Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals

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 (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 CO₂.