Exposure to stress has consistently been shown to impair performance on such
tasks in nonhuman primates and male rodents,14 but until recently, neither sex differences nor estrogen effects on this phenomenon had been explored. The first studies to examine sex differences in the effects of stress on PFC function elicited the stress response in young adult male and female rats with injections Inhibitors,research,lifescience,medical of varying doses of the benzodiazepine inverse agonist FG7142. FG7142 is a well-documented anxiogenic drug that is frequently used as a model for stress, given its reliability in producing the biochemical and physiological effects of stress: increased corticosterone release, increased catecholamine turnover, elevated heart rate, and increased blood pressure.15 Inhibitors,research,lifescience,medical selleck Moreover, animals that have been administered FG7142 exhibit classic stress-related behaviors, including defecating, urinating, freezing, and ultra-sonic vocalizations.16 Following FG7142 administration, animals were tested on a classic measure of working memory – delayed alternation in the T-maze. At high doses of FG7142, all animals displayed impairment
on the T-maze. At lower doses, however, only females showed impairment, suggesting that they were more sensitive to the detrimental effects of stress on mPFC function (Figure 1a). To test whether fluctuating hormones Inhibitors,research,lifescience,medical produced this sex effect, the experiment was repeated while female rats’ estrus phase was monitored. It was found that these rats only displayed sensitivity to FG7142 during proestrus, when estrogen levels are highest. Animals in estrus, characterized by low estrogen levels,
responded to the Inhibitors,research,lifescience,medical low dose of FG7142 in a manner comparable to that of males – that is, showing no impairment at all17 (Figure 1b). Inhibitors,research,lifescience,medical This effect was further replicated using a more conventional stress paradigm, restraint. While 2 hours of restraint stress produced working memory impairments in all groups, only females in proestrus were impaired by 1 hour of restraint as well (Figure 1c).18 Taken together, these studies suggest that fluctuating hormones can interact with stress systems to modulate PFC function during stress. Figure 1. Sex differences and estrogen effects on stress-induced working memory impairment a) Dose-response curve for male and female animals’ performance on Endonuclease working memory task delayed alternation after administration of pharmacological stressor FG7142. Mean … This idea was explored further by ovariectomizing a new group of female rats, and implanting a time-release capsule containing either estrogen (OVX + E) or cholesterol (OVX) as a control. These rats were then treated with the same low dose of FG7142 that impaired proestrus females, but not estrus females or males, and then tested on the T-maze task.