Astrocyte activation in the ventrolateral medulla modulates breathing and arousal states

Astrocytes play vital roles in regulating brain states across organisms. Specifically, they regulate breathing behaviors and associated brain states, including facilitating transitions between breathing phases by sensing changes in O₂ and CO₂ levels, regulating the sleep-wake cycle, and impacting arousal and wakefulness. Here, we test the hypothesis that astrocytes in the ventral respiratory column (VRC) are important for arousal and sigh generation in alert mice. Our results reveal that a subset of Aldh1l1 cells in the VRC are activated prior to sigh generation and are recruited by hypoxia. Chemogenetic or optogenetic activation of Aldh1l1 astrocytes in the VRC increased the probability of evoking arousals with sighs. We also demonstrated that activating Aldh1l1 astrocytes increased calcium transients in catecholaminergic neurons in the VRC immediately before arousal with sighs. We conclude that medullary astrocytes can modulate sigh generation and arousal transitions, and are important for the ventilatory and arousal response to hypoxia. The study shows that a subpopulation of brainstem astrocytes actively regulates breathing and brain states. Activating these cells alters respiratory patterns and increases sighing, revealing a key role in linking neural activity, arousal, and respiratory control.