AUTHOR=Sharples Simon A. , Parker Jessica , Vargas Alex , Milla-Cruz Jonathan J. , Lognon Adam P. , Cheng Ning , Young Leanne , Shonak Anchita , Cymbalyuk Gennady S. , Whelan Patrick J. 

TITLE=Contributions of h- and Na+/K+ Pump Currents to the Generation of Episodic and Continuous Rhythmic Activities

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=15

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2021.715427

DOI=10.3389/fncel.2021.715427

ISSN=1662-5102

ABSTRACT=<p>Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-center oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na<sup>+</sup>/K<sup>+</sup> ATPase pump (<italic>I</italic><sub>Pump</sub>) and hyperpolarization-activated currents (<italic>I</italic><sub><italic>h</italic></sub>) playing key roles. Modulation of either <italic>I</italic><sub>Pump</sub> or <italic>I</italic><sub><italic>h</italic></sub> produced transitions between episodic and continuous rhythms and silence. As maximal activity of <italic>I</italic><sub>Pump</sub> decreased, the interepisode interval and period increased along with a reduction in episode duration. Decreasing maximal conductance of <italic>I</italic><sub><italic>h</italic></sub> decreased episode duration and increased interepisode interval. Pharmacological manipulations of <italic>I</italic><sub><italic>h</italic></sub> with ivabradine, and <italic>I</italic><sub>Pump</sub> with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modeling and experimental results highlight key roles of <italic>I</italic><sub><italic>h</italic></sub> and <italic>I</italic><sub>Pump</sub> in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.</p>