Stimuli (cues) in the environment associated with reward can motivate normal behavior, bringing one in close proximity to valuable resources (i.e. food, water, mates); but they can also gain inordinate control over behavior, as is the case with addiction. The ability of reward cues to motivate both normal and maladaptive behavior occurs through Pavlovian learning processes. Thus, when a discrete cue is repeatedly paired with presentation of a reward, it can acquire the ability to act as a predictor, but can also acquire incentive motivational properties. For example, in addicts, cues that have been previously associated with the drug- taking experience acquire the ability to maintain drug-seeking behavior and instigate relapse, even when there is a strong desire to stop use. We have recently discovered that in rats there is considerable individual variation in the extent to which food cues are attributed with Pavlovian incentive motivational value (incentive salience) and this variation predicts how avidly they will later seek drugs and the propensity to relapse. Using a Pavlovian conditioning paradigm, rats can be classified as sign-trackers-those that attribute incentive salience to reward cues, or goal-trackers-those that assign only predictive value to reward cues. Thus, this animal model allows us to parse the incentive from the predictive properties of reward-associated cues and to elucidate the neural circuitry underlying these distinct forms of cue-reward learning. In the proposed studies we will exploit this natural variation in the propensity to attribute incentive salience to reward cues, using a uniquely heterogeneous population of rats. Further, we will use a novel molecular-genetic approach that uses viral vectors to express engineered artificial receptors (known as DREADD receptors), to examine how transiently modulating activity of specific brain circuits will alter the propensity to sign-track or goal-track. Specifically, the proposed studies focus on afferent systems to the paraventricular nucleus of the thalamus (PVT), a site that has gained increasing attention in the addiction literature, and has recently been shown to play a role in sign- vs. goal-tracking behavior. We will test the hypothesis that sign-tracking behavior, which is dopamine dependent, is mediated via subcortical processes including dopaminergic projections from the ventral tegmental area (VTA) to the PVT; and that goal-tracking behavior, which is dopamine-independent, is mediated via cortical top-down afferents to the PVT. We will also examine how altering activity in these specific circuits will affect patterns of food- and drug-cue-induced neuronal activity throughout the brain in sign- trackers vs. goal-trackers. This work will lead to better understanding of the neural mechanisms that go awry in psychopathologies like addiction, and has the potential to lead to novel therapeutic interventions.

Public Health Relevance

The way an individual responds to cues associated with rewards may be a key determinant in vulnerability to addiction and relapse. We will utilize a uniquely heterogeneous population of rats and cutting edge methodology to identify critical components of the neural circuitry that underlies individual differences in the motivational properties of reward-cues. The findings from these studies will enhance our understanding of the pathophysiology of substance abuse and could lead to novel targets for the treatment of addiction and related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA038599-04
Application #
9435105
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Grant, Steven J
Project Start
2015-04-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Psychiatry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
Turner, Cortney A; Flagel, Shelly B; Blandino Jr, Peter et al. (2017) Utilizing a unique animal model to better understand human temperament. Curr Opin Behav Sci 14:108-114
Flagel, Shelly B; Robinson, Terry E (2017) Neurobiological Basis of Individual Variation in Stimulus-Reward Learning. Curr Opin Behav Sci 13:178-185
Kuhn, Brittany N; Klumpner, Marin S; Covelo, Ignacio R et al. (2017) Transient inactivation of the paraventricular nucleus of the thalamus enhances cue-induced reinstatement in goal-trackers, but not sign-trackers. Psychopharmacology (Berl) :
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