Behavioral analysis of genetically modified mice indicates essential roles of neurosteroidal estrogen.
Behavioral analysis of genetically modified mice indicates essential roles of neurosteroidal estrogen.
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DOI：
10.3389/fendo.2011.00040
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发表时间：
2011
影响因子：
5.2
通讯作者：
Harada N
中科院分区：
文献类型：
--
作者：
Honda S;Wakatsuki T;Harada N
小鼠脑中的芳香化酶仅在特定脑区的神经细胞中表达，在新生期性行为变得有组织时具有短暂的峰值。芳香化酶敲除（ArKO）小鼠，揭示了雌激素在大脑中的生理功能，表现出各种异常的行为，伴随着不可检测的雌激素和血液中雄激素的增加。为了进一步阐明神经甾体雌激素对行为表型的影响，我们首先通过将受小鼠芳香化酶基因脑特异性启动子的-6.5 kb上游区域控制的人芳香化酶转基因导入受精小鼠卵中来制备脑特异性芳香化酶转基因（bsArTG）小鼠，这是因为先前显示-6.5 kb启动子区域包含负责脑特异性时空表达的最小必需元件。然后，通过将bsArTG小鼠与ArKO小鼠杂交，产生了仅在大脑中表达人芳香酶的ArKO小鼠。所得小鼠（ArKO/bsArTG小鼠）几乎从异常的性行为、攻击性行为和运动（探索性）行为中恢复，尽管其血清雌激素和雄激素水平与成年ArKO小鼠几乎相同。这些结果表明，雌激素局部合成的特定神经元的围产期小鼠大脑直接作用于神经元，并在参与控制性，攻击性和机车（探索）行为的神经元网络的组织中发挥至关重要的作用。
Aromatase in the mouse brain is expressed only in the nerve cells of specific brain regions with a transient peak during the neonatal period when sexual behaviors become organized. The aromatase-knockout (ArKO) mouse, generated to shed light on the physiological functions of estrogen in the brain, exhibited various abnormal behaviors, concomitant with undetectable estrogen and increased androgen in the blood. To further elucidate the effects of neurosteroidal estrogens on behavioral phenotypes, we first prepared an brain-specific aromatase transgenic (bsArTG) mouse by introduction of a human aromatase transgene controlled under a −6.5 kb upstream region of the brain-specific promoter of the mouse aromatase gene into fertilized mouse eggs, because the −6.5 kb promoter region was previously shown to contain the minimal essential element responsible for brain-specific spatiotemporal expression. Then, an ArKO mouse expressing the human aromatase only in the brain was generated by crossing the bsArTG mouse with the ArKO mouse. The resulting mice (ArKO/bsArTG mice) nearly recovered from abnormal sexual, aggressive, and locomotive (exploratory) behaviors, in spite of having almost the same serum levels of estrogen and androgen as the adult ArKO mouse. These results suggest that estrogens locally synthesized in the specific neurons of the perinatal mouse brain directly act on the neurons and play crucial roles in the organization of neuronal networks participating in the control of sexual, aggressive, and locomotive (exploratory) behaviors.