Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals

Abstract

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2.

Respiratory Training and Plasticity After Cervical Spinal Cord Injury

“…Within the nucleus tractus solitarius, the principal visceral sensory nucleus, PHOX2B-expressing neurons exhibit CO 2 sensitivity and increase activity after exposure to hypercapnia ( Fu et al, 2019 ). Another crucial effect of hypercapnia on brainstem nuclei is the activation of the dorsal raphe (containing serotonergic neurons) ( Smith et al, 2018 ; Kaur et al, 2020 ). Because carotid chemoafferents also activate raphe, there is also reason to believe that exposure to hypercapnia and hypoxia may further enhance serotonin-dependent mechanisms of plasticity beyond hypoxia alone ( Welch, 2021 ).…”

Chemoreceptor mechanisms regulating CO2‐induced arousal from sleep

“…2020) or has no effect on sleep‐wake patterns (Kaur et al . 2020). In contrast, optogenetic stimulation at high frequency (>20 Hz) promotes wakefulness (Ito et al .…”

“…DR 5HT innervation of the brainstem is sparse by comparison, but does include the rostral ventrolateral medulla (Vertes & Kocsis, 1994). Genetically targeted acute inhibition of DR 5HT neurons in adult mice, but not DR 5HT neurons in the medullary raphe, attenuates the CO 2 -arousal reflex without affecting the HCVR (Smith et al 2018;Kaur et al 2020). Hypoxia-induced arousal is also intact in mice lacking 5HT neurons from birth (Lmx1b f/f/p mice) (Buchanan & Richerson, 2010).…”

“…CO 2 -activated inputs to the PBel originate from the lower brainstem respiratory network (Kaur & Saper, 2019), including possible monosynaptic inputs from the RTN (Souza et al 2020). The PBel is also regulated by DR 5HT neurons, which has been shown to be important in the CO 2 -arousal reflex (Kaur et al 2020). It also receives inputs from the dorsal horn of the spinal cord and subnuclei of the NTS that process sensory feedback from the airways and CB activity (Kaur & Saper, 2019).…”

Neural basis of opioid-induced respiratory depression and its rescue

“…In addition to breathing, the PBL also regulates various homeostatic functions (39) and incorporates the alarm center, which senses deviations from the homeostasis and relays aversive signals to higher-order brain structures (38,50). At the same time, by sending tonic excitatory outputs to medulla respiratory centers (39,43,46), the parabrachial neurons can increase breathing rhythm under conditions that immediately require more oxygen due to metabolic needs, such as hypoxia (27) and hypercapnia (26), in particular, hypercapnic arousal during sleep (24,28,51); or non-metabolic behavioral demands, such as escaping from a threat (25). As a representative glutamatergic population in the PBL (Supplementary Figure 1), Oprm1-positive neurons are likely to participate in similar physiological processes.…”