NEUROENDOCRINE REGULATION OF LH AND PROLACTIN SECRETION

这项研究计划的长期目标是确定 黄体生成素和催乳素分泌的神经内分泌调节机制 哺乳动物。拟议的研究检查了下丘脑的机制，通过 睾酮(T)和雌二醇-17β(E(2))+孕酮(P(4))可能 对成年男性紧张性黄体生成素分泌的负反馈作用 和雌性老鼠。而类固醇负反馈的概念是第一个 20世纪30年代S提出的负性作用神经元的同一性 反馈类固醇及其与促性腺激素释放激素神经元的关系尚不清楚 肯定会的。我们目前的重点是确定生理作用 类固醇寻址的GABA能神经元位于斜带 终板血管器水平的Broca 视前内侧核的背内侧 (MPNdm)和漏斗状GABA能神经元(TIGA)。 黄体生成素分泌的调节。已知这些GABA能神经元 浓缩性类固醇或表达性激素受体，GABA能 已知神经元突触在GnRH神经元上，GnRH神经元在原位 最近发现表达GABA(A)β(3)受体亚单位mRNA。 正在调查的主要工作假说是类固醇- 敏感的下丘脑吻部和漏斗状GABA能神经元 介导性腺激素对GnRH神经元的负反馈作用。 建议的研究侧重于四个具体目标，以确定：(1) 卵巢切除是否减少视前和漏斗结节GABA能 神经传递被生理的、负反馈所阻止 E_2浓度P(4)，(2)是否微量输注类固醇 类固醇受体拮抗剂或反义寡核苷酸 MRNAs阻断性激素对GABA周转和GAD的影响(65或67) 这些激素敏感脑区的mRNA表达，(3)是否 类固醇受体拮抗剂微量注射到这些类固醇敏感的 脑区增加促性腺激素释放激素可通过联合输注 GABA和GABA(A)受体激动剂，以及(4)性腺切除是否减少 GAD(65或67)mRNA在含有类固醇受体的GABA能神经元中，以及 性腺切除是否增加GABA(A)β(3)受体亚单位mRNA 在GnRH神经元中的表达。这项研究将加深我们对 男性和男性下丘脑调节强直性黄体生成素分泌的机制 雌性大鼠，以及负面的，也许是积极的反馈 类固醇会影响这一机制。

The long-term objective of this research program is to determine the neuroendocrine mechanisms regulating LH and prolactin secretion in mammals. Proposed studies examine hypothalamic mechanisms by which testosterone (T) and estradiol-17beta (E(2)) plus progesterone (P(4)) may exert their negative feedback action on tonic LH secretion in adult male and female rats. While the concept of steroid negative feedback was first posited in the 1930's, the identity of the neurons acted upon by negative feedback steroids and their relationship to the GnRH neurons are not known with certainty. Our current focus is to determine the physiological role of steroid-addressed GABAergic neurons situated in the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis [DBB(ovlt)], the dorsomedial aspect of the medial preoptic nucleus (MPNdm), and the tuberoinfundibular GABAergic (TIGA) neurons, in the regulation of LH secretion. These GABAergic neurons are known to concentrate sex steroids or to express sex steroid receptor, GABAergic neurons are known to synapse on GnRH neurons, and GnRH neurons in situ recently have been shown to express GABA(A)beta(3) receptor subunit mRNA. The principal working hypothesis under investigation is that steroid- sensitive rostral hypothalamic and tuberoinfundibular GABAergic neurons mediate the negative feedback effects of gonadal steroids on GnRH neurons. Proposed research is focused on four specific aims to determine: (1) whether ovariectomy decreases preoptic and tuberoinfundibular GABAergic neurotransmission which is prevented by physiological, negative feedback concentrations of E2 + P(4), (2) whether microinfusions of steroid receptor antagonists or antisense oligonucleotides to steroid receptor mRNAs block the effects of sex steroids on GABA turnover and GAD(65 or 67) mRNA expression in these steroid-sensitive brain regions, (3) whether steroid receptor antagonist microinfusions into these steroid-sensitive brain regions increase GnRH release which is prevented by co-infusion of GABA and GABA(A) receptor agonists, and (4), whether gonadectomy decreases GAD(65 or 67) mRNA in steroid receptor-containing GABAergic neurons, and whether gonadectomy increases GABA(A)beta(3) receptor subunit mRNA expression in GnRH neurons. This research will further our understanding of the hypothalamic mechanism regulating tonic LH secretion in male and female rats, and the way in which negative, and perhaps positive, feedback steroids affect this mechanism.