Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives

Ramirez, Jan‐Marino; Dashevskiy, Tatiana; Marlin, Ibis Agosto; Baertsch, Nathan A.

doi:10.1016/j.conb.2016.08.003

Cited by 44 publications

(48 citation statements)

References 101 publications

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“…(Forster et al, 2014; Marchenko et al, 2016; Ramirez et al, 2016; Ramirez and Richter, 1996; Rekling and Feldman, 1998; Smith et al, 2000)) and is projected into the spinal phrenic nucleus either monosynaptically or indirectly via projections that are relayed in the Kölliker-Fuse nucleus, the rostral ventral respiratory group, Bötzinger complex, NTS, and several other areas (Dobbins and Feldman, 1994; Ellenberger and Feldman, 1988; Golanov et al, 2016; Huang et al, 1991; Monteau and Hilaire, 1991; Panneton, 2013; Panneton et al, 2012; Tan et al, 2010; Yokota et al, 2007; Yokota et al, 2008; Yokota et al, 2001; Yokota et al, 2004). …”

Section: Discussionmentioning

confidence: 99%

Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex

Villiere

Nakase

Kollmar

et al. 2017

Neurobiology of Disease

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Respiratory derangements, including irregular, tachypnic breathing and central or obstructive apnea can be consequences of seizure activity in epilepsy patients and animal models. Periods of seizure-associated central apnea, defined as periods >1 s with rapid onset and offset of no airflow during plethysmography, suggest that seizures spread to brainstem respiratory regions to disrupt breathing. We sought to characterize seizure-associated central apneic episodes as an indicator of seizure impact on the respiratory rhythm in rats anesthetized with urethane and given parenteral kainic acid to induce recurring seizures. We measured central apneic period onsets and offsets to determine if onset-offset relations were a consequence of 1) a reset of the respiratory rhythm, 2) a transient pausing of the respiratory rhythm, resuming from the pause point at the end of the apneic period, 3) a transient suppression of respiratory behavior with apnea offset predicted by a continuation of the breathing pattern preceding apnea, or 4) a random re-entry into the respiratory cycle. Animals were monitored with continuous ECG, EEG, and plethysmography. One hundred ninety central apnea episodes (1.04 to 36.18 s, mean: 3.2 ± 3.7 s) were recorded during seizure activity from 7 rats with multiple apneic episodes. The majority of apneic period onsets occurred during expiration (125/161 apneic episodes, 78%). In either expiration or inspiration, apneic onsets tended to occur late in the cycle, i.e. between the time of the peak and end of expiration (82/125, 66%) or inspiration (34/36, 94%). Apneic period offsets were more uniformly distributed between early and late expiration (27%, 34%) and inspiration (16%, 23%). Differences between the respiratory phase at the onset of apnea and the corresponding offset phase varied widely, even within individual animals. Each central apneic episode was associated with a high frequency event in EEG or ECG records at onset. High frequency events that were not associated with flatline plethysmographs revealed a constant plethysmograph pattern within each animal, suggesting a clear reset of the respiratory rhythm. The respiratory rhythm became highly variable after about 1 s, however, accounting for the unpredictability of the offset phase. The dissociation of respiratory rhythm reset from the cessation of airflow also suggested that central apneic periods involved activation of brainstem regions serving the diving reflex to eliminate the expression of respiratory movements. This conclusion was supported by the decreased heart rate as a function of apnea duration. We conclude that seizure-associated central apnea episodes are associated with 1) a reset of the respiratory rhythm, and 2) activation of brainstem regions serving the diving reflex to suppress respiratory behavior. The significance of these conclusions is that these details of seizure impact on brainstem circuitry represent metrics for assessing seizure spread and potentially subclassifying seizure patterns.

