Effects of exercise and transient estradiol exposure in middle-aged female rats.

The benefits of estrogen treatment on cognition in middle-aged and older women are dependent on many factors, including the timing of treatment. Moreover, the potential interactive effects with other lifestyle factors, such as exercise, are poorly understood. In this study, we tested for lasting benefits of independent and combined treatment with estrogen and voluntary exercise initiated in midlife, using a rat model of menopause. Twelve-month-old, retired female breeders were bilaterally ovariectomized and received six weeks of 17β-estradiol (E2) treatment via subcutaneous implant, with or without access to running wheels. After E2 treatment, animals in the exercise groups had running wheel access for seven additional weeks, including a two-week period of cognitive and affective testing. Thereafter, hippocampal neuronal and cellular plasticity were assessed. E2 and exercise independently exerted effects on behavioral and cellular outcome measures. Transient E2 treatment enduringly increased motor output, lowered body weight, and increased behavioral plasticity. Exercise decreased total hippocampal microglia number and increased brain weight. No additive effects of exercise and E2 treatment were observed. E2 treatment may provide a means by which to enduringly increase physical activity in middle age, but combined E2 and exercise do not produce additive benefits on hippocampal behavioral or cellular plasticity.