Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility

Abstract

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.

Assessment of behavioral flexibility in mice with conditional deletion of metabotropic glutamate receptor 2 fromEmx1-lineage neurons

“…Activation of mGlu 2 modulates striatal dopamine release through actions on subcortical circuitry (Johnson et al, 2017; Johnson et al, 2020b; Littlepage-Saunders et al, 2023). Dopamine signaling in the dorsolateral striatum contributes to habitual responding for natural reinforcers (Lerner, 2020) and for drugs including alcohol, cocaine, and heroin (Belin et al, 2009; Corbit and Janak, 2016; Corbit et al, 2014b; Hodebourg et al, 2019; Willuhn et al, 2012), whereas dopamine transmission in the dorsomedial striatum supports reversal learning (Clarke et al, 2011; Grospe et al, 2018; van der Merwe et al, 2023). Thus, it is possible that deletion of mGlu 2 from specific subcortical circuits that regulate striatal dopamine transmission could promote inflexible behaviors that facilitate excessive drug intake.…”

Optogenetic action potentials and intrinsic pacemaker interplay in retrogradely identified midbrain dopamine neurons

“…Dissecting the diversity of midbrain dopamine (DA) neurons by optotagging is a promising addition to better identify their functional properties and contribution to motivated behavior (Pallikaras et al, 2022; Steinberg et al, 2013; van der Merwe et al, 2023). Based on the selective expression of channelrhodopsin (ChR) in DA neurons, previous approaches (Cohen et al, 2012; Matsumoto et al, 2016; Mohebi et al, 2019; Stauffer et al, 2016) were based on the ability to reliably evoke short latency action potentials (APs) by light illumination in combination with the key assumption that the shape of the optogenetically evoked AP (o AP ) remains unaltered and thus can be used as an identifier for a particular DA neuron in the context of multi‐electrode in vivo recordings.…”