State-dependent contribution of the hyperpolarization-activated Na+/K+ and persistent Na+ currents to respiratory rhythmogenesis in vivo.

How rhythms are generated by neuronal networks is fundamental to understand rhythmic behaviors such as respiration, locomotion, and mastication. Respiratory rhythm is generated by the preBötzinger complex (preBötC), an anatomically and functionally discrete population of brainstem neurons, central and necessary for respiratory rhythm. In specific in vitro conditions, preBötC neurons depend on voltage-dependent inward currents to generate respiratory rhythm. In the mature and intact organism, where preBötC neurons are deeply embedded in the respiratory network, the contribution of ionic currents to respiratory rhythm is unclear. We propose that a set of ionic currents plays a key role in generating respiratory rhythm in the mature organism in vivo. By microperfusing ionic current blockers into the preBötC of adult rats, we identify the hyperpolarization-activated cation current as a critical component of the mechanism promoting respiratory rhythm, and that this current, in combination with the persistent sodium current, is essential to respiratory rhythm in vivo. Importantly, both currents contribute to rhythmic activity in states of anesthesia, quiet wakefulness, and sleep, but not when the organism is engaged in active behaviors. These data show that a set of ionic currents at the preBötC imparts the network with rhythmicity in reduced states of arousal, although the network can override their contribution to adjust its activity for nonrhythmic behaviors in active wakefulness.