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 17β-雌二醇（E2）调节弧形核（ARC）Kisspeptin（Kiss1）神经元电路，这对于至关重要 众所周知，E2是厌食症的，可以协调能量稳态和繁殖。 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 但是，繁殖成功。 表明ARC KISS1神经元直接被瘦素激发，并表明它们可能使用 在控制能量稳态中的重要作用。 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相关的肽（NPY/AGRP）神经元。 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 此外 （vglut2）femalee arc kiss1神经元中的mRNA，表明囊泡谷氨酸包装和 释放。 这对于GNRH/LH激增的指示很重要。 整合代谢激素和类固醇提示，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神经元的兴奋性在高中增加 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 mglurs，尊敬的人，降低食物的摄入量。 来自ARC KISS1神经元的AVPV/PEN KISS1神经元的输入 GNRH/LH激增时的神经元。 分子和光遗传学工具来解决以下AMS：1）在ARC KISS1神经元中阐明您 E2对CAV3和HCN离子通道的mRNA表达和功能的影响以及 VGLUT2 mRNA; 2）阐明了弧线的直接输入 KISS1神经元使用光遗传学刺激与E2治疗的女性中的全细胞记录结合在一起； 使用光遗传学阐明直接从ARC KISS1神经元到AVPV/PEN KISS1神经元的突触输入 E2处理的女性刺激和全细胞记录； 在E2处理的女性中，对GnRH释放和食物摄入的ARC KISS1神经元的光遗传学刺激。 因此，阐明电路和信号的级联级联为基础E2在下har玛us willl中的作用 提供一个神经生理框架，KISS1神经元协调生殖与变化的变化 能量状态。