Ravizza T, Galanopoulou A S, Velísková J, Moshé S L
Department of Neurology, Albert Einstein College of Medicine, K311, 1410 Pelham Parkway South, Bronx, NY, USA.
Neuroscience. 2002;115(3):685-96. doi: 10.1016/s0306-4522(02)00491-8.
Gonadal hormones are important regulators of sexual differentiation of the CNS. Exposure to testosterone and estrogen during development causes permanent organizational differences between males and females. We previously described functional sex-related differences of the GABA(A)ergic circuits of the rat substantia nigra pars reticulata (SNR) involved in the control of flurothyl seizures. This sexual differentiation of the SNR is regulated by postnatal testosterone. To assess whether the organizing effects of testosterone in the SNR are mediated via the androgen receptor (AR) and/or estrogen receptors (ER), we used immunohistochemistry to study the ontogeny of AR, ERalpha and ERbeta expression in SNR and substantia nigra pars compacta (SNC) of male and female rats. Rats on the day of birth [postnatal day (PN) 0] and at PN1, PN5, PN15 and PN30 were used. AR- and ERbeta-immunopositive cells were present in SNR and SNC in both sexes and at all ages. ERalpha was not detected in male and female SNC at PN0-PN1. In both substantia nigra (SN) regions, there were developmentally regulated sex differences in AR, ERalpha and ERbeta immunoreactivity. In the SN, each receptor showed specific intracellular localization: AR was present in the nucleus, ERalpha and ERbeta were present both in nuclear and extranuclear compartments. ERalpha was detected also in processes. At PN0-PN1, quantitative analysis revealed sex and regional differences in the distribution of SN cells expressing AR and ERalpha, while ERbeta were equally present in both sexes. The presence of gonadal steroid receptors in the SN suggests that the biological effects of gonadal hormones in the CNS extend beyond reproduction-related functions and may affect and modify motor behaviors (including seizures) in a sex-specific manner. Based on the ontogeny of SNR ERbeta, we hypothesize that postnatal injections of testosterone may regulate the nigral GABA(A) system through the aromatization pathway and activation of ERbeta.
性腺激素是中枢神经系统（CNS）性分化的重要调节因子。发育过程中接触睾酮和雌激素会导致雄性和雌性之间出现永久性的组织差异。我们之前描述了大鼠黑质网状部（SNR）中参与氟烷惊厥控制的GABA（A）能回路的功能性性别相关差异。SNR的这种性分化受出生后睾酮的调节。为了评估睾酮在SNR中的组织作用是否通过雄激素受体（AR）和/或雌激素受体（ER）介导，我们使用免疫组织化学研究了雄性和雌性大鼠SNR和黑质致密部（SNC）中AR、ERα和ERβ表达的个体发生。使用出生当天[出生后第（PN）0天]以及PN1、PN5、PN15和PN30的大鼠。两性在所有年龄段的SNR和SNC中均存在AR和ERβ免疫阳性细胞。在PN0 - PN1时，雄性和雌性SNC中均未检测到ERα。在两个黑质（SN）区域，AR、ERα和ERβ免疫反应性存在发育调控的性别差异。在SN中，每种受体都显示出特定的细胞内定位：AR存在于细胞核中，ERα和ERβ既存在于核内也存在于核外区室。在突起中也检测到了ERα。在PN0 - PN1时，定量分析显示表达AR和ERα的SN细胞分布存在性别和区域差异，而ERβ在两性中分布均等。SN中存在性腺类固醇受体表明性腺激素在CNS中的生物学作用超出了与生殖相关的功能，可能以性别特异性方式影响和改变运动行为（包括惊厥）。基于SNR中ERβ的个体发生，我们推测出生后注射睾酮可能通过芳香化途径和ERβ的激活来调节黑质GABA（A）系统。
