Parkinson's Disease, Restless Leg Syndrome (RLS), Periodic Limb Movement Disorder (PLMD), and Narcolepsy have one thing in common - patients afflicted with these disorders all respond to dopamine agonists. However, current pharmacological strategies are only partially successful since these therapies are limited by the inability to replace dopamine in the correct temporal pattern. Phasic increases in extracellular dopamine, dependent on neural activity, could have consequences distinct from tonic dopamine levels. Specifically, it seems that transient, impulse-dependent release of dopamine, on the scale of hundreds of milliseconds, is critical in the processing of complex behavioral phenomena such as learning and attention. Several lines of evidence indicate that while background firing rate affects tonic dopamine levels, it is the firing pattern, specifically the burst-pause pattern of dopamine neurons, that controls the temporal pattern of dopamine release in target regions. Additionally, bursts and pauses are thought to be central in reinforcement learning theories and many Learning Disorder deficits may be due to dysfunction in dopamine neuron physiology. Since it is likely that disruption of dopamine neuron activity pattern constitutes an important component of the pathology in a number of neurological disorders, the experiments proposed in this project will study dopamine neuron physiology at the cellular, circuit, and cognitive level.
Aims 1 and 2 of this project focus on the effects that particular channels, synapses, and neural circuits have on the burst-pause firing pattern. The experiments proposed in Aim 1 are designed to investigate the effects of three G-protein coupled receptors where differential activation of these receptors can have profoundly different consequences on dopamine neuron firing pattern.
Aim 2 will focus on the effects that individual neural circuits have on dopamine neuron firing pattern in the intact animal and determine which specific nuclei influence the neural activity of dopamine neurons.
Aim 3 will use specific behavioral studies that may be affected by the neural activity studied in the first two aims to functionally validate the results of Aims 1 and 2. These experiments will determine whether the specific synapses and neural circuits studied in this project are involved in higher brain functions that underlie complex behavioral phenomena such as learning, memory, and attention. Unlike traditional pharmacological approaches with dopamine agonists, the ability to influence the burst-pause pattern by manipulating other G-protein coupled receptors may help replace dopamine in the correct temporal pattern and have immediate medical relevance in treating the symptoms of many neurological disorders.
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