Noradrenergic alpha-2a Receptor Stimulation Enhances Prediction Error Signaling in Anterior Cingulate Cortex and Striatum

The noradrenergic system is implicated to support behavioral flexibility by increasing exploration during periods of uncertainty and by enhancing working memory for goal-relevant stimuli. Possible sources mediating these pro-cognitive effects are 2A adrenoceptors (2AR) in prefrontal cortex or the anterior cingulate cortex facilitating fronto-striatal learning processes. We tested this hypothesis by selectively stimulating 2ARs using Guanfacine during feature-based attentional set shifting in nonhuman primates. We found that 2A stimulation improved learning from errors and facilitates updating the target feature of an attentional set. Neural recordings in the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex (dlPFC), and the striatum showed that 2A stimulation selectively enhanced the neural representation of negative reward prediction errors in neurons of the ACC and of positive prediction errors in the striatum, but not in dlPFC. This modulation was accompanied by enhanced encoding of the feature and location of the attended target across the fronto-striatal network. Enhanced learning was paralleled by enhanced encoding of outcomes in putative fast-spiking interneurons in the ACC, dlPFC, and striatum but not in broad spiking cells, pointing to an interneuron mediated mechanism of 2AR action. These results illustrate that 2A receptors causally support the noradrenergic enhancement of updating attention sets through an enhancement of prediction error signaling in the ACC and the striatum.