A top-down slow breathing circuit that alleviates negative affect

Abstract

Breathing is profoundly influenced by both behavior and emotion and is the only physiological parameter that can be volitionally controlled. This indicates the presence of cortical-to-brainstem pathways that directly control brainstem breathing centers, 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 behaviors associated with negative emotions without altering valence. Calcium responses of dACC→PnC neurons are tightly correlated with changes in breathing patterns entrained by behaviors, 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.

Sniffing can be initiated by dopamine’s actions on ventral striatum neurons

“…Both the TuS and NAc have outputs into downstream structures important for homeostatic regulation/control and limbic function. Ventral striatum spiny projection neurons also feedback upon the VTA in manners regulating DA release and this too could support, even if just bisynaptically, modulation of respiratory central pattern generators which are sensitive to dopamine (Sugita et al, 2015; Jhang et al, 2023). Perhaps one clue may reside from our results wherein we attempted to stimulate sniffing under anesthesia and found that DA release into the TuS or NAc is incapable of initiating sniffing ( Fig 5A & B ).…”

“…This suggests that the functional ‘sniffing’ output from the ventral striatum is within a structure which can drive changes in breathing but not under anesthesia. It is not uncommon for stimulation of some respiratory control centers to be incapable of altering respiration under anesthesia (Arthurs et al, 2023; Jhang et al, 2023). For instance, the ventral striatum projects to hypothalamic nuclei that are known to innervate respiratory control nuclei in the respiratory pons and could support entrainment of breathing at sniffing frequencies.…”