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（由申请人提供）：15％至20％的夫妻构想困难；因此，生殖系统的失败会影响许多人。在女性中，了解排卵的控制对于帮助不孕症的人而不是多个，出生，以及开发新的方法来防止与大多数人群可接受的社会道德相一致的新颖方法，而不是多种，出生的人，至关重要。同时最大程度地减少副作用。该提案的目的是增加我们对最终导致排卵的中心神经信号产生的理解。该信号由严格发作的促性腺激素释放激素（GNRH）神经元的输出转移提供，产生了垂体激素释放的ON/OFF GNRH脉冲，其中GNRH释放连续升高了几个小时。雌二醇引发了这种GNRH激增，从而诱导了葡萄糖激素（LH）激增，随后触发排卵。为了诱导GNRH激增，中央雌二醇动作从负反馈转换为正反馈。用恒定生理水平的雌二醇（OVX+E）处理的卵巢切除（OVX）小鼠每天从阴性反馈到阳光循环的正转移，从而使可变模型的机械研究允许机械研究。在卵巢独立的小鼠中，这种以雌二醇反馈模式发生的转换发生在前弹力上。每日激增模型中的先前工作建立了雌二醇参与的几种机制，这些机制将导致在阳性反馈期间对这些细胞的负反馈和激活期间抑制GnRH神经元。在拟议的工作中，这些发现将通过实验进行扩展，这些实验范围从还原主义研究神经生物学机制到整个动物研究，旨在阐明雌二醇参与的上游神经元网络，以调节GNRH神经元和涌动产生。在AIM 1中，我们将研究前腹室（AVPV）区域中的Kisspeptin神经元，该区域假定介导雌二醇阳性反馈。我们将确定它们的输入和内在特性如何随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使用脑切片中的配对记录来改变吻肽和GNRH神经元之间的功能连通性。初步数据表明，雌二醇和/或一天中的时间都改变了对AVPV Kisspeptin神经元的发射模式，内在特性和神经传递。在AIM 2中，我们将研究急性应力破坏LH激增的机制。该目标将测试受压力破坏的神经生物学机制，并使用遗传和手术方法确定效应细胞。这个目标还将扩大我们对激增基础机制的了解到自然周期。初步数据表明，昼夜抑制激增的昼夜模式，即应激肽皮质激素 - 释放激素会抑制GNRH神经元，并且这受到性腺因子的加剧。研究兴奋性和抑制性传道网络所产生的数据的整合将增加我们对雌二醇对排卵中心神经元控制的理解。