Neural Circuitry Underlying Waking Up to Hypercapnia

Abstract

Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway collapse, followed by brief arousals that help re-establish the airway patency. These repetitive arousals which can occur hundreds of times during the course of a night are the cause of the sleep-disruption, which in turn causes cognitive impairment as well as cardiovascular and metabolic morbidities. To prevent this potential outcome, it is important to target preventing the arousal from sleep while preserving or augmenting the increase in respiratory drive that reinitiates breathing, but will require understanding of the neural circuits that regulate the cortical and respiratory responses to apnea. The parabrachial nucleus (PB) is located in rostral pons. It receives chemosensory information from medullary nuclei that sense increase in CO2 (hypercapnia), decrease in O2 (hypoxia) and mechanosensory inputs from airway negative pressure during apneas. The PB area also exerts powerful control over cortical arousal and respiration, and therefore, is an excellent candidate for mediating the EEG arousal and restoration of the airway during sleep apneas. Using various genetic tools, we dissected the neuronal sub-types responsible for relaying the stimulus for cortical arousal to forebrain arousal circuits. The present review will focus on the circuitries that regulate waking-up from sleep in response to hypercapnia.

Neurochemistry of the Kölliker‐Fuse nucleus from a respiratory perspective

“…These projections are important in the coordinated control of the upper airways with breathing during orofacial behaviors involving similar anatomical pathways, such as swallowing, cough, and vocalizations (Bautista, Fong, & Dutschmann, 2014; Browaldh et al., 2016; Jakus et al., 2008). Additionally, through connections with regions mediating the arousal component of hypoxic/hypercapnic chemoreflexes, the KF may also play a role in the state‐dependent adjustments of respiratory rate and pattern (Kaur & Saper, 2019). For instance, the KF receives chemosensory information from the lateral hypothalamus, retrotrapezoid nucleus (RTN), medullary raphe, the nucleus of the solitary tract (NTS), and the locus coeruleus (LC) (Guyenet & Bayliss, 2015; Hancock & Fougerousse, 1976; Herbert, Moga, & Saper, 1990; Kaur & Saper, 2019; Peyron et al., 1998; Robertson, Plummer, Marchena, & De, 2013; Yokota, Oka, Asano, & Yasui, 2016).…”

Basal forebrain parvalbumin neurons mediate arousals from sleep induced by hypercarbia or auditory stimuli

“…The BF is considered the final node of the ventral arm of the ARAS, since it receives input from multiple arousal systems in the brainstem and hypothalamus and contains several neurotransmitter systems with projections to the cortex (Jones, 2003;Zaborszky et al, 2012;Brown et al, 2012;Lin et al, 2015;Yang et al, 2017). Recent studies demonstrated that brainstem parabrachial nucleus glutamatergic neurons relay signals about blood carbon dioxide (CO2) levels and mediate arousals from sleep in response to hypercarbia (excessive CO2) Kaur and Saper 2019). These neurons project to the BF, and optogenetic inhibition of their terminals in the BF markedly delayed arousal from sleep in response to hypercarbia (Kaur 2017).…”

Efficacy of melatonin in non-intensive care unit patients with COVID-19 pneumonia and sleep dysregulation

“…For example, GABAergic neurons in the medullary parafacial zone located in the brain stem and the ventral tegmental area (7) and adenosine expressing neurons in the nucleus accumbens are involved in the regulation of rapid eye movement (REM) sleep, whereas the MT2 receptors selectively increase non-REM sleep (8). While the POA contains not only sleep-promoting neurons but also wake-promoting neurons (9), noradrenergic neurons in the locus coeruleus, serotonergic neurons in the dorsal raphe, and histaminergic neurons in the tuberomammillary nucleus are only implicated in regulation of wakefulness (10). Orexin/hypocretin neurons in the lateral hypothalamus play a crucial role to maintain wakefulness by orchestrating the activity of these monoaminergic neurons (11).…”