Control of pulsatile reproductive hormone secretion by sleep-wake transitions

生殖在很大程度上依赖于间歇性的、所谓的搏动性生殖激素的分泌，以维持卵巢和睾丸的正常活动。经过几十年的研究，产生这种激素分泌脉动模式的细胞最近被定义为位于下丘脑弓状核(ARN)的Kispeptin神经元。这些Kispeptin神经元间歇性地同步它们的活动，产生一系列活动，刺激促性腺激素释放激素(GnRH)神经元，进而推动血液循环中生殖激素的脉动性释放。虽然在了解ARN kispeptin神经元的特性方面已经取得了重大进展，但触发每一次活动的计时机制仍然未知。在对自由行为小鼠的ARN kispeptin神经元的活动进行观察的过程中，我们注意到有时同步活动的发生似乎与觉醒状态有关。在初步研究中，我们使用脑电(EEG)记录直接检查了ARN Kispeptin神经元的同步性与整体脑活动的关系。令人惊讶的是，我们发现Kispeptin神经元同步的所有事件中有一半恰好发生在大脑睡眠-觉醒转换的时间点；要么是睡眠-唤醒转换，要么是从唤醒到睡眠。这组研究旨在了解和探索睡眠-唤醒转换和Kispeptin神经元同步启动之间显著关联的机制。我们假设，负责控制睡眠-觉醒动力学的已知大脑回路也将直接输出信号发送到ARN Kisspeptin神经元，以引导它们的同步行为。实验将使用复杂的遗传小鼠模型，在该模型中，将有可能记录ARN kispeptin神经元的活动，同时还可以操纵已知的控制睡眠-觉醒转换的神经回路的活动。该项目提供了定义负责产生节律性生殖激素分泌的关键大脑机制之一的前景。睡眠-觉醒转换意外地参与了生殖激素分泌的计时，这可能是人类睡眠障碍与不孕不育之间已知的联系的基础。

Reproduction is critically dependent upon the episodic, so-called pulsatile, secretion of reproductive hormones to maintain the normal activity of the ovaries and testis. After decades of investigation, the cells that generate this pulsatile pattern of hormone secretion have recently been defined as being the kisspeptin neurons located in the arcuate nucleus (ARN) of the hypothalamus. These kisspeptin neurons synchronize their activity intermittently to generate a burst of activity that stimulates the gonadotropin-releasing hormone (GnRH) neurons that, in turn, drive the pulsatile release of reproductive hormones in the circulation. While significant progress has been made in understanding the properties of the ARN kisspeptin neurons, the timing mechanism triggering each episode of activity remains unknown.In the course of undertaking many studies observing the activity of the ARN kisspeptin neurons in freely behaving mice, we noticed that episodes of synchronized activity sometimes appeared to be correlated with states of arousal. In preliminary studies, we directly examined the relationship of ARN kisspeptin neuron synchronizations with overall brain activity using electroencephalogram (EEG) recordings. Surprisingly, we found that half of all episodes of kisspeptin neuron synchronizations occurred precisely at the point of brain sleep-wake transitions; either sleep-to-wake or wake-to-sleep.The present set of studies are designed to understand and explore the mechanism responsible for the remarkable association between sleep-wake transitions and the initiation of kisspeptin neuron synchronizations. We hypothesize that known brain circuits responsible for controlling sleep-wake dynamics also send direct outputs to the ARN kisspeptin neurons to entrain their synchronization behaviour. Experiments will use complex genetic mouse models in which it will be possible to record the activity of the ARN kisspeptin neurons while also manipulating the activity of neural circuits known to control sleep-wake transitions. The project offers the prospect of defining one of the key brain mechanisms responsible for generating episodes of pulsatile reproductive hormone secretion. The unexpected involvement of sleep-wake transitions in timing reproductive hormone secretion may underlie the known associations of sleep disturbance with infertility in humans.