Time uncertainty in threat prediction explains prefrontal norepinephrine release

The neuromodulator dopamine has qualities of a prediction error in temporal difference (TD) models of reward learning. However, the neuromodulatory substrates of threat prediction errors have remained elusive. Norepinephrine (NE) is released by surprise and uncertainty, and causal manipulations demonstrate a role for NE in threat learning. Thus, we hypothesized that NE encodes a threat prediction error signal, and compared NE release measurements in mice undergoing threat learning with predictions of TD learning. NE release scales with the strength of fear associations and threat imminence. However, NE temporal dynamics did not match TD learning prediction errors due to sustained release evoked by threat-associated cues. Inclusion of temporal uncertainty into TD models resolved this discrepancy, and NE fit prediction errors in such a model. Subsequent experiments manipulating temporal uncertainty and sensory feedback demonstrated a match between NE and reinforcement learning models incorporating uncertainty.