Understanding the role of dopamine in vertebrate motor control

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Nerve cells (neurons) communicate by secreting neurotransmitters, small chemical messengers, at tiny junctions between cells called synapses. Dopamine is a specialised messenger molecule that alters the way other neurons processes information. In the normal brain, dopamine controls information processing in neurons that affect movement, attention and motivation. However, disturbances in dopamine release can have devastating effects on brain function. For example, disorders such as schizophrenia, Parkinson's disease and restless leg syndrome are linked to imbalances in dopamine secretion. For this reason, dopamine secreting neurons are a major focus of bioscience research. Our understanding of dopamine function comes mainly from the study of neurons in the midbrain, a brain region that coordinates many of our sensory and motor functions. However, dopamine releasing neurons are also found in the diencephalon, a region responsible for processing sensory information, regulating motivation and controlling other body functions. A specific group of these cells extend long outgrowths (axons) into the spinal cord where they communicate with networks of neurons responsible for generation of movements such as walking, running and swimming. These dopamine neurons are thought to facilitate and stabilise locomotor behaviours, but their specific roles have not been properly analysed, and little is known about the specific mechanisms by which they might exert their effects in the spinal cord. One key reason why the roles of these cells are not well understood is because most studies have been conducted on isolated pieces of spinal cord tissue that cannot generate naturally-occurring movements.We are using zebrafish larvae to determine how dopamine neurons affect naturally-occurring forms of locomotion. These tiny larval fish contain a full complement of dopamine neurons, yet lack bone tissue and skin pigments. These features mean that we can observe, record from and experimentally manipulate neurons in intact, living fish that can produce natural swimming patterns. Our preliminary work with this model has provided some exciting new insights into the possible role for diencephalic dopamine neurons in controlling the frequency and intensity of swimming: different groups of spinal cord neurons are activated at different speeds of swimming, with cells in one region used to produce slow, weak movements and those in another region used for fast, intense movements. We have found that laser removal of spinally-projecting dopamine neurons reduces the activity in spinal cells used for fast, intense movements. Thus, we suspect that dopamine precisely regulates the production of more intense forms of locomotor behaviour. We will test this suggestion by using a laser to selectively remove the dopamine neurons of interest. We will then record the electrical activity patterns of spinal cord neurons involved in the generation of swimming. This will allow us to study loss of dopamine signals in the spine affects nerve cells used for low and high speed movements. Once we have identified the cell types that dopamine affects, we will make recordings of the electrical activity of these individual neurons to examine the mechanisms underlying these changes. Finally, we will use high speed video motion capture to understand how removal of dopamine neurons affects the movements of freely-behaving zebrafish. In completing this work we aim to shed important new light on the fundamental processes underpinning vertebrate motor control. Moreover, as spinal cord-projecting dopamine neurons have been implicated in disorders such as Parkinson's disease and restless leg syndrome, our finding may help us to better understand dopamine-related diseases that can have debilitating effects on locomotor behaviour.