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The amygdala, a key upstream regulator of the hypothalamic GnRH pulse generator

杏仁核，下丘脑 GnRH 脉冲发生器的关键上游调节器

基本信息

批准号：
BB/W005913/1
负责人：
Kevin O'Byrne
金额：
$ 80.8万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FW005913%2F1
关键词：
amygdala key upstream regulator hypothalamic

项目摘要

This project provides a unique opportunity to unravel the mechanism by which psychogenic stress impacts on the control of reproductive function in mammals. Reproduction is critically dependent upon a neural oscillator that is responsible for the episodic secretion of pulses of the neurohormone gonadotrophin-releasing hormone (GnRH), that drives the pulsatile secretion of the gonadotrophic hormones, luteinising hormone (LH) and follicle stimulating hormone (FSH). This neural oscillator, known as the GnRH pulse generator, comprises Kisspeptin neurones that co-express the neuropeptides Neurokinin B and Dynorphin A (known as KNDy neurones) in the hypothalamic arcuate nucleus (ARC). The KNDy oscillator provides the essential episodic stimulatory kisspeptin signal to the GnRH neurones. With the very recent neuronal tract-tracing studies mapping the diverse afferent inputs to the KNDy neurones, there is now a substantial international effort to elucidate the pathways conveying metabolic, circadian, and other key homeostatic signals regulating the KNDy neural network. The amygdala, a part of the limbic brain typically associated with emotions and anxiety, has strong projections to the KNDy system. We have shown that kisspeptin signalling in the amygdala robustly regulates the most critical parameter of the GnRH pulse generator, namely its frequency, which is critical for normal follicular development and spermatogenesis. This finding has facilitated a recent surge of interest in the amygdala's control of fundamental reproductive processes, including pubertal timing, ovulation and fertility. We have shown in preliminary studies that amygdala kisspeptin operates through GABA signalling and that psychological stress-induced suppression of GnRH pulse generator frequency is mediated via the stress neuropeptide urocortin 3 in the amygdala. The present study aims to functionally characterise the neurocircuitry in the amygdala and its projections to the hypothalamic KNDy neural network. We will combine the latest state-of-the-art neuroscience technologies, enabling simultaneous in-vivo optogenetics manipulations and GCaMP gradient-index (GRIN) lens microendoscopic imaging of real time neurone calcium dynamics, with mathematically modelling. This will allow us to simulate system interactions and make predictions, which can then be tested through biological experiments and feed back into the model to develop it further. We will determine the mechanisms by which the projections from the amygdala regulate rhythmicity of the KNDY oscillator under normal and stress conditions. This project will reveal the mechanism by which the psychogenic stress systems in the amygdala regulate the hypothalamic GnRH pulse generator, thus improving our fundamental understanding of stress-related disorders of fertility and facilitating developments of more effective treatments in humans and animals.

该项目提供了一个独特的机会来揭示心因性应激影响哺乳动物生殖功能控制的机制。生殖严重依赖于神经振荡器，神经振荡器负责神经激素促性腺激素释放激素 (GnRH) 脉冲的间歇性分泌，从而驱动促性腺激素、黄体生成素 (LH) 和卵泡刺激素 (FSH) 的脉冲式分泌。这种神经振荡器被称为 GnRH 脉冲发生器，由 Kisspeptin 神经元组成，这些神经元在下丘脑弓状核 (ARC) 中共同表达神经肽 Neurokinin B 和强啡肽 A（称为 KNDy 神经元）。 KNDy 振荡器向 GnRH 神经元提供必要的情景刺激 Kisspeptin 信号。随着最近的神经元束追踪研究将不同的传入输入映射到 KNDy 神经元，现在国际上正在做出大量努力来阐明传递代谢、昼夜节律和其他调节 KNDy 神经网络的关键稳态信号的途径。杏仁核是边缘脑的一部分，通常与情绪和焦虑相关，对 KNDy 系统有强烈的投射。我们已经证明，杏仁核中的 Kisspeptin 信号传导能够强有力地调节 GnRH 脉冲发生器的最关键参数，即频率，这对于正常卵泡发育和精子发生至关重要。这一发现促使人们最近对杏仁核控制基本生殖过程（包括青春期时间、排卵和生育能力）的兴趣激增。我们在初步研究中表明，杏仁核 Kisspeptin 通过 GABA 信号传导发挥作用，而心理应激引起的 GnRH 脉冲发生器频率抑制是通过杏仁核中的应激神经肽 urocortin 3 介导的。本研究旨在从功能上描述杏仁核中的神经回路及其对下丘脑 KNDy 神经网络的预测。我们将结合最先进的神经科学技术，通过数学建模，同时实现体内光遗传学操作和实时神经元钙动力学的 GCaMP 梯度折射率 (GRIN) 透镜显微内窥镜成像。这将使我们能够模拟系统交互并做出预测，然后可以通过生物实验进行测试并反馈到模型中以进一步开发它。我们将确定在正常和应激条件下杏仁核的投射调节 KNDY 振荡器节律性的机制。该项目将揭示杏仁核中心因性应激系统调节下丘脑 GnRH 脉冲发生器的机制，从而提高我们对与应激相关的生育障碍的基本认识，并促进对人类和动物更有效的治疗方法的开发。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice.

DOI：
10.1111/jne.13207
发表时间：
2022-11
期刊：
JOURNAL OF NEUROENDOCRINOLOGY
影响因子：
3.2
作者：
Lass, Geffen;Li, Xiao Feng;Voliotis, Margaritis;Wall, Ellen;de Burgh, Ross A.;Ivanova, Deyana;McIntyre, Caitlin;Lin, Xian-Hua;Colledge, William H.;Lightman, Stafford L.;Tsaneva-Atanasova, Krasimira;O'Byrne, Kevin T.
通讯作者：
O'Byrne, Kevin T.

Posterodorsal Medial Amygdala Urocortin-3, GABA, and Glutamate Mediate Suppression of LH Pulsatility in Female Mice.