Investigating the effect of differential striatal dopamine projections on reversal learning and immediate early gene (IEG) expression

Behavioral flexibility is key to survival in a dynamic environment. One form of flexibility is reversal learning, or the ability to switch between opposing actions following a change in outcome. Key to this process is the striatum, a subcortical structure tasked with action selection and the learning of novel motor behaviors. Early development of motor behaviors is dependent on the dorsomedial striatum, which later becomes dependent on lateral striatum as behaviors become inflexible. Similarly, dopamine release in striatum mirrors this medial-to-lateral transition, suggesting that lateral dopamine release may be a key mechanism in establishing inflexible behaviors late in learning, though this has not been directly tested. To investigate this, we bred DATcre x Ai32 mice to allow selective optogenetic activation of dopamine terminals within medial, lateral, and ventral striatum. These mice performed an intracranial self-stimulation reversal task in which they received optogenetic stimulation to medial (n=7), lateral (n=7), or ventral (n=8) dopamine inputs when they pressed one of two levers before the active lever was switched. Consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating ventral or medial striatal dopamine were flexible following reversal, while activation of lateral striatal dopamine impaired reversal. This effect was associated with no difference in place preference or locomotion in an open field across groups. In addition, pilot studies suggest optogenetic activation of medial and lateral dopamine modifies reversal for food rewards, and this manipulation may be associated with striatal immediate early genes (IEG) expression, which support synaptic plasticity and learning. This work contributes to our general understanding of how dopamine modifies subcircuits within the striatum to switch between different behavioral strategies, and may provide insight into how drugs of abuse promote inflexible, habitual behaviors in drug addiction