Spatiotemporal dynamics and targeted functions of locus coeruleus norepinephrine in a learned behavior

The locus coeruleus (LC) serves as the primary source of the neuromodulator, norepinephrine (NE), in the brain. Through a widely divergent set of projections, LC neurons have been suggested to release NE ubiquitously to regulate arousal and attention. However, LC-NE is implicated in more precise roles such as mediating learning, promoting task execution, and signaling unexpected uncertainty. Whether and how LC-NE activity facilitates these distinct aspects of behavior is unknown. Here, we show that LC-NE activity displays distinct spatiotemporal dynamics to enable two functions during a learned behavior—facilitating task execution under conditions of uncertainty, and encoding reinforcement to improve performance accuracy. To examine these functions, we used a behavioral task with graded auditory stimulus detection and task performance. Optogenetic inactivation of the LC demonstrated that LC-NE activity was causal for both task execution and optimization. Targeted recordings of LC-NE neurons using photo-tagging, two-photon micro-endoscopy, and two-photon output monitoring showed that transient LC-NE activation preceded behavioral execution and followed reinforcement. These two components of phasic activity were heterogeneously represented in LC-NE cortical outputs, such that the behavioral response signal was higher in motor cortex and facilitated task execution, whereas the negative reinforcement signal was widely distributed among cortical targets and improved performance on the subsequent trial. Modular targeting and spatiotemporal integration in target regions thus enable diverse functions, whereby some NE signal are segregated amongst targets while others are broadly distributed.