A novel mechanism underlying GnRH pulse generation by KNDy neurones

KNDy 神经元产生 GnRH 脉冲的新机制

• 批准号: BB/S000550/1
• 负责人: Kevin O'Byrne
• 金额: $ 72.86万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS000550%2F1
• 关键词: novel; mechanism; underlying; GnRH; pulse

The ability to reproduce, which is absolutely essential for survival of our species, depends on an amazing "clock" in the brain. This clock is responsible for driving the intermittent secretion of pulses of a brain hormone called gonadotrophin-releasing hormone (GnRH), which controls a cascade of hormonal signals that not only triggers puberty, but is responsible for fertile egg and sperm production across the life course. This neural clock is called the "GnRH Pulse Generator". Despite the fact that is was discovered over half a century ago, and was shown to be located in a very small area in the brain called the hypothalamus, the components of this timepiece have remained elusive until very recently. About 15 years ago there was great excitement when a new brain chemical called kisspeptin was found in the hypothalamus and shown to be a critical link in activating the GnRH nerve cells in the brain. What was even more astonishing was the discovery that these neurones producing Kisspeptin were also making two additional chemicals; a stimulatory one called Neurokinin-B (NKB) and an inhibitory one called Dynorphin-A (Dyn)(hence their name KNDy neurones). The KNDy neurones are a crucial part of the nerve network that can drive the pulses of GnRH and so drive reproduction. However, we still do not understand how the KNDy network generate the stream of kisspeptin pulses (like the ticks of a clock) to drive the GnRH pulses. Because of the complexity of this system, we have developed a mathematical model of the KNDy network to help us understand the relationships of all the key elements of this complex neural system, rather like the weather forecast models help us understand complex meteorological data. Surprisingly one of the main predictions of our mathematical model is that low level of constant activity within the KNDy network is the primary cause of the GnRH pulses. Our pilot laboratory experiments indicate that this is actually the way that the living system works and justifies a full scale examination of the model and its implications. These novel findings provide the first insight into the control of the ticking function of the GnRH pulse generator. With continued development of our mathematical model and complementary laboratory experimentation we will discover how the pulses of hormone release are controlled and also discover how other parts of the brain, most notably the emotional centres in a region called the amygdala, can influence or modulate the GnRH pulse generator and reproduction in humansThis project provides a unique opportunity not only to unravel the mechanism underlying the pulsatile nature of GnRH secretion, which is essential for reproduction, but to establish the key interactions with the emotional stress systems in the amygdala that modulate the pulse generator, thereby helping future developments of more effective treatments for stress-related disorders of fertility and health.

繁殖的能力，这是绝对必要的生存我们的物种，取决于一个惊人的“时钟”在大脑中。这个时钟负责驱动称为促性腺激素释放激素（GnRH）的脑激素脉冲的间歇性分泌，该激素控制着一系列激素信号，不仅触发青春期，而且负责整个生命过程中的受精卵和精子生产。这个神经时钟被称为“GnRH脉冲发生器”。尽管它是在半个多世纪前被发现的，并且被证明位于大脑中一个叫做下丘脑的非常小的区域，但直到最近，这个时钟的组成部分仍然难以捉摸。大约15年前，当一种名为kisspeptin的新的大脑化学物质在下丘脑中被发现时，人们感到非常兴奋，并且被证明是激活大脑中GnRH神经细胞的关键环节。更令人惊讶的是，这些产生Kisspeptin的神经元还产生了两种额外的化学物质：一种是刺激性的，称为神经激肽B（NKB），另一种是抑制性的，称为强啡肽A（Dyn）（因此它们被称为KNDy神经元）。KNDy神经元是神经网络的重要组成部分，可以驱动GnRH的脉冲，从而驱动生殖。然而，我们仍然不明白KNDy网络如何产生kisspeptin脉冲流（就像时钟的滴答声）来驱动GnRH脉冲。由于这个系统的复杂性，我们开发了KNDy网络的数学模型，以帮助我们理解这个复杂神经系统中所有关键元素的关系，就像天气预报模型帮助我们理解复杂的气象数据一样。令人惊讶的是，我们的数学模型的主要预测之一是，KNDy网络内的低水平恒定活动是GnRH脉冲的主要原因。我们的试点实验室实验表明，这实际上是生命系统的工作方式，并证明了对模型及其含义的全面检查。这些新的发现提供了对GnRH脉冲发生器的滴答功能的控制的第一个见解。随着我们数学模型和补充实验室实验的不断发展，我们将发现激素释放的脉冲是如何控制的，也会发现大脑的其他部分，特别是杏仁核区域的情感中心，可以影响或调节GnRH脉冲发生器和人类的生殖这个项目提供了一个独特的机会，不仅解开机制的脉动性质GnRH分泌，这是必不可少的生殖，但建立与杏仁核中的情绪压力系统，调节脉冲发生器的关键相互作用，从而帮助未来开发更有效的治疗与生育力和健康有关的疾病的压力。

项目成果

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.

Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice.

• DOI: 10.1210/endocr/bqab206
• 发表时间: 2021-12-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Ivanova D;Li XF;McIntyre C;Liu Y;Kong L;O'Byrne KT
• 通讯作者: O'Byrne KT

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

• DOI: 10.1210/endocr/bqac196
• 发表时间: 2022-12-19
• 期刊: Endocrinology
• 影响因子: 4.8

Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

• DOI: 10.1101/2021.06.20.449139
• 发表时间: 2021-06
• 期刊: bioRxiv
• 作者: D. Ivanova;Xiao-feng Li;C. McIntyre;Yali Liu;Ling-Ling Kong-Ling;K. O'Byrne

Posterodorsal medial amygdala urocortin-3, GABA and glutamate mediate suppression of LH pulsatility in female mice

后背内侧杏仁核 urocortin-3、GABA 和谷氨酸介导雌性小鼠 LH 搏动的抑制

• DOI: 10.1101/2022.07.07.499104
• 发表时间: 2022
• 作者: Ivanova D