The roles of dopamine and the sodium pump in the spinal control of locomotion
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Date
2017Author
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Abstract
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.
Type
Thesis, PhD Doctor of Philosophy
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