Circuit Mechanisms Underlying the Contribution of Leptin Receptor-Expressing Neurons in the Nucleus Tractus Solitarius to Ventilatory Homeostasis.

Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent respiratory pauses during sleep; however, the neural mechanisms governing respiratory stability remain poorly understood. In this study, we identify the ratio of sigh expiratory volume to eupneic expiratory volume as a potential predictor of post-sigh apnea in susceptible C57BL/6J mice. We demonstrate that leptin signaling within the nucleus tractus solitarius (NTS) is critical for maintaining respiratory drive and suppressing apnea. Chemogenetic activation of Leptin receptor b-expressing NTS (NTSLepRb) neurons significantly reduced apnea incidence, whereas their ablation exacerbated respiratory dysfunction. Moreover, NTSLepRb neurons mediate these effects through anatomically and functionally segregated projections to the dorsomedial hypothalamus and the lateral parabrachial nucleus. These findings define a specific leptin-mediated brainstem circuit that stabilizes respiratory output, providing new mechanistic insights and potential therapeutic targets for sleep-disordered breathing.