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  • Overall we found that all hormone treatment groups were


    Overall, we found that all hormone treatment groups were able to learn spatial working and reference memory tasks, as shown by their performance across days on the WRAM (days 2–12, collapsed across the 4 trials) and the MWM (days 1–5, collapsed across the 4 trials). During the acquisition phase of the WRAM (block 1 of testing), when rats were initially learning the rules of the task, the E2-only and Levo-only treatment groups made fewer WMI errors across all 4 trials compared to the vehicle group, indicating that E2-only and Levo-only treatments enhanced working memory performance during the learning phase of the task relative to control treatment. With reference to prior publications testing E2 (using various regimens, doses, and rat ages), in general, our results here are consistent with previously published findings suggesting enhanced cognitive performance with E2-only treatment (Bimonte and Denenberg, 1999, Daniel et al., 1997, Daniel et al., 2006, Fader et al., 1999, Gibbs and Johnson, 2008, Luine et al., 1998, Rodgers et al., 2010). Our results are also consistent with previously published findings of enhanced cognitive performance with Levo-only treatment (Braden et al., 2017, Simone et al., 2015). When evaluating all 4 trials combined, the combination of E2 + Levo obviated the working memory benefits of E2-only and Levo-only. There has been only one other published preclinical study testing an estrogen/Levo combination, whereby the synthetic 2,4-Diacetylphloroglucinol ethinyl estradiol (EE) plus Levo was tested in a different model and behavior paradigm: the young ovary-intact rat tested in object memory (Simone et al., 2015). However, even with the important differences between our studies, similar results were reported, with the EE plus Levo hormone combination treatment attenuating EE-induced improvements in novel object memory and Levo-induced enhancements in visuospatial memory in ovary-intact young rats (Simone et al., 2015). Preclinical studies testing other combination hormone therapies have also shown that, in Ovx rodents, the addition of natural progesterone to E2 treatment can reverse the enhancing cognitive effects of E2 (Bimonte-Nelson et al., 2006, Harburger et al., 2007, Lowry et al., 2010). It has also been shown that the addition of MPA to an E2 treatment resulted in impaired learning on the MWM compared to E2 treatment alone (Lowry et al., 2010). Interestingly, results from this study showed that working memory demand influenced the direction of hormone treatment effects on cognitive performance specifically during the acquisition phase of the WRAM. On trial 3, when the working memory load was moderate, the E2-only, Levo-only, and E2 + Levo treatment groups made fewer WMI errors than the vehicle group, suggesting that all hormone treatments enhanced performance relative to control treatment during this moderate demand trial. However, on trial 4, when the working memory load was highest, the E2 + Levo treatment group made more WMI errors compared to E2-only and Levo-only treatment groups, revealing that this estrogen/progestin combination treatment impaired high demand working memory ability relative to each individual hormone treatment. This is additionally represented in Fig. 2F, with effects clearly illustrated by the interaction between the moderate and the high working memory load trials (trials 3 and 4) and treatment (E2 + Levo group vs. the vehicle group). Taken together, these results indicate that the hormones E2 and Levo impact cognitive function in a model of surgical menopause, with the direction of this mnemonic impact dependent on: (1) whether E2 and Levo are administered alone as an individual exogenous regimen or together as a hormone combination exogenous regimen and (2) cognitive demand. Each individual hormone regimen and the combined hormone regimen enhanced cognitive performance when the working memory demand was moderate; however, when the working memory demand was high, these 2 hormones in combination impaired performance compared to each hormone alone. These findings are in accordance with previous studies demonstrating distinct hormone effects across an increase in working memory demand, including with estrogens (Bimonte and Denenberg, 1999, Hiroi et al., 2016, Mennenga et al., 2015b), progestogens (Braden et al., 2011, Braden et al., 2015, Braden et al., 2017), and androgens (Camp et al., 2012, Mennenga et al., 2015c).