Adaptive responding to stimulus-outcome associations requires noradrenergic transmission in the medial prefrontal cortex

Abstract

A dynamic environment, such as the one we inhabit, requires organisms to continuously update their knowledge of the setting. While the prefrontal cortex is recognized for its pivotal role in regulating such adaptive behavior, the specific contributions of each prefrontal area remain elusive. In the current work, we investigated the direct involvement of two major prefrontal subregions, the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), in updating Pavlovian stimulus-outcome (S-O) associations following contingency degradation. Specifically, animals had to learn that a specific cue, previously fully predicting the delivery of a specific reward, was no longer a reliable predictor. First, we found that chemogenetic inhibition of mPFC, but not of vlOFC, neurons altered the rats ability to adaptively respond to degraded and non-degraded cues. Next, given the growing evidence pointing at noradrenaline (NA) as a main neuromodulator of adaptive behavior, we decided to investigate the possible involvement of NA projections to the two subregions in this higher-order cognitive process. Employing a pair of novel retrograde vectors, we traced NA projections from the locus coeruleus (LC) to both structures and observed an equivalent yet relatively segregated amount of inputs. Then, we showed that chemogenetic inhibition of NA projections to the mPFC, but not to the vlOFC, also impaired the rats ability to adaptively respond to the degradation procedure. Altogether, our findings provide important evidence of functional parcellation within the prefrontal cortex and point at mPFC-NA as key for updating Pavlovian S-O associations. Significant statementThe ability to update stimulus-outcome (S-O) associations is a key adaptive behavior, essential for surviving in an ever-changing environment. The prefrontal cortex is well-known for playing a key role in this process. The discrete contribution of each prefrontal subregion and of different neurotransmitters, however, remains unclear. In the current study, we show that inhibiting medial prefrontal (mPFC), but not ventrolateral orbitofrontal cortex (vlOFC), neurons impairs the rats ability to update S-O associations following contingency degradation. Moreover, we demonstrate that discrete noradrenergic projections to the two subregions exist and that inhibiting the ones projecting to the mPFC, but not to the vlOFC, once again impairs the rats behavior, thereby implying a substantial contribution of noradrenaline in orchestrating this higher-order cognitive process.