Figure 2 - uploaded by Christopher G Wilson
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Projections of locus coeruleus (LC) noradrenergic cells to hypoglossal motoneurons. A: Schematic of a coronal section showing location of pontine noradrenergic cell groups. B: LC neurons labeled with transsynaptic pseudorabies virus that expresses green fluorescent protein (PRV-GFP) following injection of PRV-GFP into the genioglossus muscle and a survival time of 5 days. C: Tyrosine hydroxylase-containing cells (TH, red) were identified by immunohistochemisty in the same section of the LC. D: Overlay of confocal microscopy images shown in B and C; yellow color indicates neurons that are colabeled for TH and PRV-GFP (yellow) as indicated by the arrows.
Source publication
A central neuronal network regulates airway functions from the nares to the bronchioles and is an integral component of a regulatory system for brain control of breathing and airway patency during wakefulness and sleep. This network, components of which include sleep generating sites and monoaminergic neurons in particular, is characterized by reci...
Citations
... This may suggest that selective targeting of the 5-HT system drives the efficacy of SSRI treatment in increasing post-seizure ventilation, while NE may play a larger role driving autoresuscitation, a protective cardiorespiratory reflex that can serve as a ''last ditch" effort to prevent terminal apnea, which often takes the form of large, spontaneous gasps (Erickson, 2020). The role of NE in breathing is well documented and undoubtably plays a role in the mechanisms behind periictal respiratory dysfunction (Whelan and Young, 1953;Haxhiu et al., 2003). Future investigations delineating the role of 5-HT and NE in this pathway are certainly warranted. ...
Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT2 receptor agonists. SSRIs and 5-HT2 agonists increased postictal breathing frequency (fR), tidal volume (VT), and minute ventilation (VE) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT2 agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT2A antagonist MDL-11939 reduced the effect of citalopram on fR, VT, and VE, and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT2 family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.
... Studies using nasal pharyngoscopy, computed tomography (CT), and magnetic resonance imaging, or pharyngeal pressure monitoring, have shown that closure occurs in most subjects with OSA at one or more sites within the oral pharyngeal region, and that this region may be narrower in OSA patients compared to controls during wakefulness [28][29][30][31][32]. Although the retropalatal region of the oropharynx is the most common site of airway collapse, narrowing is a dynamic process, varying markedly among and within subjects and often including the retroglossal and hypopharyngeal areas [33,34]. Neuromuscular control of breathing during sleep also plays a key role in OSA pathogenesis, e.g. ...
Introduction:
Obstructi ve sleep apnoea is an increasingly prevalent clinical condition with significant impact on individuals and public health. Continuous positive airway pressure therapy is the standard treatment, but adherence is limited and alternative treatments are needed. In this context, non-invasive and invasive methods for the electrical stimulation of upper airway dilator muscles have been demonstrated to be effective in selected patients. Areas covered: This review will cover investigations on the clinical effects, safety, and tolerability of non-invasive and invasive electrical stimulation of the upper airway for the management of obstructive sleep apnoea. Following a search of the relevant literature published on PubMed this review is focused mainly on data obtained from randomized clinical trials and clinical studies. Expert commentary: The available evidence provides a rationale to consider upper airway electrical stimulation as treatment for selected patients with obstructive sleep apnoea, who have poor adherence or experience difficulties with continuous positive airway pressure therapy. Non-invasive stimulation using transcutaneous electrodes and implantable hypoglossal nerve stimulator technologies may provide an alternative to continuous positive airway pressure for the treatment of obstructive sleep apnoea via restoration of neuromuscular tone and improved upper airway patency.
... The cholinergic system thus plays an important role in the neural control of respiration and in the pathophysiology of sleep disturbances in neurodegenerative disorders [63][64][65][71][72][73]. ...
Objectives:
Patients with obstructive sleep apnea syndrome (OSAS) show neurocognitive impairment, but the exact mechanisms that cause cognitive dysfunctions remain unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this exploratory study was to test the hypothesis that impaired cognitive performances in OSAS patients are associated with a dysfunction of the cholinergic system, as assessed by SAI.
Methods:
We applied SAI technique in a group of 13 patients with OSAS and compared the data with those from a group of 13 age-matched healthy subjects. All the patients underwent a sleep study, an extensive neuropsychological evaluation, and TMS examination.
Results:
Mean SAI was significantly reduced in our OSAS patients when compared with controls. The neuropsychological evaluation showed impairments in most cognitive areas in the OSAS patients. SAI values were strongly correlated with the neuropsychological test scores.
