Role of basolateral amygdala projections in mediating individual differences in motivation and flexibility

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PROJECT SUMMARY While many individuals try drugs of abuse, only a subset transition to addiction. Studying individual differences in addiction vulnerability is a critical step towards understanding the neurobiological underpinnings of motivation for drugs and their impact on the brain and behavior. Nine of eleven of the DSMV criteria for diagnosing individuals with substance use disorder relate to heightened motivation for drugs or behavioral inflexibility, characterized by persistence to seek and take drugs despite negative consequences. The dual nature of this psychological profile inspires this research program, which considers both motivation and flexibility prior to drug experience in order to understand addiction vulnerability. Phenotypic behavioral differences, termed sign-tracking and goal-tracking, differentially predict vulnerability to drug seeking. Sign- and goal-tracking traits are observed in rodents and humans, and are a promising trait distinction for characterizing addiction vulnerability across species. Sign-trackers show heightened motivation for food- and drug-associated discrete cues compared to goal-trackers. Recent work from our laboratory shows that sign- tracking rats are inflexible, continuing to respond to previously rewarded cues, even when the value of the reward has been degraded. Taken together, the “tracking trait” distinction is an ideal model to explore individual differences in both motivation and flexibility prior to drug experience. But what are the brain mechanisms underlying these trait differences? The basolateral amygdala is a critical brain site for initial encoding of cue value that is key for supporting both appetitive motivation and flexibility through its interactions with downstream targets, the nucleus accumbens and insular cortex. We propose that individual differences in appetitive motivation and behavioral flexibility of sign- and goal-trackers are mediated by distinct basolateral amygdala projections to the nucleus accumbens and insular cortex. Here we use coordinated neurobiological approaches to test specific predictions of our hypothesis. Frist, we examine whether neuronal activity in distinct basolateral amygdala pathways supports appetitive motivation in sign- and goal-trackers. Next, we determine whether these circuits are differentially engaged and critical for driving variations in flexible behavior of sign- and goal-trackers when outcome value gets worse. Then, we determine the impact of disrupting basolateral amygdala input on encoding in downstream nucleus accumbens and insular cortex during appetitive motivation and modification of outcome value. Finally, we determine whether the basolateral amygdala pathway activated during initial learning biases the individual towards an appetitive motivated or flexible behavioral strategy. We make use of novel tools to be the first to investigate the role of specific basolateral amygdala pathways in driving the distinct behavior of sign- and goal-trackers. The proposed approaches may yield new biomarkers of addiction vulnerability and identify new prevention and diagnostic strategies for treatment of addiction.