Behavioral effects of estrogen receptor gene disruption in male mice

Abstract

Gonadal steroid hormones regulate sexually dimorphic development of brain functions and behaviors. Their nuclear receptors offer the opportunity to relate molecular events in neurons to simple instinctive mammalian behaviors. We have determined the role of estrogen receptor (ER) activation by endogenous estrogen in the development of male-typical behaviors by the use of transgenic estrogenreceptor-deficient (ERKO) mice. Surprisingly, in spite of the fact that they are infertile, ERKO mice showed normal motivation to mount females but they achieved less intromissions and virtually no ejaculations. Aggressive behaviors were dramatically reduced and male-typical offensive attacks were rarely displayed by ERKO males. Moreover, ER gene disruption demasculinized open-field behaviors. In the brain, despite the evident loss of functional ER protein, the androgendependent system appears to be normally present in ERKO mice. Together, these findings indicate that ER gene expression during development plays a major role in the organization of male-typical aggressive and emotional behaviors in addition to simple sexual behaviors.It is well established that gonadal steroid hormones, by acting on the central nervous system, regulate various neuroendocrine events related to reproduction and reproductive behaviors in both sexes. In males, testosterone is a major hormone that facilitates both sexual and aggressive behaviors. The mechanisms underlying the behavioral effects of testosterone, however, are complicated by the fact that endogenous testosterone can act not only through the androgen receptor (AR) as can testosterone metabolite (5␣-reduced dihydrotestosterone), but also can act through estrogen receptors (ER) after being aromatized to estradiol in the target tissues including the brain. The relative importance of AR and ER in the facilitation of male sexual behaviors by testosterone has been studied (1, 2), but a clear role for ER gene expression needs to be determined.Aggressive behaviors in male mice can be regulated in adulthood by both AR-and ER-dependent mechanisms depending on the genotype of the animals (3). Some evidence for the involvement of estrogen-dependent mechanisms in male aggressive behaviors has been obtained by comparing relative efficiencies of testosterone, dihydrotestosterone, and estrogen (4, 5) and by concurrent injection of an aromatase inhibitor with testosterone (6, 7). These findings, however, do not provide direct evidence for the role of the ER gene product itself. Furthermore, the antiestrogen tamoxifen gave inconsistent behavioral effects; both inhibitory (8) and facilitatory (9) effects on aggression in male mice have been reported. Until recently, there was never a direct way to manipulate endogenous steroid receptor function to determine the behavioral role of ER.This became possible through the development of ERdeficient mutant mice (ERKO) by the use of homologous recombination techniques (10-12) .Using ERKO mice, we have assessed more directly the role of ER gene-dependent brai...

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