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  • When a hour delay period


    When a 6-hour delay iCRT 14 receptor was implemented for the WRAM, neither of the E2-treated groups (E2-only and E2 + Levo) differed in WMC errors between the postdelay trials and the baseline trials. This suggests that exogenous E2 treatment protected from a delay-induced impairment in performance on working memory. Of note, the addition of Levo to E2 did not reverse the protective effects of E2 only against delay-induced impairment in working memory performance. However, the vehicle and Levo-only treatment groups exhibited impaired performance, where they made more WMC errors on the postdelay trials relative to their baseline performance. Together, these findings demonstrate a potential protective effect of E2 on cognitive function across the delay period that was not seen with the vehicle and the Levo-only treatment, regardless of whether Levo is on board with the E2 treatment or not. These results are consistent with previous studies where E2 enhanced cognitive performance following the implementation of a delay period (Harburger et al., 2007, Talboom et al., 2008). For instance, one study trained aged Ovx mice on the MWM and then immediately administered vehicle, E2, or E2 plus a low or high dose of progesterone treatment (Harburger et al., 2007). After a 24-hour delay period, results showed that the E2 treatment enhanced performance (Harburger et al., 2007). The addition of a low dose of progesterone did not alter the beneficial cognitive effects of E2 on postdelay performance, but the addition of a high dose of progesterone attenuated the beneficial cognitive effects of E2 on postdelay performance (Harburger et al., 2007). Another study from our laboratory also showed that E2 treatment had beneficial effects on overnight forgetting on the MWM task compared to vehicle control (Talboom et al., 2008). Collectively, these results reveal a protective role of E2 in cognitive function after the implementation of a delay period. The hormone impact was working memory-specific in the present study. For the spatial reference memory MWM, all treatment groups decreased in swim distance to the platform across all days of testing. However, there were no treatment differences in the swim distance to the platform, suggesting similar spatial reference memory performance on SOS response task. On the probe trial for MWM, all treatment groups swam a greater percent distance in the NE target quadrant, which previously contained the platform, compared to the opposing SW quadrant. Thus, results from the MWM task showed that all groups were able to effectively learn the spatial reference memory task and spatially localize to the platform location in a similar pattern. It is important to note that the MWM was administered after the WRAM. Some studies suggest that previous cognitive experience can impact learning and memory performance (Markowska, 2002, Talboom et al., 2014). Thus, prior learning experience may have affected learning and memory performance on the MWM in the present study and may be in part contributing to the lack of significant treatment effects on the MWM. However, these data are consistent with the lack of a treatment effect for the spatial reference memory measure of the WRAM in the present study. In the present study, we confirmed E2 exposure by showing that E2 treatment elevated circulating levels of E2 and its metabolite, estrone, relative to vehicle treatment, and by demonstrating that uterine horn weight increased with E2 treatment as compared to vehicle treatment. In women, the addition of a progestogen is meant to offset the uterine stimulation induced by estrogen, and this has been seen in rat models (Armstrong, 1968, Creasy et al., 1992, Mennenga and Bimonte-Nelson, 2015). However, in the present study, the addition of Levo to E2 treatment did not significantly reduce the E2-induced increase in uterine horn weight. This may be explained in part by the 5:1 E2 to Levo ratio used in the present study, which was based on the dose of Levo that has previously been shown to enhance spatial learning and memory when administered alone. Additional investigation is warranted to address whether decreasing the E2 to Levo ratio, including the 3:1 ratio used in Climara Pro, can significantly reduce uterine horn stimulation.