Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals

• Published in: Nature communications Vol. 11; no. 1; p. 2769
• Main Authors: Kaur, Satvinder, De Luca, Roberto, Khanday, Mudasir A., Bandaru, Sathyajit S., Thomas, Renner C., Broadhurst, Rebecca Y., Venner, Anne, Todd, William D., Fuller, Patrick M., Arrigoni, Elda, Saper, Clifford B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-06-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/44; 13/51; 14; 14/1; 14/19; 14/63; 631/378/1385/1877; 631/378/3920; 64/110; 64/60; 9/26; 96/109; 96/35; Animals; Apnea; Arousal; Arousal - physiology; Blood; Brain stem; Brain Stem - metabolism; Calcitonin; Calcitonin Gene-Related Peptide - metabolism; Carbon Dioxide; Deletion; Disease Models, Animal; Dorsal Raphe Nucleus - metabolism; Glutamatergic transmission; Humanities and Social Sciences; Hypercapnia; Hypercapnia - metabolism; Latency; Male; Mice; Mice, Transgenic; multidisciplinary; Neurons; Optogenetics; Parabrachial Nucleus; Peptides; Receptors; Science; Science (multidisciplinary); Serotonergic Neurons - metabolism; Serotonin; Serotonin - genetics; Serotonin Plasma Membrane Transport Proteins - genetics; Sleep; Sleep disorders
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16518-9

During obstructive sleep apnea, elevation of CO
2
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 (PBel
CGRP
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 DR
Sert
neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DR
Sert
terminals in the PBel. This effect was mediated by 5HT
2a
receptors which are expressed by PBel
CGRP
neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT
2a
receptors is critical for modulating the sensitivity of the PBel
CGRP
neurons that cause arousal to rising levels of blood CO
2
.
Dorsal raphe 5HT(DR
Sert
) neurons regulate arousal from hypercapnia by their projections to the neurons in the external lateral parabrachial nucleus (PBel) that are glutamatergic and also express calcitonin gene related peptide (PBel
CGRP
). The DR
Sert
input to the PBel modulates the arousal system to rising levels of blood CO
2
, and may be mediated by 5HT
2a
receptors on the PBel
CGRP
neurons.