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It has been proposed that upregulation of the noradrenergic (NA) system through exposure to novelty might be one of the key components for building cognitive reserve and resilience to neurodegeneration. A personality trait that promotes greater interest in novel experiences is Openness to Experience (OE). Individuals who are high in OE exhibit strong curiosity towards novelty and are more likely to be exposed to novel stimuli throughout the lifespan. Performing voxel-based morphometry analyses, we examined whether OE in 135 healthy young adults was associated with Locus Coeruleus (LC)-the main core of the noradrenergic system. We also investigated whether LC mediates the relationship between OE and a key measure of reserve, IQ In comparison with other neuromodulators’ seeds (Dorsal and Median Raphe [DR-MR]-5-HT, Ventral Tegmental Area [VTA]-DA-and Nucleus Basalis of Meynert [NBM]-Ach-), results show that greater LC integrity was related to greater OE and IQ. Additionally, mediation analyses revealed that only LC mediated the relationship between OE and IQ. Furthermore, a Bayesian multiple regression was conducted to model the contribution of both isolated and combined neuromodulator seeds to OE trait express. This approach found that the LC+ VTA could account for more variance in OE expression compared to the LC alone. Other weaker but significant associations were observed between DR and OE, between LC+ NBM and Conscientiousness and between DR+ NBM and Extraversion. These results are together suggestive that OE is primarily underpinned by monoaminergic functioning, and that the LC-NA …