Department of Mathematics and Statistics, University of Exeter, Stocker Road, Exeter EX4 4PY, UK.
Living Systems Institute, University of Exeter, Stocker Road, Exeter EX4 4PY, UK.
J R Soc Interface. 2024 Aug;21(217):20240143. doi: 10.1098/rsif.2024.0143. Epub 2024 Aug 28.
Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region that is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections' outputs on the GnRH pulse generator's activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity and offers insights into stress-related dysregulation.
正常的生殖功能和生育能力依赖于促性腺激素释放激素（GnRH）的节律性分泌，而 GnRH 的分泌则受到下丘脑 GnRH 脉冲发生器的驱动。 GnRH 脉冲发生器的一个关键调节因子是内侧杏仁核的后背部亚核（MePD），这是一个参与处理外部环境线索的脑区，包括应激的影响。然而，使 GnRH 分泌产生动态、应激触发调节的神经元通路在很大程度上仍然未知。在这里，我们采用建模的方法来探索动态输入对 GnRH 脉冲发生器活性的影响。我们引入并分析了一个代表由 GABA 能和谷氨酸能神经元群体组成的 MePD 神经元回路的数学模型，并将其与我们的 GnRH 脉冲发生器模型相结合。我们的分析剖析了 MePD 兴奋性和抑制性投射对 GnRH 脉冲发生器活性的影响，并揭示了 MePD 谷氨酸能投射对 GnRH 脉冲发生器的功能相关性，我们通过光遗传学对此进行了探测。我们的研究阐明了 MePD 神经元动力学如何影响 GnRH 脉冲发生器的活性，并为应激相关的失调提供了深入了解。
