In a dynamic environment, organisms must continuously update learned action-outcome associations. Central to this flexibility is the prefrontal cortex, whose computations are finely tuned by neuromodulatory inputs. Yet, the temporal dynamics and circuit specificity of this regulation remain unclear. Here, we investigate the contribution of orbitofrontal noradrenaline (OFC-NA) to flexible updating in rats performing an instrumental reversal learning task. Using fiber photometry, we observe transient increases in OFC-NA release following reward deliveries on reversal day, and we find that the magnitude of these responses predicts the speed of behavioral adaptation. Chemogenetic and optogenetic manipulations of NA projections from the locus coeruleus (LC) to the OFC show that perturbing these signals delays reversal learning in a graded, mode-dependent manner, with chemogenetic inhibition having the strongest impact. Together, our findings establish OFC-NA as a temporally precise neuromodulatory mechanism, gating flexible adaptation to changing environmental contingencies.
Piccin et al. (Sun,) studied this question.