Disturbances within the dopamine system are thought to contribute to the etiology of several disorders in humans, including schizophrenia and Parkinson's disease. Studies investigating the consequences of damage to the dopamine system have revealed the marked degree of compensatory capacity available to these neurons, suggesting that simple changes in dopamine levels are unlikely to underlie major human disorders. Instead, it is likely that dysfunctions within the dopaminergic system occur via disturbances in the regulatory processes controlling their activity. One way to address the role of autoregulation in the normal or abnormal function of an organism is to first damage the system and then examine the compensatory changes that occur. This proposal investigates several aspects of the dopamine system function in the basal ganglia of both intact rats and rats with partial lesions of the dopamine system. This is done using a combination of in vivo and in vitro recording techniques, and centers around four aspects of basal ganglia function: 1) the processes through which dopamine neurons regulate their activity, including. the function of somatodendritic autoreceptors and the factors involved in controlling their firing pattern; 2) how these autoregulatory systems are influenced by striatonigral feedback systems, and how these systems lead to a hyper-responsive state of dopamine neurons in partially lesioned rats; 3) the properties of dopaminoceptive neurons in the striatum and accumbens, their response to dopamine administration, and the influence of dopamine on afferent processes and network properties of these nuclei; and 4) how the basal ganglia influences thalamic function and how this correlates with behavior. By examining the dopamine system in the basal ganglia from dopamine cell regulation through dopamine-mediated actions on feedback and output systems, an integrated view of the basal ganglia function in normal and dysfunctional states may be achieved. In addition to the scientific goals of this research plan, it will provide for a significant level of scientific advancement and professional growth for the applicant to be achieved through collaborations and extended scientific interactions with other investigators. In addition to enabling the development and implementation of advanced neurophysiological techniques, it will provide the time necessary for the PI to expand into new areas of investigation and improve the PI's background knowledge in clinically related research. This proposal is oriented toward providing an integrated view of how the basal ganglia is regulated under normal and compromised conditions. By using basic science techniques to investigate systems thought to be involved in human psychiatric or neurological disorders, this research has the potential of providing information of value to the development of more effective therapeutic approaches to treat such conditions.
