NOREPINEPHRINE COORDINATES ASTROCYTE-NEURON COMPUTATIONS TO SUPPORT ADAPTIVE BEHAVIOR ACROSS MULTIPLE TIMESCALES

Adaptive behavior relies on the brain’s ability to process information across multiple timescales, from rapid responses to salient events to gradual adjustments in behavioral strategy after feedback. The locus coeruleus–norepinephrine (LC-NE) system is a key regulator of these processes, yet how it coordinates cortical computations across timescales remains unclear.
During adaptive decision-making in mice, phasic LC-NE activity encodes pre-execution reward expectation, influencing action selection within hundreds of milliseconds, and post-reinforcement reward prediction errors (RPEs) that support behavioral adaptation seconds later. Combining experiments with advanced computational analysis and modeling, we show that these computations are implemented through two cortical pathways: one directly targeting neurons to rapidly drive behavior, and another engaging astrocytes to extend LC-NE RPE signals over behaviorally relevant timescales.
Using prefrontal cortex (PFC) recordings with optogenetic inhibition of LC-NE neurons, we show that LC-NE release enhances behaviorally relevant stimulus information on short timescales by boosting single-neuron responsiveness and reshaping population noise correlations, improving performance under uncertainty. After surprising outcomes, reinforcement signals required for trial-to-trial adaptation were transiently encoded by neuronal populations and did not bridge the inter-trial interval, despite LC-NE-dependent increases in next-trial stimulus information. Two-photon calcium imaging revealed that astrocytes extend LC-NE post-reinforcement signals for several seconds. Disrupting astrocyte dynamics or astrocyte–neuron signaling abolished both LC-NE-dependent stimulus information modulation in PFC and behavioral adjustments after surprising outcomes.
Together, these findings reveal how LC-NE coordinates cortical computation and behavior across timescales, and position astrocytes as slow contextual modulators of neuronal information processing during adaptive behavior.