Ovarian Hormone Regulation of LHRH Biosynthesis

LHRH 生物合成的卵巢激素调节

• 批准号: 8099322
• 负责人: SANDRA L PETERSEN
• 金额: $ 8.63万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099322
• 关键词: Adenylate Cyclase; Aging; Agonist; Animals; Anteroventral Thalamic Nucleus; Brain region; Cell Nucleus; Cells; Cyclic AMP; Data; Equilibrium; Estradiol; Estrogens; Female; Gene Expression; Glutamate Decarboxylase; Glutamate Transporter; Glutamates; Gonadotropin Hormone Releasing Hormone; Green Fluorescent Proteins; Human; Hypothalamic structure; Infertility; Lead; Ligands; Light; Link; Measures; Mediating; Messenger RNA; Modeling; Mus; Nerve Degeneration; Neurons; Neuropeptides; Neurotensin; Neurotransmitters; Norepinephrine; Ovarian; Ovarian hormone; Ovulation; Pattern; Peptides; Phenotype; Photoperiod; Preoptic Areas; Principal Investigator; Progesterone Receptors; Puberty; Rattus; Research; Rosa; Signal Transduction; Steroids; Structure; Testing; Time; Transgenic Organisms; Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide Receptors; Vasopressin Receptor; Vasopressins; Work; base; gamma-Aminobutyric Acid; hormone biosynthesis; hormone regulation; immunocytochemistry; inhibitor/antagonist; insight; nerve supply; neurodevelopment; neuronal cell body; neuroprotection; neurotransmission; nonhuman primate; novel; premature; prevent; programs; receptor; relating to nervous system; sex; suprachiasmatic nucleus; transmission process; vesicular GABA transporter; vesicular glutamate transporter 2

The long-term objective of this research is to determine how ovarian steroids trigger luteinizing hormone-releasing hormone (LHRH) and LH surge release, thereby inducing ovulation. In these studies, we will investigate mechanisms through which potoperiod and estrogen signals interact to regulate novel dual-phenotype GABA/glutamate neurons in the anteroventral periventricular nucleus (AVPV) of females. The specific aims of this proposal are: 1) To verify that GABA/glutamate neurons communicate directly with LHR neurons we will use anterograde and retrograde tracing and immunocytochemistry in rats and mice; 2) We will use electrophysiological studies in which LHRH neurons are identified by GGP expression to verify that AVPV GABA/Glutamate neurons release predominantly GABA during the morning and predominantly glutamate in the afternoon; 3) To determine whether vasopressin (VP) and/or noradrenaline (NA) trigger the midday rise in GABA release linked to the LH surge. We will examine the effects of specific VP and NA receptor antagonists on expression of a marker of GABA release, glutamic acid decarboxylase 67 (GAD67) mRNA. We will also determine whether changes in GAD67 mRNA levels are blocked when animals are placed in constant light and if such changes, as well as LH surge release, can be induced with VP and/or NA receptor agonists; 4) To determine whether autofeedback inhibits GABA synthesis while stimulating glutamate release prior to the LH surge, we will administer GABAB receptor antagonists and measure changes in GAD67 mRNA levels in AVPV cell bodies, as well as vesicular GABA transporter and vesicular glutamate transporter in dual-phenotype terminals contacting LHRH neurons; 5) We will determine whether VIP stimulates cAMP-dependent NT gene expression through ligand-independent activation of PR on the afternoon of the LH surge. The results of these studies may provide new targets for examination in humans and nonhuman primates and may lead to a better understanding of the neural aspects of puberty, infertility and hypothalamic aging. In addition, establishing that GABA neurons are able to switch from inhibitory neurotransmission to excitatory transmission will have important implications for understanding GABA and glutamatergic "dual-signaling" in other brain regions. Finally, the results of these studies may provide key insights into how E2 regulates such diverse functions as sex-specific neurodevelopment, neuroprotection and neurodegeneration

这项研究的长期目标是确定卵巢类固醇如何触发黄体生成 促性腺激素释放激素（LHRH）和LH激增释放，从而诱导排卵。在这些研究中，我们 将研究光周期和雌激素信号相互作用调节新的 双表型GABA/谷氨酸神经元在前腹侧室周核（AVPV）的女性。 该建议的具体目标是：1）验证GABA/谷氨酸神经元直接与 在大鼠和小鼠的LHR神经元中，我们将使用顺行和逆行追踪以及免疫细胞化学; 2） 我们将使用电生理学研究，其中LHRH神经元通过GGP表达来鉴定，以验证 AVPV GABA/谷氨酸神经元在早晨主要释放GABA， 3）为了确定加压素（VP）和/或去甲肾上腺素（NA）是否触发了下午的谷氨酸; GABA释放的午间上升与LH激增有关。我们将研究特定VP和NA的影响 受体拮抗剂对GABA释放标志物谷氨酸脱羧酶67（GAD 67）表达的影响 mRNA。我们还将确定GAD 67 mRNA水平的变化是否被阻断， 置于恒定光照下，如果VP和/或NA可诱导此类变化以及LH峰释放， 受体激动剂; 4）为了确定自动反馈是否抑制GABA合成，同时刺激 在LH峰之前的谷氨酸释放，我们将给予GABAB受体拮抗剂并测量 AVPV细胞体中GAD 67 mRNA水平的变化，以及囊泡GABA转运蛋白和囊泡GABA转运蛋白的变化。 谷氨酸转运蛋白在双表型终端接触LHRH神经元; 5）我们将确定是否 VIP通过非配体依赖性激活PR刺激cAMP依赖性NT基因表达 LH激增的下午这些研究的结果可能为人类的检查提供新的目标 和非人类灵长类动物，并可能有助于更好地了解青春期、不孕症的神经方面 和下丘脑老化此外，确定GABA神经元能够从抑制性转换为抑制性， 神经传递到兴奋性传递将对理解GABA和 在其他大脑区域的“双重信号”。最后，这些研究的结果可能提供关键的 深入了解E2如何调节性别特异性神经发育、神经保护等多种功能 和神经变性