Brain Circuitry for Arousal from Apnea.

We wanted to understand the brain circuitry that awakens the individual when there is elevated CO₂ or low O₂ (e.g., during sleep apnea or asphyxia). The sensory signals for high CO₂ and low O₂ all converge on the parabrachial nucleus (PB) of the pons, which contains neurons that project to the forebrain. So, we first deleted the vesicular glutamate transporter 2, necessary to load glutamate into synaptic vesicles, from neurons in the PB, and showed that this prevents awakening to high CO₂ or low O₂ We then showed that PB neurons that express calcitonin gene-related peptide (CGRP) show cFos staining during high CO₂ Using CGRP-Cre-ER mice, we expressed the inhibitory opsin archaerhodopsin just in the PB^CGRP neurons. Photoinhibition of the PB^CGRP neurons effectively prevented awakening to high CO₂, as did photoinhibition of their terminals in the basal forebrain, amygdala, and lateral hypothalamus. The PB^CGRP neurons are a key mediator of the wakening response to apnea.