Abstract :
[en] Cognitive inhibition, one of the main executive functions, allows to suppress the production of predominant but inappropriate responses in order to promote more adapted ones. These mechanisms are regulated by cognitive control processes, varying in a context-dependent manner, and responsible for the active maintenance of tasks goals and goal-related information. The role of the neurotransmitter dopamine (DA) in modulating executive functioning (behavior and brain-related activity) received increased interest over the last decade (Barnes et al., 2011), particularly through the effect of the COMT Val158Met polymorphism (Witte and Floël, 2012), well-known to impact the level of prefrontal DA (Chen et al., 2004). However, unsolved issues remains such as (1) the variability of the influence of the dopaminergic system with regard to different form of inhibition, and (2) the effects of DA-mediated signaling on the antero-posterior network underlying interference resolution and on the implementation of different cognitive control strategies during the processing of interfering events.In that context, the general objective of this research work was to capitalize on a candidate-gene approach as a means to investigate the interactive effect of an intrinsic factor (the dopaminergic activity) and an extrinsic factor (the context) on performance and brain-related activity associated with specific inhibitory mechanisms.By means of behavioral and functional magnetic resonance imaging (fMRI) studies, we explored the effects of the prefrontal level of DA, and DA receptors activity, on behavioral efficiency and brain-related activity during tasks involving inhibition. Various inhibitory tasks were administered outside the MRI scanner to participants genotyped for the COMT rs4680, DRD1 rs4532 and MAOA rs6323 polymorphisms; three genetic variants affecting the level of DA or the activity of the DA D1-receptors (DRD1). Within the scanner, modified versions of the Stroop and Sternberg tasks (Sternberg, 1966; Stroop, 1935) were administered to three groups of young adults varying according to their COMT Val158Met genotype [Val/Val (VV; low DA level), Val/Met (VM; intermediate DA level) and Met/Met (MM; high DA level)]. Based on the theory of dual mechanisms of control (Braver et al., 2007), the tasks were built up to induce proactive or reactive control processes according to the tasks context. Our results demonstrated for the first time that: (1) the inhibition of automatic saccades is influenced by the interaction between the level of DA and the DRD1 activity (Study 1); (2) proactive control during a verbal inhibitory task is specifically associated with an increased activity in the anterior cingulate cortex in individuals with a high cortical level of DA (Met-allele carriers), while an increased activity was observed in the middle frontal gyrus in carriers of the Val allele (Study 2); (3) during reactive control, the antero-posterior functional connectivity linked to interference resolution is influenced by the COMT genotype, such that fronto-temporal areas appeared more « connected » in individuals with a low level of DA (VV homozygous) (Study 4); (4) during proactive control, interference resolution during a working memory task is specifically associated to an increased activity in a large frontal network in VV homozygous individuals, especially in the left superior frontal gyrus during the transition from storage to recognition processes (Study 3). As a whole, these results suggest the level of DA as well as the activity of the DRD1 receptors are crucial factors to simultaneously take into account when investigating the influence of the dopaminergic system on inhibitory functioning. From a cognitive viewpoint, task context but also the kind of working memory representations (stable vs. flexible) during interference resolution seems particularly important to understand the effect of dopaminergic modulation on inhibitory efficiency.
