Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals

Satvinder Kaur,Patrick M Fuller,Sathyajit S Bandaru,Renner C Thomas,Anne Venner,William D Todd,Rebecca Y Broadhurst,Roberto De Luca,Elda Arrigoni,Mudasir A Khanday,Clifford B Saper

doi:10.1038/s41467-020-16518-9

Satvinder Kaur, Patrick M Fuller + Show 9 more

Open Access

https://doi.org/10.1038/s41467-020-16518-9

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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.

Highlights

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency
We have recently shown that neurons in the external lateral parabrachial nucleus that express calcitonin gene-related peptide (PBelCGRP neurons) are required for EEG arousal, but not the increase in respiratory drive, induced by hypercapnia
Based on the proposed role of the dorsal raphe (DR) serotonergic neurons in CO2 chemosensitivity, we hypothesized that the DR may supply a serotonergic input to the PBelCGRP neurons via 5HT2a receptors to sensitize them to CO2-responsive inputs

Summary

Introduction

Elevation of CO2 during apneas contributes to awakening and restoring airway patency. In addition to the PBelCGRP neurons, Richerson, Buchanan, Dymecki and their colleagues have emphasized the importance of serotonergic neurons for CO2 arousal They point out that many serotonin neurons in the medullary raphe and the dorsal raphe (DR) are CO2 (or pH) responsive[8,9] and that their absence during development in Lmx1bf/f/p::ePet1-Cre mice results in frequent apneas and high infant mortality as well as impaired arousal to CO2 in adults[10,11,12]. We examined the role of the DR serotonergic neurons in CO2 arousal first by deleting them genetically, by activating them chemogenetically, and by inhibiting their cell bodies and their terminals optogenetically with archaerhodopsin T (ArchT)

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