Conclusions:
These findings suggest that the cognitive deficits in OSAS may be, at least in part, secondary to alterations in cholinergic neurotransmission, presumably caused by nocturnal hypoxemia. TMS studies may shed light on the pathophysiological mechanisms of the cognitive disturbances in OSAS patients.
... The mechanisms of action inferred from the literature include changes in temperature, resetting of chemosensitivity, and direct effects on respiratory medullary neurons (Kuwaki, 2010;Shahid et al., 2012;Young et al., 2005). Leptin and orexin receptors are in the brainstem, both peptides influence metabolism, and anatomic connections occur that could influence autonomic output and respiratory drive (Haxhiu et al., 2003;Shirasaka et al., 2003). Pauses occur in the leptin receptor deficient mouse, the ob/ob mouse, a strain arising as a spontaneous mutation out of the B6 strain . ...
Background:
The hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing.
Methods:
In C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/h during sleep-wake states at baseline and with an intracerebroventricular administration of vehicle, 4 nMol of agonist OB(DL), and 4 nMol of an antagonist, TCS OX2 29.
Results:
A significant reduction (p=0.035, f=2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p=0.03, f=3.8), NREM (p=0.003, f=6.98) and REM (p=0.03, f=3.92) with the agonist reducing the rate of apneas during sleep from 29.7±4.7 (M±SEM) to 7.3±2.4 during sleep (p=0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels.
Conclusions:
The B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4 nMol given intracerebroventricularly will reduce events in sleep and also wakefulness.
... There are several neurobiological mechanisms that might underlie the potential modulatory role of REM in asthma. REM sleep is characterized by increased cholinergic outflow and ablated noradrenergic signals in the brainstem [25][26][27], which are in turn critical modulators of the caliber and reactivity of the lower airways in mice [25][26][27]. In addition, animal models of allergic asthma have illustrated that allergic lung inflammation may affect central noradrenergic control of cholinergic outflow to the airways, thereby augmenting bronchoconstrictive reflex responses in the asthmatic state [28]. ...
... There are several neurobiological mechanisms that might underlie the potential modulatory role of REM in asthma. REM sleep is characterized by increased cholinergic outflow and ablated noradrenergic signals in the brainstem [25][26][27], which are in turn critical modulators of the caliber and reactivity of the lower airways in mice [25][26][27]. In addition, animal models of allergic asthma have illustrated that allergic lung inflammation may affect central noradrenergic control of cholinergic outflow to the airways, thereby augmenting bronchoconstrictive reflex responses in the asthmatic state [28]. ...
Rationale. The sleep-related factors that modulate the nocturnal worsening of asthma in children are poorly understood. This study addressed the hypothesis that asthmatic children have a REM sleep-related vulnerability trait that is independent of OSA. Methods. We conducted a retrospective cross-sectional analysis of pulse-oximetry signals obtained during REM and NREM sleep in control and asthmatic children (n = 134). Asthma classification was based on preestablished clinical criteria. Multivariate linear regression model was built to control for potential confounders (significance level P ≤ 0.05). Results. Our data demonstrated that (1) baseline nocturnal respiratory parameters were not significantly different in asthmatic versus control children, (2) the maximal % of SaO2 desaturation during REM, but not during NREM, was significantly higher in asthmatic children, and (3) multivariate analysis revealed that the association between asthma and REM-related maximal % SaO2 desaturation was independent of demographic variables. Conclusion. These results demonstrate that children with asthma have a REM-related vulnerability trait that impacts oxygenation independently of OSA. Further research is needed to delineate the REM sleep neurobiological mechanisms that modulate the phenotypical expression of nocturnal asthma in children.
... The cholinergic system plays an important role in the neural control of respiration and in the pathophysiology of sleep disturbances in neurodegenerative disorders [1,2,14,24,30,31]. One study concluded that the decrease in pontine cholinergic projections may contribute to OSA in multi-system atrophy [12]. ...
Previous publications have shown beneficial effects of cholinergic medication on obstructive sleep apnea (OSA) in Alzheimer's disease (AD) patients. We hypothesized that cholinergic medication could also improve OSA in non-AD patients. The present study evaluated the effects of donepezil on OSA in non-AD patients.
A randomized, double-blind, placebo-controlled study was conducted. The final sample consisted of 21 male patients with mild to severe OSA and AHI >10 divided into two groups, a donepezil-treated group (n=11) and a placebo-treated group (n=10). The dosage was one tablet/day (5 mg) for the first two weeks and two tablets/day (10 mg) for the last two weeks. Polysomnography and sleepiness evaluations were performed at baseline and after one month of treatment. Groups were compared using two-way ANOVA for repeated measures with treatment-group and treatment-time as the main factors and time-treatment as an interaction effect.
