Dorsal raphe serotonin neurons mediate Co ₂ -induced arousal from sleep

Arousal from sleep in response to CO ₂ is a critical protective phenomenon. Dysregulation of CO ₂ -induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO ₂ -induced arousal is unknown. Because CO ₂ is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo-and mechano-sensors is required for CO ₂ -induced arousal. However, populations of neurons that are not involved in the regulation of breathing are also chemosensitive. Among these are serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) that comprise a component of the ascending arousal system. We hypothesized that direct stimulation of these neurons with CO ₂ could cause arousal from sleep independently of enhancing breathing. Dialysis of CO ₂ -rich acidified solution into DRN, but not medullary raphe responsible for modulating breathing, caused arousal from sleep. Arousal was lost in mice with a genetic absence of 5-HT neurons, and with acute pharmacological or optogenetic inactivation of DRN 5-HT neurons. Here we demonstrate that CO ₂ can cause arousal from sleep directly, without requiring enhancement of breathing, and that chemosensitive 5-HT neurons in the DRN critically mediate this arousal. Better understanding mechanisms underlying this protective reflex may lead to interventions to reduce disease-associated morbidity and mortality.