Central actions of estrogens: Effects of GnRH neurons

雌激素的中枢作用：GnRH 神经元的作用

• 批准号: 8513026
• 负责人: Suzanne M MOENTER
• 金额: $ 45.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-11 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513026
• 关键词: Action Potentials; Address; Adipose tissue; Adult; Adverse effects; Affect; Animal Model; Animals; Biological Neural Networks; Brain; Cells; Cognition; Comprehension; Contraceptive Agents; Corticotropin-Releasing Hormone; Couples; Data; Diet; Effectiveness; Effector Cell; Electrophysiology (science); Elements; Estradiol; Estrogen Receptors; Estrogens; Exhibits; Failure; Feedback; Female; Fertility; Gene Expression; Generations; Genetic; Glutamates; Goals; Gonadotropin Hormone Releasing Hormone; Grant; Hormones; Hour; Individual; Infertility; Investigation; Knowledge; Lead; Light; Literature; Luteinizing Hormone; Mediating; Methods; Modeling; Monitor; Multiple Birth Offspring; Mus; Nature; Neuroglia; Neurons; Neurophysiology - biologic function; Neurosecretory Systems; Operative Surgical Procedures; Output; Ovarian hormone; Ovary; Ovulation; Pathway interactions; Pattern; Peptides; Peripheral; Physiologic pulse; Physiological; Pituitary Hormones; Population; Proestrus; Property; Psychosocial Stress; Regimen; Regulation; Reproduction; Reproductive system; Role; Sex Behavior; Signal Transduction; Slice; Source; Stress; Structure of nucleus infundibularis hypothalami; Study models; Synapses; Synaptic Transmission; System; Testing; Testosterone; Time; Unwanted pregnancy; Work; acute stress; data integration; gamma-Aminobutyric Acid; in vivo; kisspeptin; male; neurobiological mechanism; neuroprotection; neurotransmission; novel; prevent; public health relevance; receptor; relating to nervous system; reproductive; research study; social; tool; transcription factor

DESCRIPTION (provided by applicant): Between 15 and 20% of couples have difficulty conceiving; failures of the reproductive system thus affect many individuals. In females, understanding the control of ovulation is critical for helping those with infertility conceive singe, as opposed to multiple, births, and for developing novel methods to prevent unwanted pregnancy in manners that are consistent with the acceptable social mores of most of the population, while minimizing side effects. The goal of this proposal is to increase our understanding of the generation of the central neural signal that ultimately leads to ovulation. This signal is provided by a shift in output of gonadotropin-releasing hormone (GnRH) neurons from one that is strictly episodic, producing on/off GnRH pulses that drive pituitary hormone release, to one in which GnRH release is continuously elevated for several hours. Estradiol initiates this GnRH surge, which induces the luteinizing hormone (LH) surge that subsequently triggers ovulation. To induce the GnRH surge, central estradiol action switches from negative feedback to positive feedback. Ovariectomized (OVX) mice treated with constant physiological levels of estradiol (OVX+E) undergo daily shifts from negative to positive feedback that are timed to the light-dark cycle, allowing mechanistic studies in a reduced variable model. In ovary-intact mice, this switch in estradiol feedback mode occurs on proestrus. Previous work in the daily surge model established several mechanisms engaged by estradiol that would lead to suppression of GnRH neurons during negative feedback and activation of these cells during positive feedback. In the proposed work, these findings will be extended with experiments that range from reductionist investigation of neurobiological mechanisms to whole animal studies, all aimed at elucidating the upstream neuronal networks engaged by estradiol to regulate GnRH neurons and surge generation. In Aim 1, we will study kisspeptin neurons in the anteroventral periventricular (AVPV) region, postulated to mediate estradiol positive feedback. We will determine how their inputs and intrinsic properties change with estradiol and time of day. We will also study how estradiol feedback alters functional connectivity between kisspeptin and GnRH neurons using paired recordings in brain slices. Preliminary data indicate firing pattern, intrinsic properties and neurotransmission to AVPV kisspeptin neurons are altered both by estradiol and/or time of day. In Aim 2, we will study the mechanisms by which an acute stress disrupts the LH surge. This aim will test the neurobiological mechanisms that are disrupted by stress, and determine effector cells using genetic and surgical approaches. This aim will also expand our knowledge of mechanisms underlying the surge to the natural cycle. Preliminary data indicate a diurnal pattern to stress inhibition of surge generation, that the stress peptide corticotropin- releasing hormone inhibits GnRH neurons and that this is exacerbated by gonadal factors. Integration of the data resulting from the study of an excitatory and an inhibitory afferet network into existing knowledge will increase our understanding of the central neuronal control of ovulation by estradiol.

描述（申请人提供）：15% - 20%的夫妇有受孕困难；因此，生殖系统的故障影响了许多个体。在女性中，了解排卵的控制对于帮助那些不孕不育的人单胎而不是多胎是至关重要的，对于开发新的方法以符合大多数人可接受的社会习俗的方式防止意外怀孕，同时最大限度地减少副作用是至关重要的。这项提议的目的是增加我们对最终导致排卵的中枢神经信号产生的理解。这个信号是由促性腺激素释放激素（GnRH）神经元输出的转变提供的，从一个严格的偶发性，产生驱动垂体激素释放的GnRH脉冲，到一个GnRH释放持续升高几个小时。雌二醇引发GnRH激增，进而诱导黄体生成素（LH）激增，进而触发排卵。为了诱导GnRH激增，中央雌二醇的作用从负反馈转变为正反馈。卵巢切除（OVX）小鼠接受恒定生理水平的雌二醇（OVX+E）治疗，每天经历从负反馈到正反馈的转变，这是定时的光-暗周期，允许在减少变量模型中进行机制研究。在卵巢完好的小鼠中，雌二醇反馈模式的这种开关发生在发情前期。之前在每日激增模型中的工作建立了雌二醇参与的几种机制，这些机制会导致GnRH神经元在负反馈期间受到抑制，而这些细胞在正反馈期间被激活。在拟议的工作中，这些发现将通过从神经生物学机制的还原论研究到全动物研究的实验来扩展，所有这些实验都旨在阐明雌二醇参与的上游神经元网络，以调节GnRH神经元和激增的产生。在Aim 1中，我们将研究腹侧脑室周围（AVPV）区域的kisspeptin神经元，假设其介导雌二醇正反馈。我们将确定它们的输入和内在特性如何随着雌二醇和一天中的时间而变化。我们还将研究雌二醇反馈如何改变kisspeptin和GnRH神经元之间的功能连接，使用成对的脑切片记录。初步数据表明，雌二醇和/或一天中的时间改变了AVPV kisspeptin神经元的放电模式、内在特性和神经传递。在Aim 2中，我们将研究急性应激破坏LH激增的机制。这一目标将测试被压力破坏的神经生物学机制，并使用遗传和外科方法确定效应细胞。这一目标也将扩大我们对自然周期激增背后机制的认识。初步数据表明应激抑制激增产生的昼夜模式，应激肽促肾上腺皮质激素释放激素抑制GnRH神经元，并且性腺因素加剧了这种情况。将兴奋性和抑制性影响网络的研究数据整合到现有知识中，将增加我们对雌二醇对排卵的中枢神经元控制的理解。