FUNCTIONAL ORGANIZATION OF THE BASAL GANGLIA

National Institute Of Mental Health

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Abstract

Resesarch in the Section on Neuroanatomy is concerned with the role of the basal ganglia in behavior. The basal ganglia receives inputs from all cortical areas, processes that input through the striatum, whose output pathways provide feedback, through the thalamus, to cortical areas involved in the selection and control of behavior. Our work focuses on two general questions of basal ganglia function. First, what is the organization of cortical input to the striatum, which is necessary to understand what information the cortex provides to the basal ganglia? Second, what does the striatum do to or with that cortical input, which is essential to understand how the basal ganglia affects frontal cortical function? We address these questions in order to better establish how disorders of the basal ganglia, such as Parkinson's disease, result in clincial movement disorders, or whether the basal ganglia might also be involved in such mental disorders, such as Attention Deficit Hyperactivity Disorder, or in the abuse of psychoactive drugs. Work done in this past year addressed primarily the second question. Current work is focussed on extending our prior findings that dopamine, through the segregation of the D1 and D2 dopamine receptor subtypes in the "direct" and "indirect" striatal output neurons, functions to regulate the balanced activity striatal output pathways that determine the output of the basal ganglia. The experimental approach involves determining the response of identified "direct" and "indirect" striatal neurons to treatments of drugs that are selective for receptor subtypes. Neuronal responses are measured as changes in the levels of expression of various genes that provide markers of receptor-mediated signal transduction, most commonly one of a variety of so-called immediate early genes (IEGs). In the prototypical study, D1 agonists increase and D2 agonists decrease IEG expression respectively in "direct" and "indirect" striatal neurons. Methods developed provide the ability to quantitate small changes in levels of messenger RNAs at the cellular level in neurons identified on the basis of which receptor subtypes they express. This approach enables the examination of the responses to excitatory glutamatergic input from the cortex as they are modulated by dopaminergic, serotonergic, and opioid peptidergic receptor systems to regulate the relative balance of activity in the "direct" and "indirect" basal ganglia pathways. Neurologic movement disorders such as Parkinson's disease occur, as least in part, as a consequence of an imbalance in the function of these striatal pathways.