Roles of estrogen receptors α and β in differentiation of mouse sexual behavior

doi:10.1016/j.neuroscience.2005.10.018

Neuroscience

Volume 138, Issue 3, 27 March 2006, Pages 921-928

https://doi.org/10.1016/j.neuroscience.2005.10.018 Get rights and content

Abstract

Sex differences in brain and behavior are ubiquitous in sexually reproducing species. Developmental differences in circulating concentrations of gonadal steroids underlie many sexual dimorphisms. During the late embryonic and early perinatal periods, the testes produce androgens, thus, male brains are exposed to testosterone, and in situ testosterone is aromatized to estradiol. In contrast, females are not exposed to high concentrations of testosterone or estradiol until puberty. In many species, neural sex differences and sexually dimorphic behaviors in adults are initiated primarily by estradiol exposure during early development. In brain, estradiol activates two independent processes: masculinization of neural circuits and networks that are essential for expression of male-typical adult behaviors, and defeminization, the loss of the ability to display adult female-typical behaviors. Here, data for the roles of each of the known estrogen receptors (estrogen receptor α and estrogen receptor β) in these two processes are reviewed. Based on work done primarily in knockout mouse models, separate roles for the two estrogen receptors are suggested. Estrogen receptor α is primarily involved in masculinization, while estrogen receptor β has a major role in defeminization of sexual behaviors. In sum, estradiol can have selective effects on distinct behavioral processes via selective interactions with its two receptors, estrogen receptor α and estrogen receptor β.

Section snippets

Sexual dimorphisms and interactions between ERα and ERβ

In mouse embryos ERβ mRNA is measurable in brain starting at E10.5, prior to gonadal differentiation. Expression of ERα is noted first at E16.5 (Lemmen et al., 1999). Sex differences in ERα and ERβ have been demonstrated in neonatal and adult brains. In the rat mPOA and bed nucleus of the stria terminalis, ERα binding is greater in females than in males during several embryonic and perinatal time points (Kuhnemann et al., 1994). In situ hybridization in rat embryos reveals signal for ERα

Role for ERα in masculine behavior

In the first report on an engineered mouse strain with a permanent disruption of the ERα gene, the male KO mice were described as subfertile, with lower testes weights and reduced sperm counts as compared with wild type (WT) littermates (Lubahn et al., 1993). Subsequent studies of the male reproductive system described elevated T, normal LH levels, and a reduced ability of ERαKO males to sire litters and/or deposit sperm plugs when paired with females (Eddy et al 1996, Rissman et al 1997b).

Role for ERβ in masculine behavior

The first report of an engineered ERβKO mouse describes a normal reproductive tract and fertility in males (Krege et al., 1998). In contrast to ERα, the lack of functional ERβ does not impair normal expression of adult masculine sexual behavior or olfactory preference in testes-intact male mice (Ogawa et al 1999, Temple et al 2003, Kudwa et al 2005). When standard tests for male sexual behavior were performed, adult WT and ERβKO males showed equivalent latencies to perform the various

Role for ERβ in defeminization

The hypothesis that ERα and ERβ play different roles in defeminization cannot be tested in ERαKO mice. ERα is required for induction of progestin receptors which in turn are critical for the demonstration of lordosis (Olster and Blaustein 1988, Mani 2003, Kudwa et al 2004). Thus testing ERαKO males, or females, for feminine sexual behavior likely will not be effective because they lack the PR needed to express adult female sexual receptivity. On the other hand ERβKO female mice display normal

Summary, implications and future directions

The data presented here reinforce the hypothesis that masculinization and defeminization are separate neural processes. This has been illustrated before, for example, female rat pups infused with prostaglandin E2 (PGE2) on the day of birth have masculinized adult sexual behavior when given the appropriate adult hormone treatments and testing regimen. Likewise, inhibition of PGE2 in male pups disrupts their normal adult copulatory behavior (Amateau and McCarthy, 2004), yet males with disrupted

Conclusion

In summary, we hypothesize that ERβ plays an essential role in sexual differentiation of brain and behavior. Whether defeminization also requires ERα is not clear, but interactions between the two receptors within several brain nuclei, including those involved in sexual behavior, have been well-documented (Temple et al 2001, Lindberg et al 2003, Nomura et al 2003). In the future we hope to identify the substrates that underlie the defeminization process by targeting neurons containing ERβ

Acknowledgments

The author is grateful to Ms. Savera Sheety and Ms. Aileen Wills for expert technical assistance. This work was supported by NIH awards R01 MH57759 and K02 MH01349 (E.F.R.), A.E.K. was supported by F31 MH70092.

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Roles of estrogen receptors α and β in differentiation of mouse sexual behavior

Abstract

Section snippets

Sexual dimorphisms and interactions between ERα and ERβ

Role for ERα in masculine behavior

Role for ERβ in masculine behavior

Role for ERβ in defeminization

Summary, implications and future directions

Conclusion

Acknowledgments

Brain Res Bull

Brain Res Bull

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Brain Res Dev Brain Res

Physiol Behav

Brain Res

Horm Behav

Brain Res

Brain Res Bull

Neurobiol Learn Mem

Neuropharmacology

Brain Res Bull

Behav Brain Res

Horm Behav

Brain Res Dev Brain Res

Horm Behav

Brain Res

Brain Res

Brain Res

Behav Brain Res

Horm Behav

Horm Behav

Psychoneuroendocrinology

Mech Dev

Behav Brain Res

Horm Behav

Brain Res Mol Brain Res

Physiol Behav

Horm Behav

Brain Res

Brain Res Dev Brain Res

Horm Behav

Physiol Behav

Pharmacol Biochem Behav

Brain Res Dev Brain Res

Horm Behav

Brain Res

Brain Res

Horm Behav

Neurosci Lett

Psychoneuroendocrinology

Horm Behav

Horm Behav

Brain Res Dev Brain Res

Brain Res

Sexual differentiation of brain and behavior in the zebra finchcritical periods for effects of early estrogen treatment

J Neurobiol

Two sexually dimorphic cell groups in the human brain

J Neurosci

Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior

Nat Neurosci