This application is directed towards understanding the role of the dopaminergic system in higher cognitive function such as working memory and cognitive control. These somewhat ill-defined terms generally refer to cognitive systems that require two functionally opposing processes: (1) the stable 'on-line'maintenance of information (necessary for "cognitive stability") and (2) the flexible updating of that information in response to novel task-relevant information (necessary for "cognitive flexibility"). We will test the hypothesis that these cognitive processes are highly dependent on precisely balanced dopaminergic transmission within the striatum and prefrontal cortex (PFC). Specifically, we will test the hypothesis that augmentation of dopamine in the PFC promotes cognitive stability by increasing distractor-resistance whereas dopamine augmentation in the striatum promotes cognitive flexibility by allowing the updating of newly relevant representations. Manipulation of the dopaminergic system has been shown to modulate the function of fronto-striatal circuitry, but the direction and extent of these effects vary widely across individuals and tasks. Through pharmacological manipulation and genetic variation of dopamine in humans, and measurements of their effects with both fMRI and PET, we expect to elucidate the factors that determine this large variability in drug effects and characterize the nature of the complex relationship between dopamine and cognition. Dopamine is of fundamental importance to the etiology and clinical manifestations of a wide variety of neurological and psychiatric disorders such as Parkinson's disease, traumatic brain injury, attention deficit hyperactivity disorder, schizophrenia and drug addiction. A further understanding of the relationship between dopamine and cognition should advance our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems.
The proposed research is relevant to public health because it will advance our understanding of the role of the dopamine in cognition. Many psychiatric and neurological disorders such as Parkinson's disease, traumatic brain injury, attention-deficit disorder, addiction and schizophrenia have been shown to affect, or are proposed to involve selective dysfunction of the dopaminergic system. The proposed research is also relevant to NIH's mission because it will lead to basic knowledge about dopamine function that can provide valuable insights into the understanding, diagnosis and treatment of a wide range of clinical conditions.