• Depression and anxiety traits predict distinct salience network connectivity patterns. • Depression-linked risk is associated with hypo-connectivity and reward deficiency. • Anxiety-linked risk is associated with hyper-connectivity and threat vigilance. • Nicotine reward sensitivity interacts with depressive traits to modulate rsFC. • Gene × Trait interactions (DRD2, 5-HTTLPR) reveal distinct connectivity endophenotypes. Smoking trajectories in young adults vary, with some light smokers escalating to dependence while others reduce or quit. Depressive and anxious traits relate to altered large-scale network connectivity, including the salience network (SN). Dopaminergic (DRD2 Taq1A) and serotonergic (5-HTTLPR) variants may further shape these trajectories, but trait–gene links to neural circuits and nicotine sensitivity remain unclear. Sixty-eight young light smokers (18–24) completed nicotine and placebo sessions. Resting-state fMRI assessed functional connectivity; reward sensitivity was measured with the Probabilistic Reward Task. Depressive/anxious traits and DRD2/5-HTTLPR genotypes were obtained, and smoking progression was tracked. Depressive traits predicted weaker SN connectivity (insula–ACC; insula–dlPFC) but stronger insula–sgACC coupling. Anxious traits predicted weaker precentral–insula/dlPFC connectivity and stronger precentral–temporal–sgACC connectivity. Higher depressive traits combined with nicotine-enhanced reward sensitivity (NERS) predicted reduced prefrontal–limbic connectivity, whereas depression with smoking progression predicted increased insula–striatal–hippocampal connectivity. Gene × trait interactions suggested distinct endophenotypes: Depression × DRD2 predicted sgACC–insula and hippocampus–ACC connectivity; Anxiety × 5-HTTLPR predicted ACC–PCC and hippocampus–dlPFC connectivity. The sgACC within the SN may act as a convergence hub linking affective traits, genetic risk, and nicotine sensitivity: depression-related risk reflects hypo-salience/reward deficiency, whereas anxiety-related risk reflects hyper-salience/vigilance.
Gunn et al. (Sun,) studied this question.