Classical conditioning is arguably the most fundamental tool we possess for adapting our behavior to a changing environment. Appetitive classical conditioning can be thought of as the process that establishes a learned association between reinforcement and the stimuli in the environment that signal its availability. This form of "reinforcement learning" provides organisms with a potent means to use predictive information to mold and guide preparatory action in an effort to maximize reward. The past three decades have been marked by major advances in our understanding of the neurobiological mechanisms that underlie reinforcement learning. In particular, short "phasic" bursts of neuronal activity in dopamine neurons, which are thought to produce rapid and transient increases in extracellular dopamine concentration throughout the striatum, have received considerable attention as a necessary component of the reinforcement process for both natural and drug reward. The central dogma in catecholamine research has held that dopamine transmission proceeds as a uniform broadcast signal from the midbrain to all target structures in the forebrain. However, there is mounting evidence that separate nuclei within the striatum may receive differential signals in response to primary rewards and conditioned cues at different stages in the learning process. It is hypothesized that this regional specificity in the dynamics and stability of dopamine signaling corresponds to the largely segregated roles in both learning and behavioral control that dopamine may play in these structures. The current proposal will test these hypotheses with three specific aims.
Aim 1 will examine the impact of learning history and specific features of the task on the stability of phasic dopamine in the ventral striatum.
Aim 2 will examine the influence of phasic dopamine on the activation of the striatum during different stages of learning and assess the coincident regional control of behavior.
Aim 3 will examine phasic dopamine release in the ventral and dorsal striatum during multiple stages of reinforcement learning (acquisition, extended training and extinction) with the goal of correlating and comparing the development of specific behaviors to the profile of phasic signaling in each structure.

Public Health Relevance

Although adaptive under normal circumstances, reinforcement learning is one of several contributing factors to the powerful control drug-related stimuli have over drug-seeking and drug-taking behaviors in many models of addiction. The phasic activation of the neuromodulator dopamine is implicated in both reinforcement learning and many aspects of drug abuse. The primary goal of this proposal is to examine the contribution of phasic dopamine release in specific brain regions to reinforcement and behavioral control.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Sorensen, Roger
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University of Washington
Schools of Medicine
United States
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Hart, Andrew S; Clark, Jeremy J; Phillips, Paul E M (2015) Dynamic shaping of dopamine signals during probabilistic Pavlovian conditioning. Neurobiol Learn Mem 117:84-92
Willuhn, Ingo; Burgeno, Lauren M; Groblewski, Peter A et al. (2014) Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat Neurosci 17:704-9
Hart, Andrew S; Rutledge, Robb B; Glimcher, Paul W et al. (2014) Phasic dopamine release in the rat nucleus accumbens symmetrically encodes a reward prediction error term. J Neurosci 34:698-704
Willuhn, Ingo; Tose, Amanda; Wanat, Matthew J et al. (2014) Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats. J Neurosci 34:10616-23
Howe, Mark W; Tierney, Patrick L; Sandberg, Stefan G et al. (2013) Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature 500:575-9
Clark, Jeremy J; Collins, Anne L; Sanford, Christina Akers et al. (2013) Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training. J Neurosci 33:3526-32
Flagel, Shelly B; Clark, Jeremy J; Robinson, Terry E et al. (2011) A selective role for dopamine in stimulus-reward learning. Nature 469:53-7
Parker, Jones G; Zweifel, Larry S; Clark, Jeremy J et al. (2010) Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning. Proc Natl Acad Sci U S A 107:13491-6