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. 2021 Jun 18;33(9):e13002.
doi: 10.1111/jne.13002. Online ahead of print.

Oestrogen treatment modulates the impact of cognitive experience and task complexity on memory in middle-aged surgically menopausal rats

Stephanie V Koebele  1   2 , Alicia M Quihuis  1   2 , Courtney N Lavery  1   2 , Zachary M T Plumley  1   2 , Arthur J Castaneda  1   2 , Heather A Bimonte-Nelson  1   2
Affiliations

Oestrogen treatment modulates the impact of cognitive experience and task complexity on memory in middle-aged surgically menopausal rats

Stephanie V Koebele et al. J Neuroendocrinol. .

Abstract

Menopause has been linked to changes in memory. Oestrogen-containing hormone therapy is prescribed to treat menopause-related symptoms and can ameliorate memory changes, although the parameters impacting oestrogen-related memory efficacy are unclear. Cognitive experience and practice have been shown to be neuroprotective and to improve learning and memory during ageing, with the type of task playing a role in subsequent cognitive outcomes. Whether task complexity matters, and whether these outcomes interact with menopause and oestrogen status, remains unknown. To investigate this, we used a rat model of surgical menopause to systematically assess whether maze task complexity, as well as order of task presentation, impacts spatial learning and memory during middle age when rats received vehicle, low-17β-oestradiol (E2 ) or high-E2 treatment. The direction, and even presence, of the effects of prior maze experience differed depending on the E2 dose. Surgical menopause without E2 treatment yielded the least benefit, as prior maze experience did not have a substantial effect on subsequent task performance for vehicle treated rats regardless of task demand level during the first exposure to maze experience or final testing. High-dose E2 yielded a variable benefit, and low-dose E2 produced the greatest benefit. Specifically, low-dose E2 broadly enhanced learning and memory in surgically menopausal rats that had prior experience on another task, regardless of the complexity level of this prior experience. These results demonstrate that E2 dose influences the impact of prior cognitive experience on learning and memory during ageing, and highlights the importance of prior cognitive experience in subsequent learning and memory outcomes.

Keywords: ageing; cognitive reserve; memory; menopause; oestradiol.

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Conflict of interest statement

