To adjudicate between competing demands and desires, decision-makers must exert executive control. Twoforms of executive control, self-control and outcome monitoring, are especially closely related to drugaddiction. First, variations in these traits predict susceptibility to addiction and to relapse. Second, both chronicand acute abuse of drugs, as well as withdrawal, produce cognitive impairments in these traits. Third, the brainnetworks that are most closely associated with these cognitive functions are also implicated in drug abuse andcraving. 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 directprojections from the brain's dopamine centers. Dopamine is a critical molecule in drug addiction, and alsoplays a central role in reward-based decision-making, but in practice almost nothing is known about the effectsof dopamine on the systems that govern these processes. In fact, although dopaminergic inputs to ACC likelyhave a critical role in executive dysfunction and addiction, this role is poorly understood. We therefore seek toelucidate the circuit-level neural mechanisms that support these executive processes, both under normalconditions and under the influence of systemic dopamine. We propose, first, to record responses of singleneurons in ACC in a delay of gratification and a risky decision-making task, so as to understand the role ofACC in these tasks. Second, we propose to characterize the effects of a systemic dopamine agonist onbehavior and single neuron responses in ACC, generating a dose response curve and using specific agonistsand 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 tasksfollowing administration of a systemic dopamine agonist, so as to identify the changes in neuronal responsespatterns mediated by dopamine. We hypothesize that the ACC contributes to executive cognition by inhibitingthe temptation to defect in a delay of gratification task and by providing a phasic monitoring signal that alsopredicts subsequent adjustments in behavior. We also hypothesize that dopamine will reduce self-control andwill increase monkeys' dependence on recent outcomes, and will do so by increasing tonic firing rates of ACCneurons.I have been a post-doctoral fellow in the Department of Neurobiology at Duke University for three years, andbefore that I was a graduate student at the University of California Berkeley. I have been doing single-unitphysiology 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 myideas in numerous talks and posters. I have developed many new and complex tasks to study complexcognitive 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 ofsingle-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 arenaturally complementary. Because of their sophisticated cognitive abilities and brains that are similar to thoseof humans, monkeys are an ideal organism for the study of executive function. My extensive experience withsingle-unit physiology makes me an idea candidate to use pharmacological methods with physiology. TheK99/R00 award will allow me to develop the expertise in pharmacology to do so. My career development plancalls for a close collaboration with William Wetsel, a professor of Psychiatry at Duke who studies the effects ofdrugs and genetic manipulations that affect neurotransmitter levels on behavior and brain responses inrodents. I will also enroll in a Pharmacology course at Duke. Finally, I will also obtain scientific and professionalcounseling 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 MedicalCenter. Dr. Platt is an Associate Professor at Duke and a leading figure in neuroeconomics, currently servingas the president of the Society for Neuroeconomics, and in neuroethology, currently editing a book on thetopic. 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 theprominence of the Platt Lab and of Duke University, this is an ideal environment to perform the researchdescribed 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.
| Strait, Caleb E; Blanchard, Tommy C; Hayden, Benjamin Y (2014) Reward value comparison via mutual inhibition in ventromedial prefrontal cortex. Neuron 82:1357-66 |
| Blanchard, Tommy C; Hayden, Benjamin Y (2014) Neurons in dorsal anterior cingulate cortex signal postdecisional variables in a foraging task. J Neurosci 34:646-55 |
| Blanchard, Tommy C; Wolfe, Lauren S; Vlaev, Ivo et al. (2014) Biases in preferences for sequences of outcomes in monkeys. Cognition 130:289-99 |
| Hayden, Benjamin; Pasternak, Tatiana (2013) Linking neural activity to complex decisions. Vis Neurosci 30:331-42 |
| Heilbronner, Sarah R; Hayden, Benjamin Y (2013) Contextual factors explain risk-seeking preferences in rhesus monkeys. Front Neurosci 7:7 |
| Blanchard, Tommy C; Pearson, John M; Hayden, Benjamin Y (2013) Postreward delays and systematic biases in measures of animal temporal discounting. Proc Natl Acad Sci U S A 110:15491-6 |
