558. Pallidal prototypic neuron and astrocyte activities regulate flexible reward-seeking behavior

Abstract

Abstract Background Behavioral flexibility—the ability to update actions when contingencies change—is essential for survival and depends heavily on basal ganglia circuitry. Although the basal ganglia integrate contextual, reward, and motor-planning signals to enable adaptive control, most mechanistic work on behavioral flexibility has focused on the striatum, including subregion- and cell-type–specific circuits and plasticity mechanisms involved in action selection, reversal learning, and cognitive control. In contrast, the contributions of other basal ganglia nuclei, particularly the external globus pallidus (GPe), remain comparatively underexplored. Aims & Objectives We investigated the role of GPe astrocytes and prototypic GPe neurons projecting to the subthalamic nucleus (STN) in reversal learning, with the goal of identifying circuit mechanisms that support the acquisition, stabilization, and rapid updating of action strategies following contingency shifts. Method To dissect heterogeneous GPe circuitry and identify cellular correlates of flexible behavior, we used multi-channel fiber photometry to simultaneously monitor calcium activity in GPe astrocytes and prototypic neurons during longitudinal operant reward-seeking learning. In GFAP-Cre/DIO-GCaMP6s mice, we performed an FR1 operant task that incorporated context reversals and quantified activity patterns across the initial learning, stabilization, and reversal phases. To test causal involvement, we inhibited or deleted prototypic neurons using chemogenetic and circuit-ablation approaches. We further validated circuit specificity and information flow by integrating optogenetic manipulations and computational analyses. Results GPe prototypic neurons were necessary for behavioral flexibility. During context reversals, prototypic activity changed in a context-dependent manner, tracking behavioral optimality as action–outcome contingencies shifted. Selective deletion of GPe prototypic neurons impaired the ability to adjust behavior after reversals while sparing initial task acquisition, indicating a specific role in updating action strategies rather than general performance. Circuit interrogation revealed that prototypic neurons integrate inputs from the dorsolateral striatum (DLS) and STN. Notably, our data suggest that prototypic neurons can influence basal ganglia output nuclei via collateral projections, supporting a non-canonical pathway for regulating flexible behavior. Discussion & Conclusions Our findings support a convergent “non-canonical information flow” model, in which DLS and STN signals converge onto GPe prototypic neurons to orchestrate adaptive behavioral switching following contingency changes (DLS/STN ⋄ GPe⋄ GPi/SNr). By integrating excitatory and inhibitory information streams, GPe prototypic neurons appear to provide a key control node for reversal learning and behavioral optimization in changing environments. Defining this GPe circuit mechanism offers a new framework for understanding impaired behavioral adaptation and suggests potential circuit-informed therapeutic strategies for disorders marked by reduced flexibility, including obsessive-compulsive disorder, autism spectrum disorder, Parkinson’s disease, and addiction.