Many individuals experiment with drugs of abuse over their lifetime, but only a relatively small subset become addicted. Nonetheless, drug addiction is a prominent health concern, costing the United States over $600 billion annually, and the high propensity to relapse makes it an incredibly difficult problem to treat. One factor that makes some individuals more susceptible to relapse is the degree to which cues in the environment can assert inordinate control over behavior. For example, presentation of cues (i.e. syringes, pipes, etc.) previously associated with drug-taking behavior has been shown to trigger feelings of drug craving in human addicts, which leads to drug-seeking behavior and relapse. This phenomenon is mediated in part by Pavlovian-learning processes. However, the neurobiology underlying these processes has proven difficult to understand since they are a result of complex emotional and motivational states. Recently, an animal model has been developed by Dr. Flagel and colleagues that captures the individual variation in the propensity to attribute incentive motivational value to reward cues and thereby allows us to tease apart the underlying neurobiological mechanisms. In this model, rats that ascribe motivational value to a cue demonstrate sign-tracking behavior, as evidenced by their approach and interaction with the cue. For others, known as goal-trackers, the cue simply serves as a predictor for reward availability, and upon its presentation these animals go to the goal, or location of reward delivery. Previous work has shown that rats who demonstrate sign-tracking behavior in response to reward-associated cues have a greater tendency to relapse following extinction of drug self- administration behavior. It has also been shown that differences in the dopaminergic system, as well as other systems not normally considered part of the classic reward circuitry, underlie sign- and goal-tracking behaviors. One brain area that has shown robust differences in neuronal activity in response to cue-presentation between sign- and goal-trackers is the paraventricular nucleus of the thalamus (PVT), a region that has recently gained attention in the pre-clinical addiction literature. Interestingly, this site is well-positioned to act as an interfae between limbic, motor and cortical areas of the brain, making it a compelling target of investigation in relation to sign- and goal-tracking behaviors. The current proposal aims to uncover the role the PVT and associated circuitry plays in sign- and goal-tracking behavior. Retrograde labeling in combination with immunohistochemistry will be used to identify differences in neuronal activity in response to cue presentation in the PVT circuitry. In addition, local pharmacological manipulations will be used to assess the role of PVT glutamate, dopamine, and orexin transmission in sign- and goal-tracking behavior. These studies will advance our knowledge of the neurobiological processes that underlie the attribution of incentive motivational value to reward-paired cues, a behavioral trait that has been linked to susceptibility to relapse and addiction.

Public Health Relevance

Drug addiction is a major health concern in this country, and one of the major setbacks to successful recovery from addiction is recurring episodes of relapse. Relapse is often triggered by cues in the environment (e.g. people, places, and paraphernalia), and the ability of such cues to gain inordinate control over behavior is mediated in part by Pavlovian-learning processes. The current proposal seeks to elucidate the neural circuitry underlying these processes, and has the potential to uncover novel treatments for individuals suffering from this debilitating disorder.

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 Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Haight, Joshua L; Fuller, Zachary L; Fraser, Kurt M et al. (2017) A food-predictive cue attributed with incentive salience engages subcortical afferents and efferents of the paraventricular nucleus of the thalamus. Neuroscience 340:135-152
Fraser, Kurt M; Haight, Joshua L (2016) Diminished Dopamine: Timing, Neuroanatomy, or Drug History? J Neurosci 36:4907-9
Fraser, Kurt M; Haight, Joshua L; Gardner, Eliot L et al. (2016) Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors. Behav Brain Res 305:87-99
Haight, Joshua L; Fraser, Kurt M; Akil, Huda et al. (2015) Lesions of the paraventricular nucleus of the thalamus differentially affect sign- and goal-tracking conditioned responses. Eur J Neurosci 42:2478-88