Potential sex difference in the effects of mild acute stress on executive functions

Prefrontal cortex (PFC)-dependent executive functions (EFs) are critical for reasoning, problem-solving, self-control and planning. The PFC dopamine (DA) level has been demonstrated to modulate EFs in an inverted U-shaped curve, where an intermediate level of DA is optimal. Unlike in other brain regions, PFC DA systems: 1) relies highly on the catechol-O-methyltransferase (COMT) enzyme for clearing released DA; and 2) can be activated even by mild stress. Estradiol (E2) has been shown to down-regulate COMT gene transcription, causing the activity of COMT enzyme to be ~30% less in women than in men. Animal studies have repeatedly shown that stress facilitates cognitive functions dependent on the hippocampus and / or PFC in males, but impairs them in females. Therefore, based on Diamond’s hypothesis that baseline PFC DA levels are higher and closer to the optimal level in women during menstrual phases when their circulating E2 are elevated, than in men, we predicted that mild stress would facilitate EF performance in men but impair it in women when their circulating E2 levels are high. In a crossover design, healthy young adults (both men and women), all COMT Val¹⁵⁸Met heterozygotes, were each tested twice (once with social-evaluative stress and once without, order counterbalanced) on five EF tasks which tapped on the core EFs of inhibitory control, working memory and cognitive flexibility, and one higher-level EF, reasoning. Women were randomly assigned to the low-E2 (F-L) group or high-E2 (F-H) group. Women in the F-L group were tested during the early follicular phase (low E2 level). Women in the F-H group were tested during the midluteal phase (high E2 level). Our social-evaluative procedure was showed to succeed in inducing physiological and subjective stress responses and significantly impaired the performance of the F-H group on one index of inhibitory control, whereas the performance of the M and F-L groups showed a trend towards enhancement. Similar trends (M and F-L: stress-induced enhancement; F-H: stress-induced impairments) were found for some other indices in the first two tasks. These results emphasized that the ways of improving EFs need to be considered in a sex-specific and hormone-dependent manner.Medicine, Faculty ofGraduat