Sex with knockout models: behavioral studies of estrogen receptor alpha

Estrogens are an important class of steroid hormones, having multiple targe ts, in the body and brain, and exerting ubiquitous effects on behavior. At present, two estrogen receptors (ER alpha and beta) have been cloned and se quenced in mammals. In the brain these receptors are regionally specific, b ut both have widespread distributions, which are largely non-overlapping. G iven the newly emerging complexities of estrogen's mechanisms of action it is important to distinguish which pathways are involved in modifying which behaviors. We use a knockout mouse, lacking functional copies of the estrog en receptor alpha (ER alpha) gene, to study the mechanisms by which estroge ns mediate behaviors. There are pronounced ramifications of ER alpha gene d isruption on behavior. First, female ER alpha knockout (ER alpha KO) mice d o not display normal feminine sexual behavior. Second, treatment of adult m ice with androgens promotes masculine sexual behavior in both sexes. Howeve r, male-typical sexual behavior is severely compromised in male and female ER alpha KOs. Third, male ER alpha KOs do not exhibit the same social prefe rences for female mice as do wildtype (WT) littermates. Thus, the ER alpha is essential for normal expression of sexual behaviors. In addition, gonade ctomized ER alpha KO and WT mice rapidly learn to escape from the Morris wa ter maze. Exogenous estrogen treatment prevents WT females from learning th is task, yet, has no effect in ER alpha KO mice, suggesting that estrogens effects on learning in adult females involves the ER alpha. Based on these data we hypothesize that ER alpha mediates many of the effects of estrogen on sexual behavior, learning, and memory. (C) 1999 Elsevier Science B.V. Al l rights reserved.