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

Abstract

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 alpha-2A adrenoceptors in prefrontal cortex or the anterior cingulate cortex facilitating fronto-striatal learning processes. We tested this hypothesis by selectively stimulating alpha-2ARs using Guanfacine during feature-based attentional set shifting in nonhuman primates. We found that alpha-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 alpha-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 alpha-2AR action. These results illustrate that alpha-2A receptors causally support the noradrenergic enhancement of updating attention sets through an enhancement of prediction error signaling in the ACC and the striatum.

The Effects of Locus Coeruleus Optogenetic Stimulation on Global Spatiotemporal Patterns in Rats

“…A human brain mapping study that considered brainstem structures showed that the ACC had the strongest summed functional connectivity to all brainstem nuclei, making it a primary hub for cortical-brainstem functional connectivity (Hansen et al, 2023). Stimulation of alpha-2a adrenergic receptors in nonhuman primates was reported to increase the encoding of negative prediction errors in the ACC, linking the noradrenergic system to the ACC's involvement in learning (Hassani & Womelsdorf, 2023). Our lab has also shown the importance of reciprocal connections between the ACC and LC in affective responses to contextual novelty (Lustberg, Iannitelli, et al, 2020;.…”