Cross-Talk Between Estrogen and Metabolic Hormone Signaling in Arcuate Neurons

弓状神经元中雌激素和代谢激素信号传导之间的串扰

• 批准号: 9174776
• 负责人: Martin Jeffrey Kelly
• 金额: $ 44.97万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174776
• 关键词: AMPA Receptors; Address; Adult; Animals; Appetite Stimulants; Cues; Development; Dynorphins; Eating; Electrophysiology (science); Energy Metabolism; Estradiol; Estrogens; Female; Fertility; Frequencies; Glutamates; Goals; Health; Homeostasis; Hormonal; Hormones; Hypothalamic structure; Insulin; Ion Channel; KISS1 gene; Lead; Leptin; Light; Link; Messenger RNA; Metabolic; Metabolic syndrome; Metabotropic Glutamate Receptors; Molecular; Molecular Biology; N-Methylaspartate; Neurons; Neuropeptides; Obesity; Peptides; Physiology; Pro-Opiomelanocortin; Proestrus; Property; Regulation; Reproduction; Research; Rhodopsin; Role; Signal Transduction; Structure of nucleus infundibularis hypothalami; Synapses; Time; Whole-Cell Recordings; biophysical analysis; estrogenic; feeding; interdisciplinary approach; mRNA Expression; metabotropic glutamate receptor 3; metabotropic glutamate receptor type 1; neural circuit; neuronal circuitry; neuronal excitability; neuropeptide Y; neurophysiology; novel; novel therapeutics; optogenetics; reproductive success; steroid hormone; tool; vesicular glutamate transporter 2

Project Summary The long range goals of the proposed research are to elucidate the mechanism(s) by which metabolic states and 17β-estradiol (E2) regulate arcuate nucleus (ARC) kisspeptin (Kiss1) neuronal circuits that are critical for coordinating energy homeostasis and reproduction in females. It is well known that E2 is anorexigenic, and that Kiss1 neurons which are directly regulated by E2, are essential for pubertal development and adult reproductive success. However, their role in the control of energy homeostasis is less understood. We have shown that the ARC Kiss1 neurons are directly excited by leptin and insulin indicating that they may serve an important role in the control of energy homeostasis. Also, we have evidence that glutamate is released from ARC Kiss1 neurons and targets anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons. In addition, we have found that glutamate can differentially regulate POMC and NPY/AgRP neurons by acting on separate groups of metabotropic glutamate receptors (mGluRs). Moreover, we have discovered that E2 increases vesicular glutamate transporter 2 (vGluT2) mRNA in female ARC Kiss1 neurons, an indication of heightened vesicular glutamate packaging and release. We also have evidence that ARC Kiss1 neurons project to and excite AVPV/PeN Kiss1 neurons, which are important for the induction of the GnRH/LH surge. Thus, we believe that ARC Kiss1 neurons integrate metabolic hormone and steroid cues to regulate both energy homeostasis and reproduction. Therefore, we propose the novel hypothesis that the excitability of ARC Kiss1 neurons is increased in high estrogenic states thereby releasing glutamate to excite POMC neurons and inhibit NPY/AgRP neurons via group I and group II/III mGluRs, respectively, which decreases food intake. In addition, excitatory glutamatergic input to AVPV/PeN Kiss1 neurons from ARC Kiss1 neurons constitutes a critical stimulatory drive to GnRH neurons at the time of GnRH/LH surge. Our multidisciplinary approach incorporates a powerful set of cellular, molecular and optogenetic tools to address the following aims: 1) To elucidate in ARC Kiss1 neurons the effects of E2 on the mRNA expression and function of Cav3 and HCN ion channels and the expression of vGluT2 mRNA; 2) to elucidate the direct synaptic input to ARC POMC and NPY/AgRP neurons from ARC Kiss1 neurons using optogenetic stimulation in combination with whole-cell recording in E2-treated females; 3) to elucidate the direct synaptic input to AVPV/PeN Kiss1 neurons from ARC Kiss1 neurons using optogenetic stimulation and whole-cell recording in E2-treated females; 4) to elucidate the effects of high frequency optogenetic stimulation of ARC Kiss1 neurons on GnRH release and on food intake in E2-treated females. Therefore, elucidating the circuits and signaling cascades underlying the actions of E2 in the hypothalamus will provide a neurophysiological framework whereby Kiss1 neurons could coordinate reproduction with changes in energy status.

项目摘要 拟议研究的远距离目标是阐明代谢状态的机制 和17β-雌二醇（E2）调节弧形核（ARC）Kisspeptin（Kiss1）神经元回路，这对于对 协调女性的能量稳态和繁殖。众所周知，E2是厌食症，并且 由E2直接调节的Kiss1神经元对于青春期的发展和成人至关重要 生殖成功。但是，它们在控制能量体内稳态中的作用知之甚少。我们有 表明ARC KISS1神经元被瘦素和胰岛素直接激发，表明它们可以使用 在控制能量体内平衡中的重要作用。另外，我们有证据表明谷氨酸已释放 ARC KISS1神经元，靶向厌食性肌蛋白酶皮质素（POMC）神经元和神经元 神经肽Y/Agouti相关肽（NPY/AGRP）神经元。此外，我们发现谷氨酸可以 通过作用于单独的代谢型谷氨酸，对POMC和NPY/AGRP神经元进行了差异调节 受体（mglurs）。此外，我们发现E2增加了囊泡谷氨酸转运蛋白2 （vglut2）雌性弧KISS1神经元中的mRNA，这是囊泡谷氨酸包装增强和 发布。我们还有证据表明ARC KISS1神经元对AVPV/PEN KISS1神经元进行了启发， 这对于诱导GnRH/LH激增很重要。那就是我们相信ARC KISS1神经元 整合代谢性马酮和类固醇提示，以调节能量稳态和繁殖。 因此，我们提出了一种新的假设，即ARC KISS1神经元的兴奋在高中增加 雌激素状态，从而释放谷氨酸以激发POMC神经元并抑制NPY/AGRP神经元通过 I组和II组/III组分别降低了食物摄入量。另外，兴奋性谷氨酸能 来自ARC KISS1神经元的AVPV/Pen KISS1神经元的输入构成了刺激性驱动器 GNRH/LH激增时的神经元。我们的多学科方法结合了一组强大的蜂窝 分子和光遗传学工具以解决以下目的：1）在ARC KISS1神经元中阐明 E2对CAV3和HCN离子通道的mRNA表达和功能的影响以及 vglut2 mRNA; 2）阐明来自ARC的ARC POMC和NPY/AGRP神经元的直接突触输入 KISS1神经元使用光遗传学刺激与E2处理的女性中的全细胞记录结合使用； 3） 使用光遗传学阐明来自ARC KISS1神经元的直接突触输入到AVPV/PEN KISS1神经元 E2处理的女性中的刺激和全细胞记录； 4）阐明高频的影响 在GnRH释放和E2处理的女性中，对ARC KISS1神经元的光遗传学刺激。 因此，阐明在下丘脑中E2作用的基础电路和信号级联 提供一个神经生理框架，从中Kiss1神经元可以协调生殖与变化 能量状态。