Cues that are repeatedly associated with rewards, such as food or drugs of abuse, can exert a powerful influence over behavior. They can elicit approach or interaction even when such behavior is maladaptive ? e.g., the sight of drug paraphernalia might prompt approach by an addict in recovery. Notably, the ability of reward-associated cues to produce approach and/or interaction varies widely among individuals; for example, if a cue (e.g., extension of a lever) predicts a reward in a different location (e.g. a sugar pellet delivered to a food cup), some rats will preferentially approach and interact with the lever ? a behavior known as sign tracking (ST) ? and others will approach the site of reward delivery, a behavior known as goal tracking (GT). A propensity towards ST has been linked to susceptibility to drug-taking, relapse, and related behaviors. In addition, the neurobiological basis of sign tracking has much in common with brain processes underlying drug use, addiction, and relapse. Both ST and addiction are highly dependent on dopaminergic transmission in the mesocorticolimbic circuit, and especially on dopamine release in the nucleus accumbens (NAc). Moreover, sign trackers and goal trackers show distinct patterns of NAc dopamine release during the acquisition of reward-seeking behavior, implying that ST and GT behavior may engage different circuits ? one dopamine-dependent, and one not ? for associative learning. Despite the links among ST, drug abuse, and NAc dopamine release, we know little about the responses of individual NAc neurons during a typical ST/GT protocol, including whether they differ among individual animals that express ST or GT behavior. Moreover, it remains unclear how the differences in NAc dopamine release in sign trackers and goal trackers impact neural signaling in the accumbens in a way that supports one form of learning over another. Therefore, we propose a set of experiments to compare neural activity in the NAc during acquisition, maintenance, and extinction of reward-seeking behavior among individuals with a propensity towards sign tracking or goal tracking. To do so, we will combine electrophysiological and optogenetic approaches: first, we will record the activity of individual neurons in the NAc during key phases of an ST/GT protocol. Then, using projection-specific optogenetic techniques, we will selectively stimulate dopamine release in the NAc during acquisition or maintenance of ST/GT behavior. By stimulating during the cue or the reward on a subset of trials, we can assess the timing-specific impact of dopamine release on acquisition and expression of ST and GT, and ? using concurrent stimulation and recording ? ST/GT-related neural signaling in the NAc. The results may have important implications for our understanding of the convergence and divergence of the parallel neural learning systems thought to underlie ST and GT behavior. Furthermore, by uncovering differences in neural processing that might mediate individual variation in reward-seeking behavior, the proposed work will contribute to the pursuit of effective treatments for those individuals most vulnerable to addiction and relapse.

Public Health Relevance

Cues that become linked to rewards, such as drugs of abuse, play a major role in both the initial development of drug addiction and relapse; for example, exposure to drug paraphernalia or people and places associated with prior drug use can trigger craving and relapse in recovering addicts. However, there is a great deal of individual variation in how strongly people respond to reward-associated cues, and understanding the sources of this variation is important in understanding and devising effective treatments for addiction. Using an animal model of individual variation in cue responsivity, the proposed experiments will investigate how these behavioral differences arise in the brain, as well as how the process is modulated by dopamine ? a neurochemical that is inextricably linked to reward processing, motivation, and addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Grant, Steven J
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University of Pittsburgh
Schools of Arts and Sciences
United States
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