ROLE OF ALPHA & BETA ESTROGEN RECEPTORS IN AGGRESSION

阿尔法的作用

• 批准号: 6528847
• 负责人: SONOKO OGAWA
• 金额: $ 33.4万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528847
• 关键词: aggression; behavioral /social science research tag; estrogen receptors; gender difference; gene targeting; genetically modified animals; hormone metabolism; hormone regulation /control mechanism; inhibitor /antagonist; laboratory mouse; posttranslational modifications; receptor sensitivity; testosterone

DESCRIPTION: (Adapted from the Investigator's Abstract) It has been well established that testosterone facilitates aggression during social conflict, typically seen between male mice. Testosterone exerts its neural action not only by activating androgen receptors (AR), as its original form or as 5alpha-reduced metabolite, dihydrotesterone, but also by acting through estrogen receptors (ER), after being aromatized to estradiol. It has been previously described that activation of ER at the time of testing as well as during perinatal development plays a critical role in the induction of aggressive behavior in male mice and determines the sex differences in the levels of testosterone-inducible aggression. Two forms of ERs, a classical ER-alpha and a recently discovered ER-beta, are localized in the brain areas known to be involved in testosterone-inducible aggression. The main objective of the proposed studies is to determine the specific roles played by ER-alpha and ER-beta in the regulation of aggressive behavior. In the first part, we will determine the role of ER-beta activation, at the time of testing in adulthood, in the regulation of aggressive behavior of MALE mice by: 1) comparing the levels of estrogen-inducible aggression of ER-beta gene knockout (BERKO) mice (ER-alpha specific activation) with those of their wild type littermates (BWT; ER-alpha and ER-beta activation); and 2) examining the effects of an ER-beta specific agonist on aggressive behavior induced by an ER-alpha specific agonist or an AR-specific agonist in WT male mice. In the second part of the proposal, we will determine the roles of ER-alpha and ER-beta in testosterone-inducible aggression (toward male intruder mice) in FEMALE mice. The effects of testosterone treatment will be tested in three types of knockout mice: ER-alpha knockout (aERKO), BERKO, and double knockout of ER-alpha and ER-beta genes (dERKO). In the third part of the proposal, the possibility will be tested that aERKO FEMALE mice are "endogenously" sensitized for testosterone-inducible aggression by elevated levels of testosterone as a result of ER-alpha gene disruption. In the last part, we will test the hypothesis that neonatal ER-alpha, but not ER-beta, activation determines the responsiveness to aggression-promoting action of testosterone and its metabolites in adulthood, by manipulating neonatal steroid levels in FEMALE mice. The findings of the proposed studies will provide new insights concerning the specific roles and mechanisms played by the two types of ERs in the sex-specific regulation of aggressive behavior by gonadal steroids.

描述：（改编自研究者摘要） 确定了睾丸激素在社会冲突中促进攻击性， 通常出现在雄性小鼠之间。睾丸激素发挥其神经作用， 仅通过激活雄激素受体（AR），作为其原始形式或作为 5 α-还原代谢物，二氢睾酮，但也通过作用， 雌激素受体（ER），芳香化后的雌二醇。已经 先前描述了在测试时ER的激活以及 在围产期发育中起着关键作用， 雄性小鼠的攻击行为，并决定了性别差异， 睾丸激素诱导的攻击性两种形式的ER，一种经典的 ER-α和最近发现的ER-β都位于大脑区域， 与睾丸激素诱导的攻击性有关主要目标 这项研究的目的是确定ER-α所起的具体作用， 和ER-β在攻击行为的调节中的作用。 在第一部分中，我们将确定ER-β激活的作用， 在成年期测试的时间，在男性的攻击行为的调节 通过：1）比较雌激素诱导的ER-β攻击的水平 基因敲除（BERKO）小鼠（ER-α特异性激活）与其 野生型同窝仔（BWT; ER-α和ER-β活化）;和2）检查 雌激素受体β特异性激动剂对由一种 ER-α特异性激动剂或AR特异性激动剂。在 在提案的第二部分，我们将确定ER-α的作用， 雌激素受体β在睾丸激素诱导的攻击（对雄性入侵小鼠）中的作用 雌性小鼠。睾酮治疗的效果将在三个测试 敲除小鼠的类型：ER-α敲除（aERKO）、BERKO和双敲除 ER-α和ER-β基因（dERKO）。在建议的第三部分， 将测试aERKO雌性小鼠“内源性”致敏的可能性 睾丸激素诱导的攻击性，通过睾丸激素水平的升高， ER-α基因破坏的结果。在最后一部分，我们将测试 假设新生儿ER-α而不是ER-β激活决定了 对睾酮的攻击促进作用的反应性及其 通过操纵雌性动物的新生儿类固醇水平， 小鼠 拟议研究的结果将提供有关 这两类环境要求在环境保护方面发挥的具体作用和机制 性腺类固醇对攻击行为的性别特异性调节。