GABAergic Inhibition from the Nucleus Tractus Solitarius to Ventrolateral Medulla Phox2b Neurons Modulates Central...

Central respiratory chemoreception is a vital homeostatic mechanism maintaining arterial blood gas levels. Central respiratory chemoreceptors in the retrotrapezoid nucleus (RTN) and nucleus tractus solitarius (NTS) form interconnected circuits to regulate respiratory homeostasis. We hypothesized that NTS GABAergic neurons (NTS^GABA) modulate hypercapnic ventilatory responses by targeting ventrolateral medulla Phox2b neurons (VLM^Phox2b), particularly Phox2b-expressing RTN neurons. Stimulation of NTS^GABA neurons significantly attenuated CO₂-evoked ventilatory responses, accompanied by a reduction in CO₂-activated Phox2b-expressing RTN neurons. Neural tracing revealed that monosynaptic inputs to the VLM^Phox2b neurons primarily originate from the ventrolateral and dorsolateral subdivisions of the NTS. Photostimulation of NTS^GABA neurons retrogradely labeled from the VLM markedly suppressed respiratory drive, while chemogenetic activation of these neurons induced hypoventilation, increased spontaneous apnea, and attenuated hypercapnic ventilatory response. These findings demonstrate that activation of the NTS-VLM inhibitory circuit diminishes respiratory motor output, offering novel insights into the regulatory mechanisms of respiratory homeostasis.