Contribution of the respiratory network to rhythm and motor output revealed by modulation of GIRK channels, somatostatin and neurokinin-1 receptors

Montandon, Gaspard; Liu, Hattie; Horner, Richard L.

doi:10.1038/srep32707

Cited by 35 publications

(37 citation statements)

References 39 publications

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“…2b). In these anesthetized mice average breathing rates during the isoflurane-anesthesia and in the presence of hyperoxia (see Methods) were typically 20-25 breaths per minute, as observed in other studies 23,24 . We also note that the dorsal motor nucleus of the vagus is located just dorsal to the hypoglossal motoneuron pool 25 , and as such would be expected to be also activated by the optical stimuli.…”

supporting

confidence: 59%

“…In the studies in the anesthetized mice the average breathing rates typically averaged 20-25 breaths per minute, as in other studies 23,24 . This rate was utilized to identify if the presence of photostimulation increased the peak amplitude of the endogenous rhythmic respiratory-related tongue muscle activity during the stimulation (Peak EMG During ) compared to the rhythmic breaths immediately prior to (Peak EMG Pre ) and following (Peak EMG Post ) the photostimulation.…”

Section: Discussionmentioning

confidence: 98%

“…3b). In addition, while motor responses were statistically higher at 10 Hz compared to [15][16][17][18][19][20][21][22][23][24][25] Hz, the elicited motor responses were not significantly different across 15-25 Hz. One interpretation of these findings is that 10 Hz stimulation drives the population of activated neurons close to their endogenous firing frequency, and/or at a firing frequency that allows sufficient time between the optical pulses for optimal recovery and re-establishment of the ionic gradients that cause the cellular activation in response to light-induced activation of the opsin.…”

Section: Discussionmentioning

confidence: 99%

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Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo

Aggarwal

Liu

Montandon

et al. 2020

Sci Rep

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Motoneurons are the final output pathway for the brain's influence on behavior. Here we identify properties of hypoglossal motor output to the tongue musculature. tongue motor control is critical to the pathogenesis of obstructive sleep apnea, a common and serious sleep-related breathing disorder. Studies were performed on mice expressing a light sensitive cation channel exclusively on cholinergic neurons (ChAT-ChR2(H134R)-EYFP). Discrete photostimulations under isoflurane-induced anesthesia from an optical probe positioned above the medullary surface and hypoglossal motor nucleus elicited discrete increases in tongue motor output, with the magnitude of responses dependent on stimulation power (p < 0.001, n = 7) and frequency (P = 0.002, n = 8, with responses to 10 Hz stimulation greater than for 15-25 Hz, P < 0.022). Stimulations during REM sleep elicited significantly reduced responses at powers 3-20 mW compared to non-rapid eye movement (non-REM) sleep and wakefulness (each p < 0.05, n = 7). Response thresholds were also greater in REM sleep (10 mW) compared to non-REM and waking (3 to 5 mW, P < 0.05), and the slopes of the regressions between input photostimulation powers and output motor responses were specifically reduced in REM sleep (P < 0.001). This study identifies that variations in photostimulation input produce tunable changes in hypoglossal motor output in-vivo and identifies REM sleep specific suppression of net motor excitability and responsivity.Obstructive sleep apnea (OSA) is a common and serious breathing disorder with significant clinical, social and economic consequences 1 . OSA is characterized by repeated episodes of upper airway obstruction that occur only during sleep, with the airway obstructions leading to futile breathing efforts, asphyxia, sleep disturbance and other physiological sequalae of medical relevance 2,3 . The root cause of the upper airway obstruction is reduced activity and reflex compensatory responses of the pharyngeal muscles during sleep, whereas in wakefulness the motor activity and responsivity are sufficient to keep the airspace open 4 . Ultimately, state-dependent pharyngeal muscle activity and responsivity of the brainstem motor pools driving these muscles are pivotal to OSA pathophysiology and the phenotypic traits of OSA patients 5-8 .Such state-dependent activity of the pharyngeal musculature is central to OSA pathogenesis, and the hypoglossal motoneuron pool is the source of motor output to the largest of the pharyngeal muscles, the tongue 2,4 . Single unit recordings of tongue motor activity are an experimentally powerful indicator of the discharge patterns and recruitment characteristics of single hypoglossal motoneurons in the medulla that are otherwise inaccessible for investigation [9][10][11][12][13][14][15][16][17][18][19] . One limitation of such single-unit studies, however, is the inability to impose acute, precise and direct control over hypoglossal motor output to interrogate physiological properties relevant to tongue motor control.In the present...

