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

该项目提供了一个独特的机会，以解开机制，心理压力的影响，对控制生殖功能的哺乳动物。生殖严重依赖于神经振荡器，该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，该脉冲驱动促性腺激素、促黄体生成激素（LH）和促卵泡激素（FSH）的脉冲性分泌。该神经振荡器，称为GnRH脉冲发生器，包括Kisspeptin神经元，其在下丘脑弓状核（ARC）中共表达神经肽神经激肽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性kisspeptin信号。随着最近的神经束追踪研究将不同的传入输入映射到KNDy神经元，现在有大量的国际努力来阐明调节KNDy神经网络的代谢、昼夜节律和其他关键稳态信号的传递途径。杏仁核是大脑边缘系统的一部分，通常与情绪和焦虑有关，它对KNDy系统有很强的投射。我们已经证明，杏仁核中的kisspeptin信号转导强烈调节GnRH脉冲发生器的最关键参数，即其频率，这对正常卵泡发育和精子发生至关重要。这一发现促进了最近对杏仁核控制基本生殖过程的兴趣激增，包括青春期时间，排卵和生育。我们已经在初步研究中表明，杏仁核kisspeptin通过GABA信号传导，心理应激诱导的GnRH脉冲发生器频率的抑制是通过杏仁核中的应激神经肽urocortin 3介导的。本研究的目的是从功能上阐明杏仁核的神经回路及其向下丘脑KNDy神经网络的投射。我们将联合收割机结合最新的神经科学技术，使体内光遗传学操作和GCaMP梯度指数（GRIN）透镜显微内窥镜成像的真实的时间神经元钙动力学，数学建模同步。这将使我们能够模拟系统相互作用并做出预测，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发展。我们将确定的机制，从杏仁核的预测调节节律的KNDY振荡器在正常和应激条件下。该项目将揭示杏仁核中的心因性应激系统调节下丘脑GnRH脉冲发生器的机制，从而提高我们对应激相关生育障碍的基本理解，并促进人类和动物更有效治疗的发展。

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.