Baker, Matthew

Abstract The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual reward-seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant reward-seeking. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe◊DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation reduced habitual seeking-behaviors, which was blocked by systemic D1R agonism. Our findings reveal a novel role of this arkyGPe◊DLS circuit in constraining habitual reward-seeking, which is relevant to addictive behaviors and other compulsive disorders.

Abstract The external globus pallidus (GPe) is an integrative hub and gateway for behavioral flexibility in reward-related behaviors. However, it remains unknown whether enriched astrocytes in the GPe guide behavioral flexibility. Here, we trained mice to exhibit goal-directed and habitual reward-seeking behaviors using the behavior tasks with effort- and time-based reward delivery, respectively. Then, we examined the temporal dynamics of GPe astrocytes during goal-directed and habitual learning. Overall, GPe astrocytes were substantially silenced during habitual learning compared to goal-directed learning. In the timescale of action events, GPe astrocyte activities were increased immediately after termination of reward-taking behavior before the following action. However, during habitual learning, the increase of astrocyte activity was not evident. Moreover, support vector machine (SVM) analysis demonstrated that GPe astrocytes dynamics predicted whether mice perform goal-directed or habitual behaviors. Interestingly, chemogenetic activation of GPe astrocytes, which dampened GPe neuronal firings and habitual behaviors, exhibting goal-directed behaviors. Strikingly, brief and repeated attentional stimulations recapitulated the effect of chemogenetic activation of GPe in intervening the habitual reward-seeking behaviors with increased GPe astrocyte activities. Our findings reveal a novel insight that increasing GPe astrocytic activities attenuates habitual behavior and improves behavioral flexibility, which may provide a potential therapeutic target for decision-making-related disorders, such as obsessive-compulsive disorder and addiction.

Abstract Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal‐directed and habitual reward‐seeking behaviours, respectively. Previously, our study shows that the ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol‐drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal‐directed and habitual ethanol‐seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal‐directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E‐seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal‐directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal‐directed reward‐seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward‐seeking behaviours.