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Title: The roles of dopamine and the sodium pump in the spinal control of locomotion
Author: Picton, Laurence
ISNI:       0000 0004 5500 1756
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2017
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Rhythmically active, locomotor networks of the spinal cord are subject to both neuromodulation and activity-dependent homeostatic regulation. I first show that the neuromodulator dopamine exerts potent inhibitory effects on the central pattern generator (CPG) circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine, acting endogenously on spinal D2-like receptors, reduces spontaneous fictive swimming occurrence and shortens, slows and weakens swimming. The mechanism involves a TTX-resistant hyperpolarisation of rhythmically active CPG neurons, mediated by the direct opening of a K+ channel with GIRK-like pharmacology. This increases rheobase and reduces spike probability. I next explore how sodium pumps contribute to the activity-dependent regulation of the Xenopus swim circuit, and possible interactions of the pumps with modulators, temperature and ionic conductances. I characterise the pump-mediated ultra-slow afterhyperpolarisation (usAHP), and show that monensin, a sodium ionophore, enhances pump activity, converting the usAHP into a tonic hyperpolarisation; this decreases swim episode duration and cycle frequency. I also characterise a ZD7288-sensitive Ih current, which is active in excitatory dIN interneurons and contributes to spiking. Blocking Ih with ZD7288 decreases swim episode duration and destabilises swim bursts. Both Ih and the usAHP increase with temperature, which depolarises CPG neurons, decreases input resistance, and increases spike probability; this increases cycle frequency, but the enhanced usAHP shortens swimming. I also show that the usAHP is diminished by nitric oxide, but enhanced by dopaminergic signalling. Finally, I explore sodium pumps in the neonatal mouse. The sodium pump blocker ouabain increases the duration and frequency of drug- and sensory-induced locomotion, whilst monensin has opposite effects. Decreasing inter-episode interval also shortens and slows activity, a relationship abolished by ouabain, implicating sodium pumps in a feedforward motor memory mechanism. Finally, I show that the effects of ouabain on locomotion are dependent on dopamine, which enhances a TTX- and ouabain-sensitive usAHP in spinal neurons.
Supervisor: Sillar, Keith Thomas Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available