Basal forebrain chemogenetic inhibition converts the attentional control mode of goal-trackers to that of sign-trackers.

Sign- versus goal-tracking in rats indicate vulnerability and resistance, respectively, to Pavlovian cue-evoked addictive drug taking and relapse. Here we tested hypotheses predicting that the opponent cognitive-behavioral styles indexed by sign- versus goal tracking include variations in attentional performance which differentially depend on basal forebrain projection systems. Pavlovian Conditioned Approach (PCA) testing was used to identify male and female sign-trackers (STs) and goal-trackers (GTs), as well as rats with an intermediate phenotype (INTs). Upon reaching asymptotic performance in an operant task requiring the detection of visual signals (hits) as well as the reporting of signal absence for 40 min per session, GTs scored more hits than STs, and hit rates across all phenotypes correlated with PCA scores. STs missed relatively more signals than GTs specifically during the last 15 min of a session. Chemogenetic inhibition of the basal forebrain decreased hit rates in GTs but was without effect in STs. Moreover, the decrease in hits in GTs manifested solely during the last 15 min of a session. Transfection efficacy in the horizontal limb of the diagonal band, but not substantia innominata or nucleus basalis of Meynert, predicted the behavioral efficacy of chemogenetic inhibition in GTs. Furthermore, the total subregional transfection space, not transfection of just cholinergic neurons, correlated with performance effects. These results indicate that the cognitive-behavioral phenotype indexed by goal-tracking, but not sign-tracking, depends on activation of the basal forebrain-frontal cortical projection system and associated biases toward top-down or model-based performance. Significance Statement Sign-tracking rats (STs) have emerged as a model to study the neuro-behavioral mechanisms which bestow vulnerability for addiction-like behavior. The trait indexed by sign-tracking includes a bias toward bottom-up, or cue-driven attention and has been hypothesized to be mediated in part by a low-capacity forebrain cholinergic system. Here we show that compared to their counterparts, the goal trackers (GTs), the attentional performance of STs declines over prolonged time on task. Chemogenetic inhibition of the basal forebrain rendered the attentional performance of GTs to be similar to that of STs while not affecting the latter phenotype. Insufficient recruitment of the basal forebrain-cortical projection systems contributes to the addiction vulnerability-predicting trait indexed by sign-tracking.