Elsevier

Neuroscience

Volume 119, Issue 3, 4 July 2003, Pages 821-830
Neuroscience

The cognitive effects of ovariectomy and estrogen replacement are modulated by aging

https://doi.org/10.1016/S0306-4522(03)00213-6Get rights and content

Abstract

Recent experimental and clinical studies suggest that estrogen may be an important factor influencing neuronal function during normal and pathological aging. Using different behavioral paradigms in rodents, estrogen replacement was shown to enhance learning and memory (Luine, 1997) as well as attenuate learning deficits associated with cholinergic impairment (Daniel et al., 1998). The goal of this study was to determine whether cognitive sensitivity to estrogen manipulations (short-term ovariectomy and chronic estrogen replacement) is affected by aging. Middle-aged and old female Fischer-344 rats were used to estimate the effects of estrogen manipulations at two different stages of reproductive aging. At middle age, when the females underwent an initial stage of reproductive aging (irregular cyclicity), ovariectomy did not significantly affect the acquisition of the T-maze active avoidance as compared with Sham rats, while estrogen replacement decreased behavioral vulnerability to scopolamine. However, when tested at more advanced stage of aging (consistent diestrus), old ovariectomized rats were more sensitive to scopolamine as compared with the control rats. Moreover, estrogen treatment at this age did not produce any protective effect against scopolamine. Contrasting findings of the effects of estrogen replacement in middle-aged and old rats suggest that the ability of estrogen to enhance the basal forebrain cholinergic function declines with age. These data indicate that aging processes may substantially modulate the mechanisms of estrogen action. A “time window” during which hormone replacement must be initiated in order to be effective could be determined in terms of the stages of reproductive senescence. This study is the first to clearly demonstrate that the cognitive effects of estrogen replacement are still preserved during the initial stages of reproductive aging (irregular cyclicity) and dramatically limited as aging progresses (cessation of proestrus).

Section snippets

Subjects

F344 female rats (retired breeders) were acquired from the Hiltop Laboratory Colony (Hiltop Laboratory Animals, Scottdale, PA, USA) at 12–13 (n=65) and 20 months (n=90) of age. An additional group of rats at 6 and 10 months of age (20–22 rats per age group) were received from the same source to estimate the aging-related changes in the estrus cycle by means of vaginal cytology and estrogen concentration in the plasma. Food and water were provided ad libitum. Animals with obvious health problems

Changes in the estrous cycle and in the levels of estrogen in blood with aging and in the course of estrogen withdrawal and replacement

The duration of the estrus cycle (number of days between consecutive estruses) was significantly increased between 13 and 14 and 21 months of age (F(3,53)=27.37, P<0.0001, Fig. 1). The elongation in the duration of the estrus cycle was accompanied by a significant decrease in the number of cycles that included the proestrus stage (F(3,53)=5.62, P<0.005). However, the first sign of age-related changes in the estrus cycle was already revealed between 10 and 13–14 months of age in regularity of

Discussion

In the present study, we examined the cognitive effects of ovariectomy and estrogen replacement during aging and a possible involvement of the cholinergic system in mediating these effects. By using the T-maze active-avoidance paradigm, we showed that short-term estrogen withdrawal and estrogen replacement did not affect the escape or avoidance behavior in both middle-aged and old Fischer-344 females. However, when the cholinergic system was compromised by scopolamine, both types of estrogen

Acknowledgements

This study was supported by NIA grant AG15947 to A.L.M. The authors would like to thank Drs. J. Simpkins and S. Ross for generous help with the processing of the estrogen assays, Y. Aguirre, J. L. Morton, K. Phelan, and D. Waters for their assistance with behavioral testing and J. L. Morton for editorial help.

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