Noradrenergic alpha-2a receptor stimulation enhances prediction error signaling and updating of attention sets in anterior cingulate cortex and striatum

The noradrenergic system is believed to support behavioral flexibility. A possible source mediating improved flexibility are alpha 2A adrenoceptors (alpha 2AR) in prefrontal cortex (PFC) or the anterior cingulate cortex (ACC). We tested this hypothesis by stimulating alpha 2ARs using Guanfacine during attentional set shifting in male nonhuman primates. We found that alpha 2AR stimulation improved learning from errors and updating attention sets. Neural recordings in the ACC, dorsolateral PFC, and the striatum showed that alpha 2AR stimulation selectively enhanced neural signaling of prediction errors in neurons of the ACC and the striatum, but not in dlPFC. This modulation was accompanied by enhanced encoding of attended target features and particularly apparent in putative fast-spiking interneurons, pointing to an interneuron mediated mechanism of alpha 2AR action. These results reveal that alpha 2A receptors are part of the causal chain of flexibly updating attention sets through an enhancement of outcomes and prediction error signaling in ACC and striatum. How noradrenergic modulation could support the flexible switching of cognitive states in primates is not fully understood. Here authors show that alpha-2A noradrenergic action causally enhances cognitive flexibility by enhancing prediction error signaling and neural coding of attended target features in anterior cingulate cortex and the anterior striatum.