To adjudicate between competing demands and desires, decision-makers must exert executive control. Two forms of executive control, self-control and outcome monitoring, are especially closely related to drug addiction. First, variations in these traits predict susceptibility to addiction and to relapse. Second, both chronic and acute abuse of drugs, as well as withdrawal, produce cognitive impairments in these traits. Third, the brain networks that are most closely associated with these cognitive functions are also implicated in drug abuse and craving. One brain region in particular, the anterior cingulate cortex (ACC), is thought to be critical for both self- control and outcome monitoring and subsequent adjustment. ACC is distinguished by its strong direct projections from the brain's dopamine centers. Dopamine is a critical molecule in drug addiction, and also plays a central role in reward-based decision-making, but in practice almost nothing is known about the effects of dopamine on the systems that govern these processes. In fact, although dopaminergic inputs to ACC likely have a critical role in executive dysfunction and addiction, this role is poorly understood. We therefore seek to elucidate the circuit-level neural mechanisms that support these executive processes, both under normal conditions and under the influence of systemic dopamine. We propose, first, to record responses of single neurons in ACC in a delay of gratification and a risky decision-making task, so as to understand the role of ACC in these tasks. Second, we propose to characterize the effects of a systemic dopamine agonist on behavior and single neuron responses in ACC, generating a dose response curve and using specific agonists and antagonists to identify which dopamine receptors are involved. These goals will occur during the mentored (K99) phase. During the Independent (R00) phase, we propose to record single units in ACC in these tasks following administration of a systemic dopamine agonist, so as to identify the changes in neuronal responses patterns mediated by dopamine. We hypothesize that the ACC contributes to executive cognition by inhibiting the temptation to defect in a delay of gratification task and by providing a phasic monitoring signal that also predicts subsequent adjustments in behavior. We also hypothesize that dopamine will reduce self-control and will increase monkeys'dependence on recent outcomes, and will do so by increasing tonic firing rates of ACC neurons. I have been a post-doctoral fellow in the Department of Neurobiology at Duke University for three years, and before that I was a graduate student at the University of California Berkeley. I have been doing single-unit physiology in awake behaving monkeys for 8 years. During that time, I have published ten papers in peer- reviewed journals (seven first author), including Science, Neuron, and Current Biology, and have presented my ideas in numerous talks and posters. I have developed many new and complex tasks to study complex cognitive processes, and have recorded in cortical structures across the brain. My interests include reward- based decision-making, and especially on executive functions. In order to overcome some of the limitations of single-unit studies, I propose to combine the methods of single unit physiology with pharmaceutical techniques. Because of the role of neuromodulators in reward-based and executive processes, these two techniques are naturally complementary. Because of their sophisticated cognitive abilities and brains that are similar to those of humans, monkeys are an ideal organism for the study of executive function. My extensive experience with single-unit physiology makes me an idea candidate to use pharmacological methods with physiology. The K99/R00 award will allow me to develop the expertise in pharmacology to do so. My career development plan calls for a close collaboration with William Wetsel, a professor of Psychiatry at Duke who studies the effects of drugs and genetic manipulations that affect neurotransmitter levels on behavior and brain responses in rodents. I will also enroll in a Pharmacology course at Duke. Finally, I will also obtain scientific and professional counseling from my sponsor, Dr. Michael Platt. I will perform the mentored phase of my research in the laboratory of Dr. Platt at the Duke University Medical Center. Dr. Platt is an Associate Professor at Duke and a leading figure in neuroeconomics, currently serving as the president of the Society for Neuroeconomics, and in neuroethology, currently editing a book on the topic. The Platt Lab has long been a leader in these fields, and consistently produces top-notch research. Three post-docs in the lab have gone on to tenure-track positions at research universities. Duke itself is a top- ranked research institution that offers world-class experts and an open, collaborative atmosphere. Given the prominence of the Platt Lab and of Duke University, this is an ideal environment to perform the research described in this application.
Dopamine dysregulation is responsible for the addictive properties of drugs of abuse. However, little is known about how dopamine acts on brain circuits. The goal of this project is to characterize the role of dopamine in governing executive functions, including resisting temptation and adjusting behavior following poor choices.
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