Examining Interactive Effects of Anxiety, Dopamine and Estradiol on Neural Oscillatory Activity: Evidence for a Translational Model?

Preclinical models propose that anxiety interacts with dopamine and estradiol to influence lateral prefrontal cortex function, a region critical for working memory. However, no study has tested this model in humans. We addressed this gap by examining whether basal and estradiol’s moderate the association between worry and oscillatory neural activity (i.e., theta-gamma coupling; TGC) involved in working memory in a female sample (N=135). Participants completed a verbal working memory task (N-back) up to four times in-person. Saliva samples on the day of N-back completion were used to assay for estradiol and extract COMT gene polymorphisms, as a proxy for basal dopamine levels. TGC was computed on correct lure trials of the N-back task in the 0-500 millisecond time window post-stimulus presentation. We examined within-person and between-person differences in worry across a whole menstrual cycle. Our findings revealed that for those with high chronic worry, within-person increases in worry were associated with reduced TGC. In contrast, for those with low average levels of worry, within-person increases in worry were associated with increased TGC. We also found that acute increases in worry were associated with enhanced TGC for Val/Val carriers (those with less tonic dopamine), whereas there was no association for Met/Met carriers. The positive association between worry and TGC was enhanced for Val carriers when estradiol levels were high. This study provides preliminary evidence that dopamine and estradiol modulate the association between worry levels and working memory function. Implications and future directions will be discussed.