Pre-sympathetic C1 RVLM neurons drives sleep disordered breathing in heart failure through activation of central chemoreceptors

Abstract

Sleep-disordered breathing is closely linked to heart failure (HF) morbidity and mortality. Recently, we showed that photo-stimulation of pre-sympathetic motor neurons located within the rostro ventrolateral medulla (RVLM) drive sleep-disordered breathing in healthy conditions. However, the neural circuitry required for these effects and whether this pathway is relevant for HF pathophysiology is not known. Accordingly, we aimed to determine: i) if the generation of RVLM-induced altered breathing encompasses the activation of chemoreceptor neurons from the retrotrapezoid nucleus (RTN), and ii) if selective ablation of RVLM neurons improves breathing control and sleep architecture in HF rats. Sprague-Dawley rats received stereotaxic injections of a lenti-viral vector containing a light-sensitive cation channel (Channelrhodopsin2) in the RVLM and a Substance P-saporin toxin conjugate into the RTN. Then, 200 mm fiber optics were implanted for RVLM neurons photo-stimulation. A second group underwent volume overload to induced HF and ablation of RVLM neurons was performed using a DbH-saporin toxin (DbH-SAP). EEG and EMG leads were implanted, and rats allowed to recover before sleep/breathing studies. We found that photo-stimulation of RVLM neurons triggered breathing disorders only in the presence of a functional RTN neurons. Indeed, breathing irregularity score following RVLM photo-stimulation showed a two-fold increase (9±2 vs. 20±3, pre vs. post-stimulation) and this was absent in the presence of Substance P-saporin (10±3 vs. 12±3, pre vs. post-stimulation with Substance P-saporin). Compared to Sham rats, HF animals showed overt signs of disordered breathing and sleep fragmentation and ablation of RVLM neurons using DbH-SAP significantly improves both breathing and sleep function in HF. Our results showed that RVLM drives breathing disorders through activation of the RTN and that selective ablation of RVLM neurons offer salutary benefit for the control of sleep and irregular breathing patterns in the setting of HF. Fondecyt 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.