CO2-sensitive Cx26 hemichannels in dorsal raphe-ventral tegmental area pathway mediate hypercapnic arousal

Hypercapnic arousal is a life-preserving reflex that promotes awakening in response to elevated PCO2, yet the cellular mechanisms by which CO2 is detected remain incompletely understood. Serotonergic neurons of the dorsal raphe (DR) have been implicated in hypercapnic responses, but the molecular sensor that directly detects CO2 within this circuit is unknown. Here, we show that the CO2-gated connexin 26 (Cx26) hemichannel is expressed on serotonergic terminals projecting from the DR to the ventral tegmental area (VTA). Brief elevations in PCO2 modulated the excitability of VTA dopamine neurons through serotonergic signaling without altering glutamatergic transmission, and these effects were