Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more “natural” locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance.SIGNIFICANCE STATEMENT The sodium pump is ubiquitously expressed and responsible for at least half of total brain energy consumption. The pumps maintain ionic gradients and the resting membrane potential of neurons, but increasing evidence suggests that activity- and state-dependent changes in pump activity also influence neuronal firing. Here we demonstrate that changes in sodium pump activity regulate locomotor output in the spinal cord of neonatal mice. We describe a sodium pump-mediated afterhyperpolarization in spinal neurons, mediated by spike-dependent increases in pump activity, which is affected by dopamine. Understanding how sodium pumps contribute to network regulation and are targeted by neuromodulators, including dopamine, has clinical relevance due to the role of the sodium pump in diseases, including amyotrophic lateral sclerosis, parkinsonism, epilepsy, and hemiplegic migraine.

The fine control of movement is a prerequisite for complex behaviour and is mediated by the orderly recruitment of motor units composed of slow and fast twitch muscle fibres. The size principle was initially proposed to account for orderly recruitment; however, motoneuron size is a poor predictor of recruitment amongst functionally defined motor unit subtypes. While intrinsic properties of motoneurons are key regulators of motoneuron recruitment, the underlying currents involved are not well defined. Whole-cell patch-clamp electrophysiology was deployed to study intrinsic properties, and the underlying currents, that contribute to the differential recruitment of fast and slow motoneurons. Motoneurons were studied during the first three postnatal weeks in mice to identify key properties that establish orderly recruitment and contribute to the emergence of fine motor control. We find that fast and slow motoneurons are functionally homogeneous during the first postnatal week and are recruited based on size, irrespective of motoneuron subtype. The recruitment of fast and slow motoneurons becomes staggered during the second postnatal week due to the differential maturation of passive and active properties, particularly persistent inward currents (PICs). The current required to recruit fast motoneurons increases further in the third postnatal week, despite no additional changes in passive properties or PICs. This further staggering of recruitment currents reflects development of a hyperpolarization-activated inward current during week 3. Our results suggest that motoneuron recruitment is multifactorial, with recruitment order established during postnatal development through the differential maturation of passive properties and sequential integration of persistent and hyperpolarization-activated inward currents.

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Characterizing single cell contractility in the beating heart is strongly limited by light scattering and extreme tissue dynamics. Here, we use tissue-integrated microlasers to measure contractility in live zebrafish and living myocardial slices at a depth several times deeper than multiphoton microscopy-based techniques.

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