A novel mechanism underlying GnRH pulse generation by KNDy neurones

繁殖能力对我们物种的生存是绝对必要的，这取决于大脑中一个令人惊叹的“时钟”。这种时钟负责驱动一种名为促性腺激素释放激素(GnRH)的大脑激素的间歇性分泌，GnRH控制着一系列激素信号的级联，不仅触发青春期，而且负责整个生命过程中受精卵和精子的产生。这种神经时钟被称为“GnRH脉冲发生器”。尽管它是在半个多世纪前被发现的，而且被证明位于大脑中一个非常小的区域，称为下丘脑，但直到最近，这种时钟的部件仍然难以捉摸。大约15年前，当在下丘脑中发现了一种名为Kispeptin的新大脑化学物质时，人们非常兴奋。这种化学物质被证明是激活大脑中促性腺激素释放激素神经细胞的关键环节。更令人惊讶的是，这些产生Kispeptin的神经元还制造了两种额外的化学物质；一种名为神经激肽B(NKB)的刺激性化学物质和一种名为强啡肽A(Dyn)的抑制性化学物质(因此而得名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，从而推动生殖。然而，我们仍然不明白KNDy网络是如何产生Kispeptin脉冲流(就像时钟的滴答)来驱动GnRH脉冲的。由于这个系统的复杂性，我们开发了一个KNDy网络的数学模型来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网络内低水平的持续活动是GnRH脉冲的主要原因。我们的试验性实验室实验表明，这实际上是生命系统的工作方式，并证明了对该模型及其含义进行全面检查的合理性。这些新的发现为控制GnRH脉冲发生器的滴答功能提供了第一个洞察力。随着我们数学模型的不断发展和补充的实验室实验，我们将发现激素释放脉冲是如何被控制的，还将发现大脑的其他部分，最明显的是杏仁核区域的情绪中心，如何影响或调节GnRH脉冲生成器和人类的生殖。这个项目提供了一个独特的机会，不仅可以揭开GnRH分泌脉动性的潜在机制，这对生殖是必不可少的，而且还可以与杏仁核中调节脉冲生成器的情绪应激系统建立关键的相互作用，从而帮助未来开发更有效的治疗与应激相关的生育和健康障碍的方法。

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.