Alpha-2 agonism of the locus coeruleus impairs learning driven by negative prediction error

Refining previous learning when environmental contingencies change is a critical adaptive function. Studies have shown that systemic noradrenaline (NA) manipulations, as well as optogenetic manipulations of the locus coeruleus (LC), the primary source of forebrain NA, can strengthen long-term retention of appetitive extinction. To determine whether the contribution of NA is specific to extinction or extends to other forms of learning where reward is less than expected, we suppressed LC activity with clonidine, an 2A-adrenergic receptor agonist, in two tasks: compound extinction, where two previously rewarded cues are paired and no longer rewarded, and overexpectation, where animals are presented with two previously rewarded cues but receive a single reward rather than the expected two. In compound extinction, we found no differences between groups in training, extinction, or a spontaneous recovery test. However, animals that received clonidine reacquired responding to the previously extinguished cue significantly faster than saline animals, suggesting weakened extinction learning. In overexpectation testing, the saline group responded significantly less to a stimulus that had undergone overexpectation relative to a control stimulus, indicating that they had recalibrated their estimation of reward magnitude following training where reward was less than expected. In contrast, clonidine-treated animals did not differ in responding to the overexpectation versus control stimuli, suggesting that clonidine impaired learning resulting from overexpectation. These results demonstrate that activity of the LC is important for learning to reduce responding in both extinction and overexpectation paradigms.