Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility.

Behavioural flexibility is key to survival in a dynamic environmentWhile flexible, goal-directed behaviours are initially dependent on dorsomedial striatum, they become dependent on lateral striatum as behaviours become inflexible. Similarly, lesions of dopamine terminals in lateral striatum disrupt the development of inflexible habits. This work suggests that dopamine release in lateral striatum may drive inflexible behaviours, though few studies have investigated a causative role of subpopulations of striatal dopamine terminals in reversal learning, a measure of flexibility. Here, we performed two optogenetic experiments to activate dopamine terminals in dorsomedial (DMS), dorsolateral (DLS) or ventral (nucleus accumbens [NAc]) striatum in DAT-Cre mice that expressed channelrhodopsin-2 via viral injection (Experiment I) or through transgenic breeding with an Ai32 reporter line (Experiment II) to determine how specific dopamine subpopulations impact reversal learning. Mice performed a reversal task in which they self-stimulated DMS, DLS, or NAc dopamine terminals by pressing one of two levers before action-outcome lever contingencies were reversed. Largely consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating medial dopamine terminals reversed lever preference following contingency reversal, while mice self-stimulating NAc showed parial flexibility, and DLS self-stimulation resulted in impaired reversal. Impairments in DLS mice were characterized by more regressive errors and reliance on lose-stay strategies following reversal, as well as reduced within-session learning, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which DMS and ventral dopamine facilitate goal-directed responding, and DLS dopamine supports more inflexible responding.

Cannabidiol (CBD) drives sex-dependent impairments in omission, but has no effect on reinforcer devaluation.

Habits are inflexible behaviors that persist despite changes in outcome value. While habits allow for efficient responding, neuropsychiatric diseases such as drug addiction and obsessive-compulsive disorder are characterized by overreliance on habits. Recently, the commercially popular drug cannabidiol (CBD) has emerged as a potential treatment for addictive behaviors, though it is not entirely clear how it exerts this therapeutic effect. As brain endocannabinoids play a key role in habit formation, we sought to determine how CBD modifies goal-directed behaviors and habit formation. To explore this, mice were administered CBD (20 mg/kg i.p.) or vehicle as a control and trained on random interval (RI30/60) or random ratio (RR10/20) schedules designed to elicit habitual or goal-directed lever pressing, respectively. Mice were tested for habitual responding using probe trials following reinforcer-specific devaluation as well as omission trials, where mice had to withhold responding to earn rewards. We found that while CBD had little effect on operant behaviors or reward devaluation, CBD inhibited goal-directed behavior in a sex-specific and context dependent manner during the omission task. Beyond drug treatment, we found an effect of sex throughout training, reward devaluation, and omission. This work provides evidence that CBD has no effect on habit formation in a reward devaluation paradigm. However, the omission results suggest that CBD may slow learning of novel action outcome contingencies or decrease goal-directed behavior. This work calls for further examination of sex-dependent outcomes of CBD treatment and highlights the importance of investigating sex effects in habit-related experiments.