Dissecting the Role of Tachykinins in the Generation of GnRH Pulses

摘要 促性腺激素轴的激活需要下丘脑的搏动性释放 十肽GnRH。如果没有这些脉冲，繁殖就会受阻。尽管 GnRH版本的这一关键功能，即管理的中央机制的性质 这种脉冲式释放仍不清楚。近年来，弓状核的Kiss1神经元 原子核被认为有可能将这个脉冲产生器保持到 其共同递质速激肽、神经激肽B和强啡肽A的协同作用 (Dyn)，这导致这些神经元被称为KNDy神经元。我提出了一个模型， 哪种NKB刺激和Dyn抑制KNDy神经元释放Kispeptin导致 一种脉动模式，然后被转化为促性腺激素释放激素，从而产生促黄体生成素脉冲。 然而，我们最近发现，其他速激肽(P物质、SP和 神经激动素A，NKA)可以激活KNDy神经元，增加一层额外的复合层 这个型号。重要的是，最近对啮齿动物和猴子的研究表明， 速激肽诱导黄体生成素的释放发生在KNDy神经元的水平上，因此 Kispeptin依赖。然而，我们最近观察到，在存在 循环雌二醇(E_2)水平，NKB和SP均可引起黄体生成素释放的显著增加 以一种Kispeptin独立的方式，这与以前的模型相妥协。 重要的是，KNDy神经元和GnRH神经元(尽管程度较小)表达 SP(Tacr1)和NKB(Tacr3)的受体，表明速激肽可能能够 在合适的性激素条件下，在两个神经元水平上进行作用以诱导黄体生成素的释放。 这项提案的总体目标是描述每种速激肽在 小鼠KNDy神经元与促性腺激素释放激素的促黄体生成素脉冲的频率和幅度 神经元利用一系列互补的功能、神经解剖学和遗传学 学习。这项提议的成功完成将提供新的治疗策略 生殖障碍影响促性腺激素释放激素的分泌。

ABSTRACT The activation of the gonadotropic axis requires the pulsatile release of the hypothalamic decapeptide GnRH. Reproduction is thwarted in the absence of these pulses. Despite this critical feature of GnRH release, the nature of the central mechanisms that govern this pulsatile release remain unknown. In recent years, Kiss1 neurons of the arcuate nucleus have been posed as likely candidates to hold this pulse generator through the coordinated action of its co-transmitters tachykinin neurokinin B (NKB) and dyrorphin A (Dyn), which has led these neurons to be termed KNDy neurons. I propose a model in which NKB stimulates and Dyn inhibits kisspeptin release from KNDy neurons leading to a pulsatile pattern that would then be translated into GnRH, and therefore LH, pulses. However, we have recently documented that other tachykinins (substance P, SP and neurokinin A, NKA) can activate KNDy neurons, adding an additional complex layer to this model. Importantly, recent studies in rodents and monkeys indicate that the action of tachykinins to induce LH release happens at the level of KNDy neurons and is therefore kisspeptin-dependent. However, we have recently observed that in the presence of circulating estradiol (E2) levels, both NKB and SP evoke a potent increase in LH release in a kisspeptin-independent manner, which compromises the previous model. Importantly, KNDy neurons and GnRH neurons (albeit to a lesser extend) express the receptors for SP (Tacr1) and NKB (Tacr3), suggesting that tachykinins may be able to act at both neuronal levels to induce LH release under the right sex steroid conditions. The overall goal of this proposal is to characterize the role of each tachykinin in the frequency and amplitude of LH pulses in the mouse at the KNDy neuron vs GnRH neuron using a series of complementary functional, neuroanatomical and genetic studies. The successful completion of this proposal will offer new strategies to treat reproductive disorders affecting GnRH secretion.