NEUROENDOCRINE REGULATION OF LH AND PROLACTIN SECRETION

LH 和催乳素分泌的神经内分泌调节

• 批准号: 2673522
• 负责人: Michael Selmanoff
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2673522
• 关键词: GABA receptor; antisense nucleic acid; brain mapping; gamma aminobutyrate; gonadotropin releasing factor; hormone inhibitor; hormone regulation /control mechanism; hypothalamic pituitary axis; laboratory rat; luteinizing hormone; male castration; neural transmission; neuroanatomy; neuroendocrine system; neuronal transport; ovariectomy; pituitary gonadal axis; prolactin; sex hormones; steroid hormone receptor

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.

该研究计划的长期目标是确定 调节 LH 和催乳素分泌的神经内分泌机制 哺乳动物。 拟议的研究检查了下丘脑机制 睾酮 (T) 和雌二醇-17β (E(2)) 加孕酮 (P(4)) 可能 对成年男性的强直性 LH 分泌发挥负反馈作用 和雌性老鼠。 虽然类固醇负反馈的概念最早出现 20世纪30年代提出，神经元的身份受到负面影响 反馈类固醇及其与 GnRH 神经元的关系尚不清楚 肯定地。 我们当前的重点是确定生理作用 位于对角带的类固醇寻址 GABA 能神经元 Broca 位于终板血管器官水平 [DBB(ovlt)]，内侧视前核的背内侧 (MPNdm) 和结节漏斗部 GABA 能 (TIGA) 神经元 LH 分泌的调节。 这些 GABA 能神经元已知 浓缩性类固醇或表达性类固醇受体，GABAergic 已知神经元在 GnRH 神经元上形成突触，并且原位 GnRH 神经元 最近已被证明表达 GABA(A)beta(3) 受体亚基 mRNA。 正在研究的主要工作假设是类固醇- 敏感的下丘脑头端和结节漏斗部 GABA 能神经元 介导性腺类固醇对 GnRH 神经元的负反馈作用。 拟议的研究重点是确定四个具体目标：(1) 卵巢切除术是否会降低视前和结节漏斗部 GABA 能 被生理负反馈阻止的神经传递 E2 + P（4）的浓度，（2）是否微量注射类固醇 类固醇受体拮抗剂或反义寡核苷酸 mRNA 阻断性类固醇对 GABA 周转和 GAD 的影响（65 或 67） 这些类固醇敏感脑区的 mRNA 表达，(3) 是否 类固醇受体拮抗剂微量输注到这些类固醇敏感的患者中 大脑区域增加 GnRH 释放，这是通过共同输注来阻止的 GABA 和 GABA(A) 受体激动剂，以及 (4) 性腺切除是否会减少 含有类固醇受体的 GABA 能神经元中的 GAD(65 或 67) mRNA，以及 性腺切除术是否会增加 GABA(A)beta(3) 受体亚基 mRNA GnRH 神经元中的表达。 这项研究将加深我们的理解 下丘脑调节男性和女性强直性 LH 分泌的机制的研究 雌性老鼠，以及消极的，也许是积极的反馈的方式 类固醇会影响这一机制。