Roles of estrogen receptor-alpha gene expression in reproduction-related behaviors in female mice.

The role of gene expression of the estrogen receptor-alpha form (ER alpha) in the regulation of female reproductive behavior was investigated in estrogen receptor knockout (ERKO) mice, deficient specifically for the ER alpha, but not the ER beta, gene. Estrogen- or estrogen- plus progesterone-treated gonadectomized ERKO mice did not show any lordosis response. Detailed behavioral analysis revealed that ERKO females were also deficient in sexual behavioral interactions preceding the lordosis response. They were extremely rejective toward attempted mounts by stud male mice, which could not show any intromissions. During resident-intruder aggression tests, gonadally intact ERKO females were more aggressive toward female intruder mice than wild-type (WT) mice. Gonadectomy did not influence the levels of aggressive behavior, and their genotype differences when mice were tested both before and after gonadectomy. However, when mice were tested after gonadectomy for the first time, very few ERKO mice showed aggression. In contrast to aggression, male-type sexual behavior shown by resident mice toward female intruder mice during aggression tests was not different between ERKO and WT mice and was completely abolished after gonadectomy of the resident mice. Finally, it was also found that ERKO females showed greatly reduced levels of parental behavior toward newborn pups placed in their home cage. These changes in parental behavior were not influenced by gonadectomy. ERKO females retrieved significantly fewer numbers of pups with longer latencies compared with wild-type (WT) or heterozygous (HZ) littermates when they were tested as gonadally intact or 20-65 days after gonadectomy. In addition, during parental behavior tests, a significantly higher percentage of ERKO mice exhibited infanticide compared with WT and HZ mice, which rarely showed infanticide. Taken together, these findings suggest that ER alpha gene expression plays a key role in female mice, not only for sexual behavior but also for other interrelated behaviors, such as parental and aggressive behaviors. In addition, persistence of genotype differences in parental and aggressive behavior after gonadectomy indicates that ER alpha activation during neural developmental processes may also be involved in the regulation of these behaviors.

[1]  J. Herndon,et al.  Neonatal estrogen stimulation nd aggressive behavior in female mice. , 1970, Physiology & behavior.

[2]  R. Gandelman,et al.  Postpartum aggression in mice: Inhibitory effect of estrogen , 1975, Physiology & Behavior.

[3]  B. Svare.  Steroidal influences on pup-killing behavior in mice , 1979, Hormones and Behavior.

[4]  B. Svare,et al.  Pup-killing behavior in mice: Suppression by early androgen exposure , 1981, Physiology & Behavior.

[5]  Variation in infanticide and parental behavior in male mice due to prior intrauterine proximity to female fetuses: elimination by prenatal stress. , 1983, Physiology & behavior.

[6]  F. S. Saal.  Variation in infanticide and parental behavior in male mice due to prior intrauterine proximity to female fetuses: Elimination by prenatal stress , 1983, Physiology & Behavior.

[7]  B. Svare,et al.  Infanticide exhibited by female mice: Genetic, developmental and hormonal influences , 1983, Physiology & Behavior.

[8]  Ching-tse Lee,et al.  Pheromonal Influence on Aggressive Behavior , 1983 .

[9]  K. Miczek,et al.  Aggression persists after ovariectomy in female rats , 1984, Hormones and Behavior.

[10]  B. Svare,et al.  Infanticide: Accounting for genetic variation in mice , 1984, Physiology & Behavior.

[11]  R. E. Whalen,et al.  Induction of male-typical aggression by androgens but not by estrogens in adult female mice , 1985, Hormones and Behavior.

[12]  R. E. Whalen,et al.  Sexual differentiation of androgen-sensitive and estrogen-sensitive regulatory systems for aggressive behavior , 1987, Hormones and Behavior.

[13]  Y. Delville.  Progesterone-facilitated sexual receptivity: A review of arguments supporting a nongenomic mechanism , 1991, Neuroscience & Biobehavioral Reviews.

[14]  N. Simon,et al.  Timing of neonatal testosterone exposure in the differentiation of estrogenic regulatory systems for aggression , 1991, Physiology & Behavior.

[15]  J. Koolhaas,et al.  Differential lateral septal vasopressin innervation in aggressive and nonaggressive male mice , 1993, Brain Research Bulletin.

[16]  K. Korach,et al.  Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[17]  K. Lagerspetz,et al.  Effects of Testosterone Exposure and Fighting Experience on the Aggressive Behavior of Female and Male Mice Selectively Bred for Intermale Aggression , 1994, Hormones and Behavior.

[18]  K. Korach,et al.  Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. , 1995, Molecular endocrinology.

[19]  D. Pfaff,et al.  Effects of Testosterone and 7α-Methyl-19-Nortestosterone (MENT) on Sexual and Aggressive Behaviors in Two Inbred Strains of Male Mice , 1996, Hormones and Behavior.

[20]  K. Korach,et al.  Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. , 1996, Recent progress in hormone research.

[21]  J. Polman,et al.  ER beta: identification and characterization of a novel human estrogen receptor. , 1996, FEBS letters.

[22]  D. Pfaff,et al.  Reversal of sex roles in genetic female mice by disruption of estrogen receptor gene. , 1996, Neuroendocrinology.

[23]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Gustafsson,et al.  Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. , 1997, Endocrinology.

[25]  I. Merchenthaler,et al.  The Distribution of Estrogen Receptor-β mRNA in Forebrain Regions of the Estrogen Receptor-α Knockout Mouse. , 1997, Endocrinology.

[26]  P. Shughrue,et al.  Comparative distribution of estrogen receptor‐α and ‐β mRNA in the rat central nervous system , 1997, The Journal of comparative neurology.

[27]  K. Korach,et al.  Responses in the brain of estrogen receptor alpha-disrupted mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  K. Korach,et al.  Estrogen receptors are essential for female sexual receptivity. , 1997, Endocrinology.

[29]  K. Korach,et al.  Developmental and Physiological Effects of Estrogen Receptor Gene Disruption in Mice , 1997, Trends in Endocrinology & Metabolism.

[30]  K. Korach,et al.  Tissue Distribution and Quantitative Analysis of Estrogen Receptor-α (ERα) and Estrogen Receptor-β (ERβ) Messenger Ribonucleic Acid in the Wild-Type and ERα-Knockout Mouse. , 1997, Endocrinology.

[31]  D. Pfaff,et al.  Behavioral effects of estrogen receptor gene disruption in male mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Julia A. Taylor,et al.  Estrogen Receptor Function as Revealed by Knockout Studies: Neuroendocrine and Behavioral Aspects , 1997, Hormones and Behavior.

[33]  I. Merchenthaler,et al.  The distribution of estrogen receptor-beta mRNA in forebrain regions of the estrogen receptor-alpha knockout mouse. , 1997, Endocrinology.

[34]  N. Copeland,et al.  Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. , 1997, Molecular endocrinology.

[35]  B. McEwen,et al.  Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Pfaff,et al.  Modifications of testosterone-dependent behaviors by estrogen receptor-alpha gene disruption in male mice. , 1998, Endocrinology.

[37]  J. Gustafsson,et al.  Cloning of a novel estrogen receptor expressed in rat prostate and ovary , 2022 .