Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility

Abstract

Behavioral flexibility is key to survival in a dynamic environment. While flexible, goal-directed behaviors are initially dependent on dorsomedial striatum, they become dependent on lateral striatum with extended training as behaviors become inflexible. Similarly, dopamine release shifts from ventromedial to lateral striatum across learning, and impairment of lateral dopamine release disrupts habitual, inflexible responding. This raises the possibility that lateral dopamine release is a causative mechanism in establishing inflexible behaviors late in training, though this has not been directly tested. Here, we utilized optogenetics to activate dopamine terminals in dorsal medial (DMS), dorsal lateral (DLS), and ventral (NAc) striatum in DATcre mice to determine how specific dopamine subpopulations impact behavioral flexibility. 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. Consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating ventromedial dopamine terminals rapidly reversed lever preference following contingency reversal, while mice self-stimulating dopamine terminals in DLS showed impaired reversal learning. These impairments were characterized by more regressive errors and reliance on lose-stay strategies following reversal, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which dorsomedial dopamine facilitates goal-directed responding, and dorsolateral dopamine release is a key mechanism in supporting the transition toward inflexible behaviors.

Medial septum activation improves strategy switching once strategies are well-learned via bidirectional regulation of dopamine neuron population activity

“…Increased DA release in DLS, which is associated with general motor invigoration early in learning 8,42 , now increases the likelihood of initiating the previously learned, stereotyped motor plan 10,36 . Furthermore, inhibition of the DLS severely inhibits execution of a well-learned behavior 10 , while activation of DA release in DLS impairs reversal learning 60 . These data suggest that the MS's reduction of SNc DA population activity may be improving strategy switching by decreasing the likelihood of initiating the action sequence associated with the well learned strategy.…”