Chronic estradiol replacement to aged female rats reduces anxiety-like and depression-like behavior and enhances cognitive performance

SummaryDecline in the ovarian steroid, estradiol (E2), with the menopause transition may influence cognitive and affective processing of older women and there is evidence that hormone replacement therapies (HRTs) with E2-mimetics may provide benefit in some, but not all, women. The parameters that play a role in determining whether the response to HRTs is positive are of interest. It may be that the likelihood for positive responses is related to the timing of E2-replacement following E2 decline. As such, in the present study an animal model was utilized to investigate this. We investigated the effects of long- versus short-term E2-replacement by examining cognitive (object placement task), anxiety (open field, mirror maze, light–dark transition task), and depression (forced swim task) behavior of female rats that were ovariectomized (OVX) at middle-age (14 months) or older (19 months) and implanted with E2-filled implants at the time of surgery or after a delay of 5 months, or OVX at 14 months of age and never replaced with E2. Rats were tested at 20 months of age. The hypothesis that was tested was that rats would have reduced anxiety and depression behavior and improved cognitive performance with E2-replacement at ovarian cessation, compared to a delay in E2-replacement. Performance in the object placement task was improved in rats that were OVX and then received continuous E2-replacement, compared to those that were OVX and continuously administered placebo vehicle. In the open field and forced swim task, there was an increase in anti-anxiety and anti-depression behavior, respectively, among rats that were OVX and then received continuous E2-replacement, compared to OVX rats administered vehicle or those that experienced a delay in E2-replacement. In the mirror maze and light–dark transition task, E2-replacement at OVX, or after a delay, reduced anxiety-like behavior. Thus, E2-replacement reduced anxiety and depression behavior and improved cognitive performance of aged female rats; however, delay in E2 treatment influenced whether there were favorable effects of E2 in some tasks.