Ovarian Hormone Regulation of LHRH Biosynthesis

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。 激素释放激素(LHRH)和黄体生成素释放高峰，从而诱导排卵。在这些研究中，我们 将研究钾周期和雌激素信号相互作用的机制，以调节新的 女性前腹侧脑室周围核(AVPV)内GABA/谷氨酸双表型神经元 这项提议的具体目的是：1)验证GABA/谷氨酸神经元直接与 我们将对大鼠和小鼠的LHR神经元进行顺行和逆行追踪和免疫细胞化学；2) 我们将使用通过GGP表达来识别LHRH神经元的电生理学研究来验证 AVPV GABA/谷氨酸神经元在早晨主要释放GABA，并且主要 下午补充谷氨酸；3)确定加压素(VP)和/或去甲肾上腺素(NA)是否触发 中午GABA释放的增加与黄体生成素的激增有关。我们将研究特定的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(GAD67)表达的影响 MRNA.我们还将确定GAD67 mRNA水平的变化是否在动物被 置于恒定的光照下，如果这种变化以及黄体生成素的释放可以用VP和/或NA诱导 受体激动剂；4)确定自身反馈是否在刺激时抑制GABA的合成 谷氨酸释放之前，黄体生成素激增，我们将给予GABAB受体拮抗剂和测量 AVPV细胞体、囊泡GABA转运体和囊泡GAD67 mRNA水平的变化 与LHRH神经元接触的双表型终末谷氨酸转运体；5)我们将确定 VIP通过非配体依赖的PR激活细胞上cAMP依赖的NT基因表达 在左撇子激增的下午。这些研究的结果可能会为人类的检查提供新的靶点 和非人类灵长类动物，并可能导致更好地理解青春期、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 神经传递到兴奋性传递将对理解GABA和 谷氨酸能“双信号”在大脑的其他区域。最后，这些研究的结果可能会提供关键 对雌二醇如何调节性别性神经发育、神经保护等不同功能的见解 神经退行性变

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