Considering the effect of the interaction with time-treatment, there was a significant improvement in the obstructive apnea/hypopnea index, desaturation index, percentage of time with O(2) saturation ≤3% lower than baseline, lowest oxygen saturation, and the Epworth Sleepiness Scale (ESS) scores with donepezil treatment (p<0.05). Sleep efficiency significantly decreased (p<0.01).
Donepezil treatment improved obstructive sleep apnea index, oxygen saturation, and sleepiness in parallel with a reduction in sleep efficiency. Our findings support the concept that cholinergic transmission may influence breathing regulation in OSA patients.
... Stimulation of the raphe neurons with glutamate caused a significant increase in 5-HT level within rostral NA and inhibition of cholinergic outflow to the airway (Haxhiu et al., 1998(Haxhiu et al., , 2006. Pathologically, decreased release of 5-HT onto AVPNs is indicated to be involved in the sleep worsening of bronchial asthma (Haxhiu et al., 2003(Haxhiu et al., , 2006; and contrarily, enhanced uptake of 5-HT by central 5-hydroxytryptaminergic terminals is thought to at least, in part, account for the abrupt disappearance of asthma attacks after tianeptine treatment (Lechin et al., 2004). Therefore, clarification of the 5-hydroxytryptaminergic effect on AVPNs and elucidation of the synaptic mechanisms involved would help to understand not only the physiological central control of the airway but also those airway disorders that involve altered airway vagal functions. ...
The vagus nerves supply the major cholinergic tone to airway smooth muscles physiologically and play critical roles in the genesis of airway hyperreactivity under some pathological conditions. Postganglionic airway cholinergic tone relies largely on the ongoing activity of medullary airway vagal preganglionic neurons (AVPNs), of which the tracheobronchial-projecting ones are primarily located in the external formation of the nucleus ambiguus (eNA). AVPNs are regulated by 5-HT, and 5-HT(1A/7) and 5-HT(2) receptors have been indicated to be involved. But the mechanisms at synaptic level are unknown. In the present study, tracheobronchial-projecting AVPNs (T-AVPNs) were retrogradely labeled from the trachea wall; fluorescently labeled T-AVPNs in the eNA were recorded with whole-cell voltage patch clamp; and the effects of 5-HT(1A/7) receptor agonist (±)-8-Hydroxy-2-(dipropylamino) tetralin hydrobromide (8-OH-DPAT) (1 μmol L(-1)) and 5-HT(2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (10 μmol L(-1)) on the synaptic inputs were examined. 8-OH-DPAT significantly inhibited the GABAergic and glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) of T-AVPNs in both the frequency and amplitude but had no effect on the GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs). The 8-OH-DPAT inhibition of the GABAergic and glycinergic sIPSCs was prevented by 5-HT(1A/7) receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY-100635) (1 μmol L(-1)). 8-OH-DPAT had no effect on the glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) and caused no alterations in the baseline current and input resistance of T-AVPNs. DOI had no effect on any types of the synaptic inputs of T-AVPNs. These results suggest that 5-HT(1A/7) receptor agonist causes "disinhibition" of T-AVPNs, which might, in part, account for the reflex increase of airway resistance.
... OSA is a state-related disorder, and the most fundamental neural event that initiates OSA is the closure of the pharyngeal airway during sleep. UA dilator muscle activity maintains a patent airway during wakefulness; however, with sleep onset, this neural compensation is reduced [67], thus setting the stage for OSA. During sleep, cortical neural controlthat includes changes in neural drive, and peripheral reflex control of the chest wall muscles, UA dilator muscles, and ventilation, is compromised [67,68]. ...
... UA dilator muscle activity maintains a patent airway during wakefulness; however, with sleep onset, this neural compensation is reduced [67], thus setting the stage for OSA. During sleep, cortical neural controlthat includes changes in neural drive, and peripheral reflex control of the chest wall muscles, UA dilator muscles, and ventilation, is compromised [67,68]. Several conditions such as obesity, increased neck size, and a host of other risk factors (including changes in craniofacial structures particularly retrognathia and enlargement of the UA soft tissue structures) would alter UA anatomy. ...