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Section: Discussionmentioning

confidence: 99%

Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex

Villiere

Nakase

Kollmar

et al. 2017

Neurobiology of Disease

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“…; Ramirez et al . ). Furthermore, knowledge of the functional role of astrocytes in lamprey rhythmic activities is limited to only one report (Baudoux & Parker, ) on the involvement of glial cells in the spinal cord locomotor activity.…”

Section: Introductionmentioning

confidence: 97%

ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey

Cinelli

Iovino

Mutolo

2017

The Journal of Physiology

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Key pointsr The paratrigeminal respiratory group (pTRG) is responsible for the respiratory pattern generation in the lamprey.r The role of ATP and astrocytes, known to control respiratory activity in mammals, was investigated in the lamprey respiratory network.r ATP microinjected into the pTRG induces a biphasic response consisting of marked increases in respiratory frequency mediated by P2X receptors followed by a decrease in the respiratory motor output due to the ATP metabolite adenosine.r We provide evidence that astrocytes are involved in the genesis of the normal respiratory pattern, ATP-induced responses and acidification-induced increases of the respiratory activity.r The function of astrocytes in rhythmic networks appears to be phylogenetically conserved. AbstractThe role of ATP and astrocytes in respiratory rhythm modulation has been recently investigated in neonatal rodents. However, no information on the role of ATP and astrocytes within the respiratory network of the lamprey is available, particularly within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator. To address these issues, the present study was carried out on isolated brainstems of the adult lamprey. Bath application of ATP caused marked increases in respiratory frequency followed by decreases in the respiratory motor output, mediated by the ATP metabolite adenosine at the level of the pTRG. Bath applications and microinjections of agonists and antagonists of purinergic receptors showed that ATP increased respiratory activity through an action on pTRG P2X receptors. To disclose the respiratory role of astrocytes, we used bath application of the gliotoxin aminoadipic acid, which dramatically depressed the respiratory motor output that, however, promptly recovered following glutamine application. Furthermore, the excitatory responses to ATP-γ-S (a non-hydrolysable ATP analogue), but not to substance P, microinjected into the pTRG, were abolished. Finally, we also demonstrated that acidification-induced increases in respiratory activity were ATP-independent, but mediated by the astrocytes' glutamate-glutamine cycle. The results show for the first time that ATP and especially astrocytes strongly contribute to the modulation of the lamprey respiratory pattern. Their role in the modulation or maintenance of rhythmic neuronal activities appears to be phylogenetically conserved.

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“…These rhythms must strike a balance between a regular, intrinsic pattern and the ability to respond to changing environmental and physiological conditions. In the case of respiration, neurons in the preBötzinger Complex (preBötC) show characteristics of central pattern generator (CPG) that generates inspiratory movements and is coupled with chemosensory neurons, such as retrotrapezoid nucleus (RTN) (Feldman et al, 2013; Guyenet et al, 2016; Ramirez et al, 2016; Smith et al, 1991; Smith et al, 1989). Specifically, the glutamatergic subpopulation of preBötC neurons generates the inspiratory rhythms essential for breathing (Wang et al, 2014), while the RTN neurons (all of which are glutamatergic) provide rhythmic excitatory drive to the preBötC during early development and during active expiration upon physical exercise (Pagliardini et al, 2011; Thoby-Brisson et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Respiratory Network Stability and Modulatory Response to Substance P Require Nalcn

Yeh

Huang

Wang

et al. 2017

Neuron

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SUMMARY Respiration is a rhythmic activity as well as one that requires responsiveness to internal and external circumstances; both the rhythm and neuromodulatory responses of breathing are controlled by brainstem neurons in the preBötzinger Complex (preBötC) and the retrotrapezoid nucleus (RTN), but the specific ion channels essential to these activities remain to be identified. Because deficiency of Sodium leak channel, non-selective (Nalcn) causes lethal apnea in humans and mice, we investigated Nalcn function in these neuronal groups. We found that one-third of mice lacking Nalcn in excitatory preBötC neurons died soon after birth; surviving mice developed apneas in adulthood. Interestingly, in both preBötC and RTN neurons, the Nalcn current influences the resting membrane potential, contributes to maintenance of stable network activity, and mediates modulatory responses to the neuropeptide substance P. These findings reveal Nalcn’s specific role in both rhythmic stability and responsiveness to neuropeptides within the respiratory network.

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Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives

Cited by 44 publications

References 101 publications

Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex

Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex

ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey

Respiratory Network Stability and Modulatory Response to Substance P Require Nalcn

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