Environmental enrichment reduces the mnemonic and neural benefits of estrogen.

The degree to which memory is enhanced by estrogen replacement in postmenopausal women may depend on environmental factors such as education. The present study utilized an animal model of environmental enrichment to determine whether environmental factors influence the mnemonic and neural response to estrogen. Female mice were raised in standard (SC) or enriched (EC) conditions from weaning until adulthood (7 months). All mice were ovariectomized at 10 weeks, and tested in object recognition and water-escape motivated radial arm maze (WRAM) tasks at 6 months. Each day at the completion of training, mice received injections of 0.1 mg/kg cyclodextrin-encapsulated 17-beta-estradiol (E2), 0.2 mg/kg E2, or cyclodextrin vehicle (VEH). At the completion of behavioral testing, hippocampal levels of the presynaptic protein synaptophysin and of brain-derived neurotrophic factor (BDNF) were measured. Enrichment effects were evident in VEH-treated mice; relative to SC-VEH females, EC-VEH females committed fewer working memory errors in the WRAM and exhibited increased hippocampal synaptophysin levels. Estrogen effects depended on environmental conditions. E2 (0.2 mg/kg) improved object memory only in SC females. The same dose improved working memory in SC females, but somewhat impaired working memory in EC females. Furthermore, both doses reduced hippocampal synaptophysin levels in EC, but not SC, females. In contrast, E2 reduced hippocampal BDNF levels in SC, but not EC, females. This study is the first to compare the effects of estrogen on memory and hippocampal function in enriched and non-enriched female mice. The results suggest that: (1) estrogen benefits object and working memory more in mice raised in non-enriched environments than in those raised in enriched environments, and (2) the changes induced by estrogen and/or enrichment may be associated with alterations in hippocampal synaptic plasticity.