Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility

• Published in: The European journal of neuroscience Vol. 58; no. 12; pp. 4466 - 4486
• Main Authors: Merwe, Rochelle K., Nadel, Jacob A., Copes‐Finke, Della, Pawelko, Sean, Scott, Jesse S., Ghanem, Marwan, Fox, M., Morehouse, Caroline, McLaughlin, Robert, Maddox, Charlie, Albert‐Lyons, Ruth, Malaki, Golara, Groce, Virginia, Turocy, Alaina, Aggadi, Nada, Jin, Xin, Howard, Christopher D.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.12.2023
• Subjects: behavioural flexibility; Dopamine; Dopamine transporter; Flexibility; Neostriatum; Nucleus accumbens; optogenetics; Reversal learning; striatum; Subpopulations; reversal learning; behavioural flexibility; striatum; dopamine; optogenetics
• ISSN: 0953-816X; 1460-9568; 1460-9568
• DOI: 10.1111/ejn.15910

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. Reversal learning, a form of behavioural flexibility, is dependent on dopamine transmission, but few studies have investigated how dopamine inputs to different striatal subregions influence flexibility. Mice self‐stimulated medial, lateral or ventral dopamine terminals before undergoing spatial reversal of the active lever. Mice that self‐stimulated medial and ventral dopamine were largely flexible during reversal, but lateral stimulation resulted in less flexible responding, suggesting that this region supports inflexible behaviours.