CONFLICT OF INTERESTS

The authors declare that they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Water radial-arm maze task (WRAM) asymptotic phase performance. A-C, Working memory correct (WMC) errors across trials 2-4 of the asymptotic phase for vehicle, low-17β-oestradiol (E2), and high-E2 groups. Solid lines represent naïve subjects in each treatment group, and dashed lines represent low-demand experience subjects in each treatment group. D-F, WMC errors on the moderate working memory load trial (trial 3) only during the asymptotic phase. The low-E2 group with prior low-demand experience exhibited enhanced performance compared to the naïve low-E2 group. There was trend where the high-E2 treated group with prior low-demand experience tended to make more errors on the moderate working memory load trial the naïve high-E2 group, although this effect was statistically marginal. Data are presented as the mean ± SEM. **P < 0.01, #P < 0.10. Naïve vehicle, n = 10; naïve low-E2, n = 10; naïve high-E2, n = 9; low-demand experience vehicle, n = 11; low-demand experience low- E2, n = 10; low-demand experience high-E2, n = 10
FIGURE 2
FIGURE 2
Water radial-arm maze task (WRAM) delayed memory retention. A-F, Following a 4-hour delay between trials 2 and 3, all subjects, regardless of treatment group and prior experience, made more working memory correct (WMC) errors on trial 3 after the delay (day 13 + 14) compared to trial 3 WMC performance on the last day of baseline testing (day 12). Solid bars represent naïve subjects in each treatment group, and dashed bars represent low-demand experience subjects in each treatment group. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. Naïve vehicle, n = 10; naïve low-17β-oestradiol (E2), n = 10; naïve high-E2, n = 9; low-demand experience vehicle, n = 11; low-demand experience low-E2, n = 10; low-demand experience high-E2, n = 10
FIGURE 3
FIGURE 3
Treatment effects in naïve rats in the water radial-arm maze task (WRAM). A, B, During the asymptotic phase, the naïve low-17β-oestradiol (E2) group made more working memory correct (WMC) errors when working memory load was moderately taxed compared to naïve vehicle and naïve high-E2 groups. Further analysis of the learning phase excluding day 1, the first introduction to the maze, revealed that the naïve high-E2 group had impaired (C) working memory (WMI) and (D) reference memory (RM) compared to naïve vehicle and naïve low-E2 groups. Data are presented as the mean ± SEM. **P < 0.01, *P < 0.05, #P < 0.10. Naïve vehicle, n = 10; naïve low-E2, n = 10; naïve high-E2, n = 9
FIGURE 4
FIGURE 4
Delayed match-to-sample (DMS) day 1 only performance. Low-17β-oestradiol (E2) (B, E) and high-E2 (C, F) treated rats with prior high-demand experience made fewer errors than their naïve counterparts on trials 3-6 of DMS. A, D, G, Post hoc analysis of later trials within the first session of DMS (trials 4-6) revealed vehicle treated rats with high-demand experience made fewer errors than naïve vehicle treated rats, indicating that even with high-demand experience, ovariectomised (OVX) rats without exogenous E2 treatment required an additional platform location exposure before exhibiting enhanced performance compared to OVX rats naïve to behaviour testing. Solid bars represent naïve subjects in each treatment group, and dashed bars represent low-demand experience subjects in each treatment group. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01. Naïve vehicle, n = 11; naïve low-E2, n = 10; naïve high-E2, n = 10; high-demand experience vehicle, n = 10; high-demand experience low-E2, n = 10; high-demand experience high-E2, n = 9
FIGURE 5
FIGURE 5
Delayed match-to-sample (DMS) performance days 2-8. A-F, High-demand experienced rats treated with low-17β-oestradiol (E2) exhibited enhanced performance on trials 2-6 across all baseline testing days compared to naïve counterparts. There was a trial × experience interaction for the high-E2 treated groups where high-E2 rats with prior experience made fewer errors on earlier trials compared to naïve counterparts. Solid bars represent naïve subjects in each treatment group, and dashed bars represent low-demand experience subjects in each treatment group. Data are presented as the mean ± SEM. *P < 0.05, #P < 0.10. Naïve vehicle, n = 11; naïve low-E2, n = 10; naïve high-E2, n = 10; high-demand experience vehicle, n = 10; high-demand experience low-E2, n = 10; high-demand experience high-E2, n = 9
FIGURE 6
FIGURE 6
Delayed match-to-sample (DMS) delayed memory retention. A-D, Four-hour delays between trials 1 and 2 did not significantly impact vehicle treated rats or low-17β-oestradiol (E2) treated rats regardless of prior testing experience. E, F, High-E2 treated rats committed more total errors prior to locating the platform on the post-delay trial compared to baseline. This observation is likely resultant of lower errors on the last day of baseline testing, which exacerbated the observed difference in error scores on the post-delay trial. Solid bars represent naïve subjects in each treatment group, and dashed bars represent low-demand experience subjects in each treatment group. Data are presented as the mean ± SEM. **P < 0.01. naïve vehicle, n = 11; naïve low-E2, n = 10; naïve high-E2, n = 10; high-demand experience vehicle, n = 10; high-demand experience low-E2, n = 10; high-demand experience high-E2, n = 9
FIGURE 7
FIGURE 7
A, Body weights. Body weight (g) increased for all subjects between ovariectomy (OVX) and pump insertion time points. Following vehicle or 17β-oestradiol (E2) treatment initiation, OVX rats treated with low-E2 or high-E2 decreased body weights compared to OVX-vehicle treated rats. This difference persisted through the end of the experiment. B, Uterine wet weights at euthanasia. All groups were OVX. The low-E2 and high-E2 treated rats exhibited significantly heavier uterine wet weights at death compared to the vehicle treated rats, but there was no statistical difference in weight between E2 groups. Data are presented as the mean ± SEM. ****P < 0.0001. Vehicle, n = 21; low-E2, n = 20; high-E2, n = 19
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