Inspiratory rhythm generation is stabilized by Ih

Cellular and network properties must be capable of generating rhythmic activity that is both flexible and stable. This is particularly important for breathing, a rhythmic behavior that dynamically adapts to environmental, behavioral, and metabolic changes from the first to the last breath. The pre-Boeurotzinger complex (preBoeurotC), located within the ventral medulla, is responsible for producing rhythmic inspiration. Its cellular properties must be tunable, flexible as well as stabilizing. Here, we explore the role of the hyperpolarization-activated, nonselective cation current (Ih) for stabilizing PreBoeurotC activity during opioid exposure and reduced excitatory synaptic transmission. Introducing Ih into an in silico preBoeurotC network predicts that loss of this depolarizing current should significantly slow the inspiratory rhythm. By contrast, in vitro and in vivo experiments revealed that the loss of I-h minimally affected breathing frequency, but destabilized rhythmogenesis through the generation of incompletely synchronized bursts (burstlets). Associated with the loss of I-h was an increased susceptibility of breathing to opioid-induced respiratory depression or weakened excitatory synaptic interactions, a paradoxical depolarization at the cellular level, and the suppression of tonic spiking. Tonic spiking activity is generated by nonrhythmic excitatory and inhibitory preBoeurotC neurons, of which a large percent-age express Ih. Together, our results suggest that I-h is important for maintaining tonic spiking, stabilizing inspiratory rhythmogen-esis, and protecting breathing against perturbations or changes in network state. NEW & NOTEWORTHY The I-h current plays multiple roles within the preBoeurotC. This current is important for promoting intrinsic tonic spiking activity in excitatory and inhibitory neurons and for preserving rhythmic function during conditions that dampen net-work excitability, such as in the context of opioid-induced respiratory depression. We therefore propose that the I-h current expands the dynamic range of rhythmogenesis, buffers the preBoeurotC against network perturbations, and stabilizes rhythmogene-sis by preventing the generation of unsynchronized bursts.

Automated summary

The Ih current is important for maintaining the stability of respiratory rhythmogenesis and protecting breathing against perturbations. Loss of Ih slows down the inspiratory rhythm and destabilizes rhythm generation. Additionally, loss of Ih increases the susceptibility of breathing to opioid-induced respiratory depression and weakened excitatory synaptic interactions.