A top-down slow breathing circuit that alleviates negative affect

Abstract Breathing is profoundly influenced by both behavior and emotion1-4 and is the only physiological parameter that can be volitionally controlled4-6. This indicates the presence of cortical-to-brainstem pathways that directly control breathing centers in the brainstem, but the neural circuit mechanisms of top-down breathing control remain poorly understood. Here, we identify neurons in the dorsal anterior cingulate cortex (dACC) that project to the pontine reticular nucleus caudalis (PnC) and function to slow breathing rates. Optogenetic activation of this corticopontine pathway (dACC→PnC neurons) in mice slows breathing and alleviates anxiety-like behaviors without altering valence. Calcium responses of dACC→PnC neurons are tightly correlated with changes in breathing patterns that are entrained to behavior, such as drinking. Activity is also elevated when mice find relief from an anxiety-provoking environment and slow their breathing pattern. Further, GABAergic inhibitory neurons within the PnC that receive direct input from dACC neurons decrease breathing rate by projecting to pontomedullary breathing centers. They also send collateral projections to anxiety-related structures in the forebrain, thus comprising a neural network that modulates breathing and negative affect in parallel. These analyses greatly expand our understanding of top-down breathing control and reveal circuit-based mechanisms by which slow breathing and anxiety relief are regulated together.