Chronic estradiol replacement impairs performance on an operant delayed spatial alternation task in young, middle-aged, and old rats

Abstract

The current study examined effects of chronic estradiol replacement on a prefrontally-mediated working memory task at different ages in a rodent model. Ovariectomized young, middle-aged, and old Long-Evans rats were given 5% or 10% 17beta-estradiol in cholesterol vehicle via Silastic implants and tested on an operant delayed spatial alternation task (DSA). The two estradiol exposed groups did not perform as well as the vehicle control group did. Deficits were present at all but the longest delay, where all groups including the vehicle control group performed poorly. Surprisingly, there was not a significant effect of age or an age by estradiol interaction, despite the fact that old rats had longer latencies to respond after both correct and incorrect lever presses. These data confirm our earlier finding that chronic estradiol treatment has an impairing effect on working memory as measured on DSA task. However, contrary to expectations, young, middle-aged and old rats were similarly impaired by chronic estradiol treatment; there were no indications of differential effects at different periods of the lifespan. Also contrary to expectations, there were no indications of a decline in DSA performance with advancing age. Overall, the results demonstrate that chronic estradiol exposure causes deficits in the DSA performance of ovariectomized female rats, not only in young adulthood, but also at older ages analogous to those at which hormone replacement therapy is commonly prescribed in humans.

Figure 1

Total errors made during cued alternation in cholesterol, 5% estradiol and 10% estradiol treated rats. The middle-aged 5% estradiol replaced group committed fewer errors than did both the middle-aged vehicle and 10% estradiol replaced groups (*5% Estradiol to Cholesterol and 10% Estradiol, p<0.05). The old 5% estradiol replaced group committed more errors than did the old cholesterol replaced control group (**Cholesterol to 5% Estradiol, p<0.05). The old 5% estradiol-replaced group committed more errors than both the young and middle-aged 5% estradiol replaced groups (^Old 5% estradiol to both young and middle-aged 5% estradiol, p<0.05).

Figure 2

Proportion correct during noncued alternation training in cholesterol, 5% estradiol and 10% estradiol treated rats. The 10% estradiol replaced group performed worse on this phase of training than the cholesterol replaced control group, whereas the 5% estradiol-replaced group did not differ from the control group or the 10% group (*10% estradiol to cholesterol, p<0.05).

Figure 3a

Proportion correct during DSA across 5-day blocks of testing in cholesterol, 5% estradiol and 10% estradiol treated rats. The cholesterol control group performed better than both the 5% and 10% estradiol replaced groups for blocks 2 through 5 (*Cholesterol to both 5% estradiol and 10% estradiol, p<0.05).

Figure 3b

Proportion correct during DSA testing across five delays in cholesterol, 5% estradiol and 10% estradiol treated rats. The cholesterol replaced control group performed better than the 10% estradiol replaced group at the 0 second delay (**Cholesterol to 10% estradiol, p<0.05), and both the 5% and 10% estradiol replaced groups at the 3, 6, and 9 second delays (*Cholesterol to both 5% estradiol and 10% estradiol, p<0.05).

Figure 4a

Proportion correct during DSA testing at the 6-second delay across 5-day blocks of testing in young, middle-aged and old rats. The old rats performed better at the 6-second delay during the first three 5-day blocks of testing (*Old to both young and middle-aged rat, p<0.05).

Figure 4b

Proportion correct during DSA at the 9-second delay across 5-day blocks of testing in young, middle-aged and old rats. Although post hocs were not statistically significant, the figure indicates that the old rats performed better during the first three 5-day blocks of testing.

Figure 5a

Total win-stay errors committed during DSA testing in cholesterol, 5% estradiol and 10% estradiol treated rats. The cholesterol replaced group committed significantly fewer win-stay errors than both the 5% and 10% estradiol replaced groups (*Cholesterol to both 5% estradiol and 10% estradiol, p<0.05).

Figure 5b

Total lose-stay errors committed during DSA testing in cholesterol, 5% estradiol and 10% estradiol treated rats. The cholesterol replaced group committed significantly fewer lose-stay errors than both the 5% and 10% estradiol replaced groups (*Cholesterol to both 5% estradiol and 10% estradiol, p<0.05).

Figure 6

Total lose-stay errors committed during DSA testing in young, middle-aged and old rats. The old rats made fewer lose-stay errors than the middle-age rats (**Old to middle-aged only, p<0.05).