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Title: Dopaminergic Modulation of Mammalian Locomotor Networks
Author: Humphreys, Jennifer
Advisor: Whelan, Patrick
Keywords: Health Sciences
Issue Date: 13-May-2013
Abstract: Central pattern generators (CPGs), which are intrinsic to the spinal cord, contain sufficient circuitry to generate complex and coordinated muscle activities necessary for locomotion. A class of neurotransmitters termed monoamines (dopamine, serotonin, noradrenaline) exerts neuromodulatory effects on mammalian CPGs. Monoamines are released within the spinal cord during walking and can change the excitability of neurons that comprise the CPG. In contrast with the other monoamines, the neuromodulatory role of dopamine (DA) on locomotor CPGs has been largely neglected in the mammal. Therefore, the goal of my work was to examine the multiple changes in locomotor CPG network output induced by DA. I have employed a “systems” to “cells” approach. Utilizing the neonatal mouse isolated spinal cord preparation and electrophysiological techniques, I first characterized how DA modulates locomotor patterns evoked by either drug application or electrical stimulation. I found that while DA application boosts the stability of a fictive drug-evoked locomotor rhythm, it functions to depress the activation of locomotor networks following ventral root stimulation. By examining disinhibited rhythms, where the Renshaw cell pathway was blocked, I found that DA depresses a putative recurrent excitatory pathway that projects onto rhythm generating circuitry of the spinal cord. These data demonstrate that DA can potentiate network activity, while at the same time, reducing the gain of recurrent excitatory feedback loops from motoneurons onto the network. Next, at the motoneuronal level I examined the ability of DA to modulate the intrinsic membrane property of postinhibitory rebound (PIR), which has been shown to play an important role in producing stable rhythmic locomotor patterns. I found that DA boosts the PIR response in motoneurons, which may account for part of the mechanism by which DA exerts a modulatory role during drug-evoked locomotion. Finally, using a pharmacological approach, I confirm that the primary ionic conductance underlying the observed PIR response in motoneurons, T-type calcium conductance, also plays an important role at the level of the CPG network. Collectively, my work demonstrates that in a mammalian system, DA exerts complex modulatory actions at the level of the CPG network and ultimately contributes to the sculpting of motor output.
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