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supporting

confidence: 59%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo

Aggarwal

Liu

Montandon

et al. 2020

Sci Rep

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“…One concern and a potential source of conflicting experimental outcomes is that it is unknown if the above described effects were due to activation of somatodendritic or presynaptic receptors in the local area, with one exception (Montandon et al . ). Additionally, a locally applied antagonist leaves receptors on terminals in projection regions unblocked.…”

Section: Discussionmentioning

confidence: 97%

Differential impact of two critical respiratory centres in opioid‐induced respiratory depression in awake mice

Varga

Reid

Kieffer

et al. 2019

The Journal of Physiology

150

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Key pointsr The main cause of death from opioid overdose is respiratory depression due to the activation of µ-opioid receptors (MORs).r We conditionally deleted MORs from neurons in two key areas of the brainstem respiratory circuitry (the Kölliker-Fuse nucleus (KF) and pre-Bötzinger complex (preBötC)) to determine their role in opioid-induced respiratory disturbances in adult, awake mice.r Deletion of MORs from KF neurons attenuated respiratory rate depression at all doses of morphine.r Deletion of MORs from preBötC neurons attenuated rate depression at the low dose, but had no effect on rate following high doses of morphine. Instead, high doses of morphine increased the occurrence of apnoeas.r The results indicate that opioids affect distributed key areas of the respiratory network in a dose-dependent manner and countering the respiratory effects of high dose opioids via the KF may be an effective approach to combat overdose.Abstract The primary cause of death from opioid overdose is respiratory failure. High doses of opioids cause severe rate depression and increased risk of fatal apnoea, which correlate with increasing irregularities in breathing pattern. µ-Opioid receptors (MORs) are widely distributed throughout the brainstem respiratory network, but the mechanisms underlying respiratory depression are poorly understood. The medullary pre-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) are considered critical for inducing opioid-related respiratory disturbances. We used a conditional knockout approach to investigate the roles and relative contribution of MORs in KF and preBötC neurons in opioid-induced respiratory depression in Adrienn Varga received her Ph.D. from Case Western Reserve University, where she studied the neural processes underlying navigation in an insect model. This work provided her with an appreciation for how the central nervous system integrates sensory information to shape motor commands. For her postdoctoral work at the University of Florida, she has continued to build on this previous training by moving into the rodent respiratory system, which provides a powerful model for relating sensory cues to the coordination of rhythmic behaviours. An important component of this research is seeking to define the neural mechanisms underlying opioid-induced respiratory depression.A. G. Varga and others J Physiol 598.1 awake adult mice. The results revealed dose-dependent and region-specific opioid effects on the control of both respiratory rate and pattern. Respiratory depression induced by an anti-nociceptive dose of morphine was significantly attenuated following deletion of MORs from either the KF or the preBötC, suggesting cumulative network effects on respiratory rate control at low opioid doses. Deletion of MORs from KF neurons also relieved rate depression at near-maximal respiratory depressant doses of morphine. Meanwhile, deletion of MORs from the preBötC had no effect on rate following administration of high doses of morphine. Instead, a severe ataxic breathing pa...

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“…The mice were also kept warm with a heating pad. We inserted the microdialysis probe into the medulla 6.7 mm posterior, 1.2 mm lateral, and 5.7 mm ventral to bregma according to the standard brain atlas 23 and prior experience 24 . For wild-type or Gabrd −/− mice, baseline levels were recorded for at least 30 min followed by 120 min of recordings during microperfusion of the selected agents.…”

Section: Methodsmentioning

confidence: 99%

δ-Subunit Containing GABAA Receptors Modulate Respiratory Networks

Montandon

Liu

et al. 2017

Sci Rep

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Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAA receptors (δGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function in the preBötzinger Complex (preBötC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBötC δGABAARs in anesthetized rats and wild-type mice decreased breathing rate. In δGABAAR knockout (Gabrd −/−) mice, however, δGABAARs activation had no effect on breathing rate. We then found that during active wakefulness associated with behaviors and movements, diaphragm activation was higher in the Gabrd −/− compared to wild-type mice, but not in other states. These findings identify that δGABAARs modulate the respiratory network, which is critical to understand how δGABAARs change breathing in pathological conditions affecting extra-synaptic GABAA receptor function such as exposure to anesthetics and neurosteroids.

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Contribution of the respiratory network to rhythm and motor output revealed by modulation of GIRK channels, somatostatin and neurokinin-1 receptors

Cited by 35 publications

References 39 publications

Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo

Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo

Differential impact of two critical respiratory centres in opioid‐induced respiratory depression in awake mice

δ-Subunit Containing GABAA Receptors Modulate Respiratory Networks

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