Frontal norepinephrine represents a threat prediction error under uncertainty

Background To adapt to threats in the environment, animals must predict them and engage in defensive behavior. While the representation of a prediction error signal for reward has been linked to dopamine, a neuromodulatory prediction error for aversive learning has not been identified. Methods Here, we measured and manipulated norepinephrine release during threat learning using optogenetics and a novel fluorescent norepinephrine sensor. Results We found that norepinephrine response to conditioned stimuli reflects aversive memory strength. When delays between auditory stimuli and footshock are introduced, norepinephrine acts as a prediction error signal. However, temporal difference prediction errors do not fully explain norepinephrine dynamics. To explain noradrenergic signaling, we used an updated reinforcement learning model with uncertainty about time and found that it explained norepinephrine dynamics across learning and variations in temporal and auditory task structure. Conclusions Norepinephrine thus combines cognitive and affective information into a predictive signal and links time with the anticipation of danger.