Schematic depicting proposed neural mechanisms by which A6 neurons regulate inspiratory and expiratory responses to high chemical drive. Parasagittal views of the brainstem showing the location of the medullary ventral respiratory group and C1 catecholaminergic region, as well as the pontine LC A6 neurons (red) and Facial Motor Nucleus (VII). The respiratory rhythmogenic sites of the pre-Bötzinger Complex (pre-BötC, inspiratory neurons) and parafacial Respiratory Group (pFRG, for active expiration and sigh), as well as the expiratory Bötzinger Complex (BötC), rostral Ventral Respiratory Group (rVRG; containing inspiratory bulbo-spinal premotor neurons) and caudal Ventral Respiratory Group (cVRG; containing expiratory bulbo-spinal premotor neurons) are also shown. (A) Sigh response during systemic hypoxia: A6 neurons might be directly activated by systemic hypoxia (↓ O2)34,35 or by sigh-promoting bombesin-like pFRG38 and C1 catecholaminergic neurons40 to increase the frequency of sighing through adrenergic receptor activation of pre-BötC42. (B) Active inspiratory and expiratory responses during hypercapnia: A6 neurons, activated by CO27 or C1 catecholaminergic neurons59, enhance inspiration and VE through adrenergic receptor activation of pre-BötC52,53. A6 neurons might also provide either tonic9 or expiratory-related14 excitatory input to the conditional expiratory oscillator located in the pFRG or directly to the cVRG, for onward relay to expiratory spinal motoneurons, enhancing active expiration.