Physiological property of estrogen-HEADreceptor positive hypothalamic neurons visualized in transgenic rats

雌激素参与大脑发育过程中的内分泌和行为性别分化，以及成年后生殖神经内分泌和行为的性别特异性调节。细胞雌激素信号传导通过核雌激素受体（ER）进行，其包括经典的ERα以及最近克隆的ERβ。这两种ER均表达于视前区（POA）、下丘脑、边缘系统等结构，这些结构与生殖调控有关。然而，ERβ是否像ERα一样具有性别特异性表达仍存在争议。两种ER在同一神经元中的共定位也尚未确定，这将通过形成异源二聚体来改变转录的特异性，并根据它们所含的ERα和ERβ的比例在不同细胞中产生对雌激素的不同反应。雌、雄雌激素受体α基因敲除小鼠均表现为易发性，雌激素受体β基因敲除小鼠均表现为易发性。 ...更多信息 雌性的生殖力降低。ERα或ERβ基因敲除的雌性动物均存在不排卵和出血性或多囊卵巢。该综合征至少部分是由于促性腺激素释放激素（GnRH）分泌的中枢机制，因为几种减少促性腺激素分泌的方案可以改善缺陷。雌激素对雌激素α破坏的雌性和雄性小鼠促性腺激素分泌的负反馈作用受到损害，但雌激素可以诱导雄性阉割小鼠POA中的孕激素受体，推测是通过雌激素β诱导的。雌激素诱导的孕激素受体作为一种神经元转录因子，通过改变参与GnRH神经元调节的神经递质的合成或活性，在雌性大鼠体内触发GnRH峰。POA的前腹侧室周核（AVPV）中的孕酮受体可能特别重要。AVPV具有性二态性，雌性大鼠的多巴胺能神经元是雄性大鼠的3倍多。AVPV还含有肽能神经元或谷氨酸受体亚单位的性二态群体，并且通过其直接投射到GnRH神经元而与雌性特异性GnRH排卵释放有关。事实上，局限于该区域的小病变阻断了雌性大鼠促性腺激素的周期性释放，并最终导致无排卵、持续性发情状态。在AVPV附近的第三脑室注射孕酮受体反义寡核苷酸阻断受体蛋白的诱导，阻止促黄体生成激素的激增。我们发现AVPV中ERβ的表达存在显著的性别差异。ERβ mRNA共定位于84%的雌激素ERα免疫阳性细胞中，可能具有多巴胺能的性质。将ERβ反义寡核苷酸注入AVPV附近的第三脑室，减少ERβ蛋白，并产生恒定的阴道间情期。少

Estrogens are involved in both endocrine and behavioral sex differentiation during brain development and sex-specific regulation of reproductive neuroendocrinology and behavior in adulthood. Cellular estrogen signaling is conveyed by nuclear estrogen receptors (ER) which include the classical ERα as well as the recently cloned ERβ. Both ERs are expressed in the preoptic area (POA), hypothalamus, limbic structures, which have been implicated in the regulation of reproduction. It is controversial, however, whether ERβ is expressed in sex-specific manner like ERα. Co-localization of the two ERs in identical neurons, which would alter the specificity of the transcription by forming heterodimers and produce variable responses to estrogen in different cells depending on the ratios of ERα and ERβ they contain, is also yet to be established.Disruption of either ERα or ERβ by gene targeting affects various aspects of reproduction. Female and male ERα knockout mice are inflertile and ERβ knockou … More t females have a reduced fecundity. Anovulation and hemorrhagic or polycystic ovary are present in either the ERα or ERβ knockout females. The syndrome is due, at least partially, to the central mechanism for the secretion of gonadotropin-releasing hormone (GnRH), because several regimens that decrease gonadotropin secretion ameliorate the defects. Negative feedback action of estrogen on gonadotropin secretion is compromised in ERα-disrupted female and male mice, but progesterone receptor can be induced by estrogen in the POA of male castrates, presumably through ERβ. The major caveat associated with the use of ER knockout mice, however, is that the two ERs may interact to modulate transcriptional activity in certain cells, making separate identification of the action of ERα and ERβ difficult.Estrogen-induced progesterone receptors act as a neuronal transcription factor which triggers GnRH surge in the female rat by altering synthesis or activity of neurotransmitters involved in the regulation of GnRH neurons. Progesterone receptors in the anteroventral periventricular nucleus (AVPV) of the POA may be particularly important. The AVPV is sexually dimorphic with over 3 times as many dopaminergic neurons in the female rat compared with males. The AVPV also contains sexually dimorphic populations of peptidergic neurons or glutamate receptor subunits, and has been implicated in the female-specific ovulatory release of GnRH with its direct projections to GnRH neurons. Indeed, small lesions confined to this region block the cyclic release of gonadotropins in the female rat and culminates in an anovulatory, persistent estrous state. Injections of progesterone receptor antisense oligonucleotides into the third ventricle adjacent to the AVPV blocks the induction of the receptor protein and prevents luteinizing-hormone surge.We found a striking sex difference in the ERβ expression in the AVPV.Neonatal steroid status altered the sexual phenotype. ERβ mRNA co-localized in 84% of estrogen ERα immunoreactive cells, and may be dopaminergic in nature. Infusion of ERβ antisense oligonucleotides into the third ventricle adjacent to the AVPV diminished ERβ protein and produced constant vaginal diestrus. Less