Decoding the neural circuits governing essential breathing behaviors

Breathing is a fundamental, innate behavior controlled by the neural circuits that integrate signals between the body and the brain. This process is precisely tuned to respond promptly to physiological stimuli, such as changes in blood gas levels and airway irritants, ensuring homeostasis and protecting the body from environmental challenges. Despite the vital importance, the mechanisms by which sensory signals are processed to regulate diverse breathing behaviors remain incompletely understood. In our recent research, we examined the molecular and functional diversity of neurons within the nucleus of the solitary tract (NTS) in mice, a critical relay center in the brain that receives afferent inputs from visceral organs. Using single-cell transcriptomics, we identified 19 molecularly distinct NTS neuronal populations, including two groups of neurons uniquely expressing neuropeptide genes. Through subsequent functional analysis, we discovered that optogenetic activation of these two NTS neuronal populations elicited distinct breathing behaviors: sighing and coughing, respectively. Further experiments, including chemogenetic inhibition and genetic ablation, demonstrated that these neuronal populations mediate specific respiratory responses to distinct interoceptive challenges. The first population was found to drive sighing behavior in response to hypoxia, while the second facilitated coughing during tussive challenges. We further identified two parallel neural circuits connecting the body and the brain, mediated by these neuronal populations, which process specific afferent inputs and engage distinct downstream pathways to regulate these breathing behaviors. Our work advances the understanding of the neural control of breathing by identifying endogenous circuits responsible for sighing and coughing. This research provides new insights into the organization of respiratory control circuits, with implications for understanding how the brain ensures robust breathing responses to physiological and environmental demands. NIH R01AT011652, R01HL156989 (P.L.) and F31HL165733 (N.G.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.