Adapting behavior and cognition to meet changing environmental demands is critical for optimizing wellbeing. Previous research has identified an important role for the neuromodulator dopamine, particularly with respect to its effects on the striatum, in regulating cognitive flexibility, that is, the ability to flexibly update the contentsof working memory and relevant goals. Variability in the striatal dopamine system has been associated with alterations in cognitive flexibility, and indeed, a variety of neuropsychiatric disorders including attentional deficit disorder, Parkinson's disease, schizophrenia, and drug addiction are characterized by abnormalities in both dopaminergic neurotransmission and cognitive control. Importantly, both appetitive and aversive motivation are thought to phasically increase and decrease, respectively, the release of dopamine into the striatum, thus raising the possibility that motivational context may differentially impact cognitive control processes. Recent work has demonstrated that reward motivation increases cognitive flexibility, but only in individuals with higher baseline levels of striatal dopamine. Research examining the impact of aversive motivation on cognitive control has been much more limited; in one study, threat of punishment was associated with reduced updating of working memory content, suggesting that aversive motivation may bias individuals away from cognitive flexibility and toward cognitive stability. However, to date, no work has explicitly examined the role of baseline dopamine system function in mediating the influence of aversive motivation on cognitive control processes or the frontostriatal circuitry that supports them. By exploiting genetic variants known to impact the striatal dopamine system, and using a targeted psychopharmacological intervention, the proposed fMRI experiment seeks to fill this gap by examining the effect of striatal dopamine variability on patterns of brain activation and cognitive flexibility in the face of aversive motivation.
A second aim of the proposed research is to characterize the role of the habenula in moderating the impact of an aversive motivational context on cognitive control processes. The habenula is a small region of the epithalamus that has recently been implicated in inhibiting striatal DA release in response to potential punishment; if inhibition of striatal DA resulting fro aversive motivation impacts the frontostriatal circuitry supporting cognitive flexibility, the habenula may provide a critical linkage between motivation and cognitive control. Together, the proposed research will expand our knowledge of the neurobiological mechanisms that may contribute to individual differences in the relation between motivation and cognition. Further, results of this work may inform our understanding of cognitive control abnormalities in neuropsychiatric disorders characterized by aberrant DA neurotransmission and of the impact of both therapeutic and illicit drug use on aspects of cognitive control.

Public Health Relevance

Dopamine plays a critical role in our ability to flexibly adapt cognition and behavior in the face of a changing or threatening environment. Indeed, a range of neurobehavioral disorders, including Parkinson's disease, drug addiction, and ADHD, are characterized not only by dopamine system dysfunction, but also by abnormalities in cognitive flexibility, even in situations involving potential negative consequences. Elucidating the role of dopamine in regulating cognitive flexibility under conditions of potential harm will enhance our basic knowledge of dopamine system function and variation, and provide insights into the impact of disease state and both therapeutic and illicit drug use on aspects of cognitive control.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Grant, Steven J
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University of California Berkeley
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United States
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Berry, Anne S; Shah, Vyoma D; Furman, Daniella J et al. (2018) Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release. Neuropsychopharmacology 43:1201-1211