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，以及成年期生殖神经内分泌和行为的性别特异性调节。细胞雌激素信号是由核雌激素受体（ER）传递的，包括经典的ERα和最近克隆的ERβ。这两种er都在视前区（POA）、下丘脑、边缘结构中表达，这些结构与生殖调节有关。然而，ERβ是否像ERα一样以性别特异性的方式表达尚存争议。这两种er在同一神经元中的共定位，是否会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，在不同的细胞中对雌激素产生不同的反应，也有待证实。通过基因靶向破坏ERα或ERβ会影响生殖的各个方面。雌性和雄性ERα敲除小鼠不育，而雌性ERβ敲除小鼠生殖力降低。在ERα或ERβ基因敲除的女性中存在无排卵和出血性或多囊卵巢。该综合征至少部分归因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改善了这种缺陷。雌激素对促性腺激素分泌的负反馈作用在er α-紊乱的雌性和雄性小鼠中均不明显，但雌激素可在雄性去势动物的POA中诱导孕激素受体，可能是通过ERβ介导的。然而，与ER敲除小鼠相关的主要警告是，这两种ER可能相互作用以调节某些细胞的转录活性，使得很难单独鉴定ERα和ERβ的作用。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，引发雌性大鼠GnRH激增。孕激素受体在前腹侧脑室周围核（AVPV）可能是特别重要的。雌性大鼠的AVPV具有两性二态性，其多巴胺能神经元数量是雄性大鼠的3倍以上。AVPV还含有多肽能神经元或谷氨酸受体亚基的两性二态群体，并与GnRH的雌性特异性排卵释放有关，其直接投射到GnRH神经元。事实上，这一区域的小病变阻断了雌性大鼠促性腺激素的循环释放，最终导致无排卵、持续的发情状态。将黄体酮受体反义寡核苷酸注射到毗邻AVPV的第三脑室，可阻断受体蛋白的诱导，防止黄体生成素激增。我们发现在AVPV中ERβ的表达存在显著的性别差异。新生儿类固醇状态改变了性表型。ERβ mRNA共定位于84%的雌激素ERα免疫反应细胞中，可能具有多巴胺能性质。将ERβ反义寡核苷酸输注到AVPV附近的第三脑室可减少ERβ蛋白并产生持续的阴道痛。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