This work seeks to understand the how the synaptic afferent inputs to midbrain dopamine neurons interact with their intrinsic properties to produce the range of firing patterns exhibited in vivo, and how these firing patterns exert their effects on the target neurons in the striatum. We will first produce a computer model of the dopamine neurons in vitro that replicates the effects of pharmacological manipulations on the regular spontaneous firing that characterizes dopamine neurons in the absence of afferent input, and provides insight into the mechanisms that convert this regular firing into burst firing or irregular firing. Then we will extend the model to the situation in vivo. The model will be used not only to elucidate the key currents, parameters, and mechanisms responsible for the generation and modulation of their electrical activity, but also to suggest therapeutic approaches for Parkinson's disease and other pathological conditions in which dopamine release plays a role. Currently such therapeutic strategies, including maximizing release from surviving or transplanted dopamine neurons, are limited by the inability to replace dopamine in the correct spatial and temporal pattern. Several lines of evidence indicate that not only the firing rate but also the firing pattern of these neurons is significant. Computational models supplemented by the techniques of nonlinear forecasting and nullcline analysis, will used to test our hypotheses about how various pharmacological agents exert their effects on the firing pattern of dopamine neurons, and how these changes in firing pattern might impact their targets in the striatum. We will identify model mechanisms and parameters responsible for characteristics of apamin and NMDA-induced burst firing such as variations in spike amplitude and interspike interval (ISI) as well as depolarization block, identify mechanisms responsible for irregular firing both in the model and in real neurons in vivo and in vitro, formulate a model of burst firing induced by synaptic excitation in vivo, and test our hypotheses regarding the functionality of irregular firing and the role of Dl receptor activation in focusing striatal activity.
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