The orbitofrontal cortex (OFC) and mesolimbic dopamine represent two neural substrates that are critical for adaptive motivated behavior, and their dysfunction has been implicated in the neuropathological mechanisms underlying substance use disorders. Neurons in both the OFC and the dopaminergic midbrain signal information related to learned values associated with reward-predicting stimuli, and both substrates are thereby thought to contribute to value-based decision making. Although each substrate may influence how the other stores and updates this value information, recent research has provided evidence of their distinct contributions to reward learning. Thus, investigations of the relative independence versus interactions of the OFC and mesolimbic dopamine function represent an open area of research that will enhance our understanding of the neurobiology underlying motivated behavior. The proposed studies aim to probe these circuit-level interactions by examining how perturbations of OFC activity affect mesolimbic dopamine transmission and value-based decision making. Toward this end, these experiments will employ a behavioral design adapted from a well-established tradition of animal learning theory and informed by recent advances in computational models of reinforcement learning. Additionally, this approach combines our lab's expertise in electrochemical detection techniques and my co-sponsor's novel viral tools for manipulating specific neuronal activity. After selectivel devaluing a previously reinforcing outcome and inactivating the OFC, I will record mesolimbic dopamine transmission using fast-scan cyclic voltammetry while rats perform a dual-reinforcer decision-making task. I will test the effects of OFC inactivation on the gradual updating of dopaminergic value signals and examine whether such dopamine release could contribute to the rats'decisions when the OFC is unavailable to flexibly guide behavioral choices. This inherently integrative and innovative approach will advance our understanding of valuation processes subserved by decision-making circuits whose normal function is disrupted in addiction.

Public Health Relevance

Drug addiction and several other psychiatric disorders involve a variety of neuropathological mechanisms that disrupt the normal functioning of corticostriatal circuits implicated in adaptive motivated behavior. The proposed experiments will investigate circuit-level interactions between the orbitofrontal cortex and mesolimbic dopamine transmission, two neural substrates thought to critically contribute to reward learning and decision making.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Babecki, Beth
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University of Washington
Schools of Medicine
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Hollon, Nick G; Burgeno, Lauren M; Phillips, Paul E M (2015) Stress effects on the neural substrates of motivated behavior. Nat Neurosci 18:1405-12
Hollon, Nick G; Arnold, Monica M; Gan, Jerylin O et al. (2014) Dopamine-associated cached values are not sufficient as the basis for action selection. Proc Natl Acad Sci U S A 111:18357-62