Aggressive behavior in inbred strains of mice during pregnancy

Ogawa, Sonoko; Makino, Junshiro

doi:10.1016/s0163-1047(84)90303-0

Cited by 34 publications

(14 citation statements)

References 22 publications

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“…Instead, half of ␣␤ERKO males actually showed aggression toward female mice, even though the females were indifferent. Behavioral patterns of ␣␤ERKO male aggression toward females were defensive-type and similar to those of pregnancy-induced and postpartum aggression in female mice (14). The other three genotypes of mice (␣ERKO, ␤ERKO, and ␣␤WT) exhibited sexual behaviors typical to each genotype, replicating our original findings (7,8,12).…”

Section: Resultssupporting

confidence: 77%

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Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO)

Ogawa

Chester

Hewitt

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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262

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Male mice with a knockout of the estrogen receptor (ER)-␣ gene, a ligand-activated transcription factor, showed reduced levels of intromissions and no ejaculations whereas simple mounting behavior was not affected. In contrast, all components of sexual behaviors were intact in male mice lacking the novel ER-␤ gene. Here we measure the extent of phenotype in mice that lack both ER-␣ and ER-␤ genes (␣␤ERKO). ␣␤ERKO male mice did not show any components of sexual behaviors, including simple mounting behavior. Nor did they show ultrasonic vocalizations during behavioral tests with receptive female mice. On the other hand, reduced aggressive behaviors of ␣␤ERKO mice mimicked those of single knockout mice of ER-␣ gene (␣ERKO). They showed reduced levels of lunge and bite aggression, but rarely showed offensive attacks. Thus, either one of the ERs is sufficient for the expression of simple mounting in male mice, indicating a redundancy in function. Offensive attacks, on the other hand, depend specifically on the ER-␣ gene. Different patterns of natural behaviors require different patterns of functions by ER genes.testosterone ͉ mounts ͉ intromissions ͉ ejaculation ͉ aggression I ntracellular estrogen receptors (ERs) play key roles in the neuroendocrine regulation of reproduction. Binding of ovarian steroid, estradiol, to ERs in female rodents triggers a series of molecular and neurochemical processes that lead to the induction of lordosis behavior, an essential behavioral component for successful reproduction (1). Normal expression of male reproductive behaviors also may depend on activation of ER, because the male gonadal steroid, testosterone, acts not only through androgen receptors (ARs) in its original form or 5␣-reduced form (dihydrotestosterone), but also through ERs after being aromatized to estradiol.Two types of ERs, ER␣ and ER␤, which bind to estradiol with a similar affinity, are identified in the brain (2-4). This field of work is well enough developed that we can attempt to move beyond the classical Beadle and Tatum ''one gene, one enzyme'' formulation, to discover patterns of gene activation influencing patterns of behavior.In knockout (KO) mice that lack the gene for either ER␣ (␣ERKO) or ER␤ (␤ERKO) individually (5, 6), male sexual behaviors are only partially disrupted or even virtually normal. ␣ERKO mice, although they rarely ejaculated and were infertile, showed almost normal levels of mounts and just reduced levels of intromissions (7). In contrast, all three components of sexual behaviors were present and robust in intact ␤ERKO males (8). Because earlier findings indicated some unique ovarian phenotype in double KO mice compared with either ␣ERKO or ␤ERKO (9), it was necessary to determine what pattern of behavioral deficits would appear in KO mice that lack both ER␣ and ER␤ genes (␣␤ERKO).In aromatase KO (ArKO) male mice sexual behaviors are strongly modified including the reduction of mount frequency and the prolonged mount latency (10). However, male ArKO mice are known to be fertile (11). It i...

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Section: Resultssupporting

confidence: 77%

“…2 A). Based on these characteristics (temporal changes and behavioral pattern), we concluded that these comprised defensive-type aggression, which is more typically seen in pregnant and postpartum female mice (14).…”

Section: Resultsmentioning

confidence: 93%

Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO)

Ogawa

Chester

Hewitt

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

262

167

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“…Aggressive behavioral patterns of ERKO male mice observed in homogeneous set tests were mild and short lasting, in contrast to male-typical aggression consisting of prolonged vigorous offensive attacks, including biting and wrestling. These aggressive behavioral patterns of ERKO males (i.e., lunge and bite or chase and bite) are very similar to those exhibited by genetically female mice (24). Taken Table 1).…”

Section: Discussionsupporting

confidence: 54%

Behavioral effects of estrogen receptor gene disruption in male mice

Ogawa

Lubahn

Korach

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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464

285

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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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“…1) Aggressive behavior exhibited by ERKO females con sisted mainly of offensive attacks (e.g.. mean cumulative duration ± SEM for Experiment 1: 36.2 ± 17.6 vs. 13.5 ± 13.5 s, ERKO vs. WT), typical of those seen during int er-male (male vs. male) aggression [7. 8] instead of female-typical aggressive behavioral pattern [9], Sexual Behavior. ERKO females did not show any lor dosis behavior in response to stud males.…”

Section: Resultsmentioning

confidence: 99%

Reversal of Sex Roles in Genetic Female Mice by Disruption of Estrogen Receptor Gene

et al. 1996

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Deficiency of normal estrogen receptor (ER) gene function led to behavioral change in female mice (ERKO females). Maternal behavior as measured by retrieving of pups was reduced. In some cases, pups were killed by the ERKO females, which was not seen in wild-type animals. Aggression toward other females was increased. Female-typical lordosis behavior was reduced for at least two reasons: less response to somatosensory stimuli on the hindquarters, as well as the fact that ERKO females were immediately treated as intruder males by resident ‘stud’ males and were thus attacked. In sum, disruption of the ER gene led to a pattern of hormonal and neural changes which caused the females to lose their normal female-typical behavior and to behave and be treated more like males.

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Aggressive behavior in inbred strains of mice during pregnancy

Cited by 34 publications

References 22 publications

Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO)

Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO)

Behavioral effects of estrogen receptor gene disruption in male mice

Reversal of Sex Roles in Genetic Female Mice by Disruption of Estrogen Receptor Gene

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