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.

Reward value and internal state differentially drive impulsivity and motivation.

Goal-directed behavior is influenced by both reward value as well as internal state. A large body of research has focused on how reward value and internal drives such as hunger influence motivation in rodent models, however less work has focused on how these factors may differentially affect impulsivity. In these studies, we tested the effect of internal drive versus reward value on different facets of reward-related behavior including impulsive action, impulsive choice and, motivation. We varied reward value by changing the concentration of sucrose in the reward outcome, and varied internal drive by manipulating thirst through water restriction. Consistent with the literature we found that both internal state and reward value influenced motivation. However, we found that in high effort paradigms, only internal state influenced motivation with minimal effects of reward value. Interestingly, we found that internal state and reward value differentially influence different subtypes of impulsivity. Internal state, and to a lesser extent, reward value, influenced impulsive action as measured by premature responding. On the other hand, there were minimal effects of either reward value or homeostatic state on impulsive choice as measured by delay discounting. Overall, these studies begin to address how internal state and reward value differentially drive impulsive behavior. Understanding how these factors influence impulsivity is important for developing behavioral interventions and treatment targets for patients with dysregulated motivated or impulsive behavior.