Defining the functional relevance of supraspinal dopaminergic signalling pathways

Supraspinal dopaminergic (DAergic) neurons are an evolutionarily conserved population of forebrain cells that have been implicated in a wide range of behavioural processes, including somatosensory processing, locomotor control and behavioural maturation. In addition, supraspinal DAergic dysfunction has been implicated in several diseases, including restless leg syndrome, cataplexy and Parkinson's disease. However, despite over four decades of research, the biological significance of these neurons and related signalling pathways are not fully understood.
We are using the larval zebrafish as a model system to determine how supraspinal DA neurons influence motor behaviour. By conducting in vivo electrophysiological recordings of awake, intact zebrafish we have demonstrated supraspinal DA neurons generate two distinct forms of output. During periods of inactivity, these neurons spike tonically whilst during motor activity, they generate repetitive bursts of spike discharge. These modes of firing are likely to have complex, potentially opposing actions on the spinal circuits that generate locomotion. However, the type of information they encode is poorly defined.
In the current project, we will use zebrafish as a model for understanding the behavioural and physiological relevance of the different firing patterns generated by supraspinal DA neurons. To do this, we will develop transgenic zebrafish lines in which supraspinal DA neuron activity can be controlled with optogenetic methods. Our aim is to induce or supress patterns of bursting and tonic firing and study the consequences to motor behaviour. In parallel, we will test the physiological effects of DA on locomotor circuitry in the spinal cord of wild type fish. Subsequently, we aim to use modelling approaches to determine how tonic and phasic activation of DA receptors affects the properties of individual components within the motor network, thereby shaping behavioural output.