Estradiol facilitates performance as working memory load increases
Introduction
Ovarian hormones exert activational (transient) effects on cognition in both rodents (Burke and Broadhurst, 1966, Diaz-Veliz et al., 1989, Farr et al., 1995, Frye, 1994, Galea et al., 1995, Luine and Rodriguez, 1994, Markus and Zecevic, 1997, Warren and Juraska, 1997) and humans (Chiarello et al., 1989, Fedor-Freybergh, 1977, Hampson, 1990a, Hampson, 1990b, Hampson and Kimura, 1988, Hartley et al., 1987, Kimura and Hampson, 1994, Komnenich et al., 1978, Phillips and Sherwin, 1992b, Silverman and Phillips, 1993). These data were derived mainly from studies assessing performance across the estrous cycle and the menstrual cycle. In addition, estrogen replacement ameliorates some deficits in memory and cognitive function associated with the menopause in women (Caldwell and Watson, 1952, Kampen and Sherwin, 1994, Phillips and Sherwin, 1992a, Robinson et al., 1994, Sherwin, 1988, Sherwin, 1994). Estradiol replacement also improves the performance of adult ovariectomized rats in various learning and memory tasks including active avoidance (Singh et al., 1994), a 2-choice working memory task (O'Neal et al., 1996), and the radial-arm maze (Daniel et al., 1996, Luine et al., 1996, Williams, 1996).
Studies utilizing the radial-arm maze compared the performance of adult ovariectomized female rats to those given estrogen replacement following ovariectomy (Daniel et al., 1996, Luine et al., 1996, Williams, 1996). However, these groups were not compared to intact, cycling females. Thus, the extent to which estrogen replacement improves the performance of ovariectomized subjects relative to intact females is not known. Further, these studies assessing estrogen replacement utilized the conventional radial-arm maze, which relies on food reinforcement. Because an animal’s hormonal state can affect food-seeking behavior, food intake and taste preferences in the rat (Bell and Zucker, 1971, Wade, 1972, Work and Rogers, 1972), studies using food reinforcement may be confounded by differences in food motivation.
We sought to investigate estrogen’s activational effects on spatial working memory without using food reinforcement. We compared the performance of ovariectomized subjects to those receiving low or moderate dose estradiol on a non-appetitively motivated, water-escape version of the radial-arm maze (Bimonte and Denenberg, 1997, Hyde et al., 1996, Hyde et al., 1998). In addition, we compared these estrogen replacement groups to cycling, intact females.
In the radial-arm maze procedure, an animal must avoid the arms in which it had previously found a reward (re-entry into a previously reinforced arm is counted as an error). As an animal progresses through a session, the number of previously reinforced choices it has made increases. Therefore, the ability to handle an increasing working memory load is required to perform successfully. In their landmark radial-arm maze paper, Olton and Samuelson (1976) hypothesized that the decrement in performance that occurred as an animal progressed through a session was ‘due to interference from previous choices and not just the passage of time’ (p. 113). Because radial-arm maze data are typically summed over choices (or trials) within a session, the assessment of group differences in the ability to handle an increase in working memory information has not been addressed. Our procedure utilizes discrete trials. Therefore, we were able to investigate how estrogen affects the ability to handle an increase in working memory information.
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Subjects and hormone treatments
The subjects were 40 female Purdue–Wistar rats bred in our closed colony. At birth, ten litters were culled to six females and two males. Following weaning on day 21, animals were housed in same-sex littermate pairs. Subjects had free access to food and water.
In adulthood, four females from each litter were randomly chosen. Under Ketaset–Rompun anesthesia, three females from each litter were ovariectomized and the remaining female received sham surgery. For ovariectomy, two dorsolateral
Body weights and vaginal smears
Mean body weights of the treatment groups, taken approximately 2 weeks after surgery, are shown in Table 1. Analysis of variance (ANOVA) found a significant main effect of treatment (F[3,36]=16.59; p<.001). As expected, Ovx females weighed the most, followed by the Sham, moderate E, and low E groups (Bell and Zucker, 1971, Wade, 1972). Vaginal smears revealed that all Ovx females exhibited a diestrous-like smear, whereas all moderate and low E females exhibited an estrous-like smear. Taken
Discussion
Despite motivational differences between our water maze and the conventional land maze that others have used (Daniel et al., 1996, Luine et al., 1996, Williams, 1996), these results demonstrate that estradiol enhances spatial working memory performance and can ameliorate the decrement in memory function associated with ovariectomy in female rats. Specifically, we found that moderate E females made fewer errors than Sham, Ovx, and low E females over the last 5 days of testing.
As trials
Acknowledgements
The authors wish to thank Dr Bruce Goldman for his expert technical advice, Kai Syvertsen for his technical assistance, Dr Robert McGivern for performing the estradiol radioimmunoassays, and Dr R. Holly Fitch for her invaluable comments on this manuscript.
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