiological challenges), is affected; e.g., responses to hypoxia and hypercapnia are compromised. Moreover, inflammation can induce long-lasting changes in breathing and affect adaptive plasticity; e.g., hypoxic acclimatization or long-term facilitation. Mediators of the influences of inflammation on breathing are most likely proinflammatory molecules such as cytokines and prostaglandins. The focus of this review is to summarize the available information concerning the modulation of the breathing function by inflammation and the cellular and molecular aspects of this process. I will consider: 1) some clinical and experimental conditions in which inflammation influences breathing; 2) the variety of experimental approaches used to understand this inflammatory modulation; 3) the likely cellular and molecular mechanisms.

Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters

Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography. The purpose of this study was to determine if the nature of the respiratory deficits in WNV-infected rodents is neurological and if deficits are due to a disorder of brainstem respiratory centers, cervical spinal cord (CSC) phrenic motor neuron (PMN) circuitry, or both. We recorded phrenic nerve (PN) activity and found that in WNV-infected mice, PN amplitude is reduced, corroborating a neurological basis for respiratory deficits. These results were associated with a reduction in CSC motor neuron number. We found no dramatic deficits, however, in brainstem-mediated breathing rhythm generation or responses to hypercapnia. PN frequency and pattern parameters were normal, and all PN parameters changed appropriately upon a CO2 challenge. Histological analysis revealed generalized microglia activation, astrocyte reactivity, T cell and neutrophil infiltration, and mild histopathologic lesions in both the brainstem and CSC, but none of these were tightly correlated with PN function. Similar results in PN activity, brainstem function, motor neuron number, and histopathology were seen in WNV-infected hamsters, except that histopathologic lesions were more severe. Taken together, the results suggest that respiratory deficits in acute WNV infection are primarily due to a lower motor neuron disorder affecting PMNs and the PN rather than a brainstem disorder. Future efforts should focus on markers of neuronal dysfunction, axonal degeneration, and myelination.

Control of breathing and volitional respiratory rhythm in humans

When breathing frequency (f) is imperceptibly increased during a volitionally paced respiratory rhythm imposed by an auditory signal, tidal volume (Vt) decreases such that minute ventilation (Ve) rises according to f-induced dead-space ventilation changes (18). As a result, significant change in alveolar ventilation and Pco(2) are prevented as f varies. The present study was performed to determine what regulatory properties are retained by the respiratory control system, wherein the spontaneous automatic rhythmic activity is replaced by a volitionally paced rhythm. Six volunteers were asked to trigger each breath cycle on hearing a brief auditory signal. The time interval between subsequent auditory signals was imperceptibly changed for 10-15 min, during 1) air breathing (condition 1), 2) the addition of a 300 ml of instrumental dead space (condition 2), 3) an increase in the inspired level of CO(2) (condition 3), and 4) light exercise (condition 4). We found that as f was slowly increased the elaborated Vt decreased in accordance to the background level of CO(2) and metabolic rate. Indeed, for any given breath duration, Vt was shifted upward in condition 2 vs. 1, whereas the slope of Vt changes according to the volitionally rhythm was much steeper in conditions 3 and 4 vs. 1. The resulting changes in Ve offset any f-induced changes in dead-space ventilation in all conditions. We conclude that there is an inherent, fundamental mechanism that elaborates Vt based on f when imposed by the premotor cortex in humans. The chemoreflex and exercise drive to breath interacts with this cortically mediated rhythm maintaining alveolar rather than Ve constant as f changes. The implications of our findings are discussed in the context of our current understanding of the central generation of breathing rhythm.

Oscillation Regularity in Noise-Driven Excitable Systems with Multi-Time-Scale Adaptation

We investigate oscillation regularity of a noise-driven system modeled with a slow after-hyperpolarizing adaptation current (AHP) composed of multiple-exponential relaxation time scales. Sufficiently separated slow and fast AHP time scales (biphasic decay) cause a peak in oscillation irregularity for intermediate input currents I, with relatively regular oscillations for small and large currents. An analytic formulation of the system as a stochastic escape problem establishes that the phenomena is distinct from standard forms of coherence resonance. Our results explain data on the oscillation regularity of the pre-Bötzinger complex, a neural oscillator responsible for inspiratory breathing rhythm generation in mammals.

Functional organization of respiratory neurones: a brief review of current questions and speculations.

This article presents a short overview of current knowledge about the medullary respiratory neurones and the generation of breathing rhythm. The background respiratory neurophysiology of the medulla and pons is briefly reviewed, with some current ideas about the organization of the pontine-medullary respiratory control system and its development. Questions and speculations about the organization and generation of respiratory rhythm are included, with a view to stimulating experiments to provide answers.

Breathing Rhythm Generation: Focus on the Rostral Ventrolateral Medulla

Current knowledge about the generation of breathing rhythm is reviewed. The respiratory neurophysiology of the medulla and particularly its rostral ventrolateral part as well as the major hypotheses of breathing rhythm generation are discussed. A model incorporating recent concepts is presented.