A Molecularly Defined Medullary Network for Control of Respiratory Homeostasis

The dynamic interaction between central respiratory chemoreceptors and the respiratory central pattern generator constitutes a critical homeostatic axis for stabilizing breathing rhythm and pattern, yet its circuit-level organization remains poorly characterized. Here, the functional connectivity between two key medullary hubs: the nucleus tractus solitarius (NTS) and the preBötzinger complex (preBötC) are systematically investigated. These findings delineate a medullary network primarily comprising Phox2b-expressing NTS neurons (NTS^Phox2b), GABAergic NTS neurons (NTS^GABA), and somatostatin (SST)-expressing preBötC neurons (preBötC^SST). Photostimulation of NTS^Phox2b neurons projecting to the preBötC potently amplifies baseline ventilation, whereas genetic ablation of these neurons or knockout of their transient receptor potential channel 5 (TRPC5) significantly blunts the CO₂-stimulated ventilatory responses. Conversely, NTS^GABA neuron stimulation inhibits or halts breathing partially via monosynaptic inhibition of NTS^Phox2b neurons projecting to the preBötC. Additionally, photostimulation of preBötC^SST neurons projecting to the NTS drives deep and slow breathing through coordinated modulation of NTS^GABA and NTS^Phox2b neurons. These findings collectively identify an important medullary network that integrates chemosensory feedback with respiratory motor output, enabling dynamic tuning of breathing patterns to metabolic demands.