Obstructive sleep apnea (OSA), characterized by recurrent upper airway (UA) collapse during sleep, is associated with significant morbidity and disorders. Polysomnogram is employed in the evaluation of OSA and apnea-hypopnea number per hour reflects severity. For normal breathing, it is essential that the collapsible UA is patent. However, obstruction of the UA is quite common in adults and infants. Normally, important reflex mechanisms defend against the UA collapse. The muscle activity of UA dilators, including the genioglossus, tensor palatini (TP), and pharyngeal constrictors, is due to the integrated mechanism of afferent sensory input → to motor function. Snoring is harsh breathing to prevent UA obstruction. Unfortunately, snoring vibrations, pharyngeal suction collapse, negative pressure, and hypoxia cause pathological perturbations including dysfunctional UA afferent sensory activity. The current paper posits that peripheral sensory stimulation paradigm, which has been shown to be efficacious in improving several neurological conditions, could be an important therapeutic strategy in OSA also.
... Although it is conceivable that increased chemosensitivity could lead to respiratory instability [20] and possibly to increased AHI in individuals with high loop gain, this effect might be overcome by the improvement of respiratory coordination and by the other above-mentioned mechanisms. The cholinergic system plays an important role in the neural control of respiration and in the pathophysiology of sleep disturbances in neurodegenerative disorders [1,2,14,24,30,31]. One study concluded that the decrease in pontine cholinergic projections may contribute to OSA in multi-system atrophy [12]. ...
Introduction/objectives: Previous publications have shown beneficial effects of cholinergic medication on obstructive sleep apnea (OSA) in Alzheimer's disease (AD) patients. We hypothesized that cholinergic medication could also improve OSA in non-AD patients. The present study evaluated the effects of donepezil on OSA in non-AD patients. Methods: A randomized, double-blind, placebo-controlled study was conducted. The final sample consisted of 21 male patients with mild to severe OSA and AHI >10 divided into two groups, a donepezil-treated group (n = 11) and a placebo-treated group (n = 10). The dosage was one tablet/day (5 mg) for the first two weeks and two tablets/day (10 mg) for the last two weeks. Polysomnography and sleepiness evaluations were performed at baseline and after one month of treatment. Groups were compared using two-way ANOVA for repeated measures with treatment–group and treatment–time as the main factors and time–treatment as an interaction effect. Results: Considering the effect of the interaction with time–treatment, there was a significant improvement in the obstructive apnea/hypopnea index, desaturation index, percentage of time with O 2 saturation 63% lower than baseline, lowest oxygen saturation, and the Epworth Sleepiness Scale (ESS) scores with donepezil treatment (p < 0.05). Sleep efficiency significantly decreased (p < 0.01). Conclusions: Donepezil treatment improved obstructive sleep apnea index, oxygen saturation, and sleep-iness in parallel with a reduction in sleep efficiency. Our findings support the concept that cholinergic transmission may influence breathing regulation in OSA patients.
... The serotonergic raphe nuclei can be basically subdivided into two major groups: the dorsal raphe nucleus is located in the pons/mesencephalon and has mainly ascending projections to forebrain structures. In contrast the raphe nuclei found in the medulla oblongata have dense projections that target areas in the brainstem and the spinal cord (Holtman et al., 1986; Lalley, 1986a,b; Aldes et al., 1989; Li et al., 1993; Dobbins and Feldman, 1994; Haxhiu et al., 2003). The latter are known to be involved in the mediation of arousal during wakefulness but also in autonomic responses of the cardio-respiratory systems in brainstem (Jacobs and Azmitia, 1992; Jacobs and Fornal, 1999; Li et al., 2006; Comet et al., 2007). ...
Neural control circuits that coordinate the motor activity of the diaphragm (DIA) and the geniohyoid muscle (GH) are potentially involved in pathological conditions such as various forms of sleep apnea. Here we investigated a differential role of the raphe magnus (RMg), pallidus (RPa) and the obscurus (ROb) nuclei in the neural control of DIA and GH muscle activity in rats under volatile anesthesia. In order to characterize a topographical organization of the raphe nuclei we analyzed changes in DIA and GH during high-frequency stimulation (HFS, 10-130 Hz, 60 micros pulse width, 40-160 microA, 30s). HFS of the RMg and the ROb induced apnea, in the latter case apnea was associated with massive tonic discharge in the GH. By contrast, HFS of the RPa induced tachypnea. At caudal stimulation sites the tachypnea was accompanied by tonic DIA activity and cessation of GH. These data suggest a differential distribution of inhibitory and excitatory drives of DIA and GH muscles within distinct raphe nuclei.
