Estradiol modulation of pacemaking kisspeptin neurons

雌二醇对起搏 Kisspeptin 神经元的调节

基本信息

批准号：
9096268
负责人：
Oline Karin Rønnekleiv
金额：
$ 42.68万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096268
关键词：
Address Adult Animals Appetite Stimulants Area Calcium Cells Central Nervous System Diseases Characteristics Development Eating Electrophysiology (science)Estradiol Exhibits Female Gene Expression Generations Goals Health Histocytochemistry Homeostasis Hormones Hypothalamic structure Ion Channel KISS1 gene KISS1R gene Light Longevity Mediating Metabolic Diseases Molecular Molecular Biology Molecular Profiling Neurons Neuropathy Pacemakers Peptides Physiology Pro-Opiomelanocortin Process Regulation Reproduction Research Reverse Transcriptase Polymerase Chain Reaction Rhodopsin Risk Signal Transduction Signaling Protein Sodium Channel Stroke Structure of nucleus infundibularis hypothalami Synapses Third ventricle structure Translating Whole-Cell Recordings Woman base biophysical properties energy balance estrogenic feeding in vivo inhibitory neuron insight interdisciplinary approach mRNA Expression neural circuit neuronal circuitry neuropeptide Y novel novel therapeutics optogenetics postsynaptic receptor research study response tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The long-range goals of the proposed research are to elucidate the molecular and cellular mechanisms by which 17ß-estradiol (E2) regulates hypothalamic kisspeptin (Kiss1) neuronal circuits in females. Kiss1 neurons are a major target of E2 and are essential for pubertal development and adult reproduction. These neurons are also important for sensing and relaying gonadal status to neurons vital for regulation of energy balance, including the hypothalamic arcuate proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons. In spite of the importance of Kiss1 neurons, relatively little is known about the biophysical properties and molecular signature of these cells, as well as the neural circuits by which they operate. We have discovered that the Kiss1 neurons in the rostral periventricular area of the third ventricle (RP3V) express the critical ion channels and receptors that permit spontaneous E2-dependent rebound burst firing. Based on the E2-dependent burst firing characteristics and their projections to arcuate neurons, we propose the novel hypothesis that the RP3V Kiss1 neurons serve as the central pacemaker neurons that provide E2-dependent excitatory drive to the anorexigenic POMC neurons and inhibitory drive to the orexigenic NPY/AgRP neurons. This kisspeptin input to POMC and NPY/AgRP neurons is vital for the estrogenic control of energy homeostasis during the ovulatory cycle in females. Elucidating the cell-specific signaling pathways and gene expression at the single cell level will help in developing new strategies for targeting hormone actions in CNS neurons. Our multidisciplinary approach incorporates a unique set of cellular, molecular, optogenetic and chemogenetic tools and our combined expertise in molecular biology, electrophysiology, histochemistry and whole animal physiology to address the following aims: 1) To elucidate the sodium channel (Nav) subunit composition and the contribution of INaP to the generation of burst firing in RP3V Kiss1 neurons in high- versus low-E2 states. 2) To elucidate the postsynaptic actions of kisspeptin on arcuate POMC and NPY/AgRP neurons using single cell RT-PCR and whole-cell recording. 3) To elucidate the direct synaptic input to arcuate POMC and NPY/AgRP neurons from RP3V Kiss1 neurons using optogenetic stimulation and whole-cell recording. 4) To examine the in vivo effects of selective chemogenetic activation or inhibition of RP3V Kiss1 neurons on food intake in low- versus high-E2 females, respectively. Collectively, these experiments will allow for the elucidation of the ion channels important for the pacemaker activity in hypothalamic Kiss1 neurons, and how this translates into actions within hypothalamic neurocircuits that are vital for not only energy homeostasis but other autonomic functions.

描述（由适用提供）：拟议的研究的远距离目标是阐明17ß-雌二醇（E2）调节女性中下丘脑亲吻蛋白（KISS1）神经元回路的分子和细胞机制。 KISS1神经元是E2的主要靶标，对于青春期发展和成人繁殖至关重要。这些神经元对于传感和传递性性腺状态对能量平衡至关重要的神经元也很重要，包括下丘脑弧形促肌蛋白酶皮质素（POMC）和神经肽Y/AGOUTI相关的肽（NPY/AGRP）神经元。尽管KISS1神经元的重要性，但对这些细胞的生物物理特性和分子特征的了解相对较少，以及它们操作的神经元。我们已经发现第三心室（RP3V）的鼻骨周围区域中的KISS1神经元表达关键离子通道允许赞助E2依赖的反弹爆发的接收器。基于E2依赖性的爆发特征及其对神经元的预测，我们提出了一个新假设，即RP3V KISS1神经元充当了中央起搏器神经元，这些神经元可为E2依赖性兴奋性驱动器，向厌食症POMC神经元和抑制性驱动器，并驱动器驱动器驱动器驱动器。这种对POMC和NPY/AGRP神经元的Kisspeptin输入对于女性排卵周期期间能量稳态的雌激素控制至关重要。阐明单细胞水平上细胞特异性的信号通路和基因表达将有助于制定针对中枢神经系统神经元中骑马作用的新策略。我们的多学科方法结合了一组独特的细胞，分子，光遗传学和化学遗传学工具，以及我们在分子生物学方面的组合专业知识，使用单个细胞RT-PCR和全细胞记录来阐明Kisspeptin对Arceptin对Arceptaute POMC和NPY/AGRP神经元的直接作用。 3）使用光遗传刺激和全细胞记录，从RP3V KISS1神经元中阐明了直接的突触输入，以从RP3V KISS1神经元中伸出pOMC和NPY/AGRP神经元。 4）分别检查选择性化学发生激活或抑制RP3V KISS1神经元对低和高E2女性食物摄入的体内影响。总的来说，这些实验将允许对下丘脑KISS1神经元中的起搏器活性重要的离子通道阐明，以及这如何转化为下丘脑神经电路内的作用，不仅对能量稳态至关重要，这对于能量稳态至关重要。