Control of pulsatile reproductive hormone secretion by sleep-wake transitions

生殖严重依赖于生殖激素的间歇性（即所谓的脉动性）分泌，以维持卵巢和睾丸的正常活动。经过几十年的研究，产生这种脉冲式激素分泌模式的细胞最近被定义为位于下丘脑弓状核（ARN）的kisspeptin神经元。这些kisspeptin神经元间歇性地同步它们的活动，以产生刺激促性腺激素释放激素（GnRH）神经元的活动爆发，进而驱动循环中生殖激素的脉冲式释放。虽然在了解ARN kisspeptin神经元的特性方面已经取得了重大进展，但触发每次活动的时间机制仍然未知。在进行许多观察自由行为小鼠ARN kisspeptin神经元活动的研究过程中，我们注意到同步活动的事件有时似乎与唤醒状态相关。在初步研究中，我们使用脑电图（EEG）记录直接检查了ARN kisspeptin神经元同步与整体大脑活动的关系。令人惊讶的是，我们发现，一半的所有情节的kisspeptin神经元同步发生在大脑的睡眠-觉醒过渡点，无论是睡眠到觉醒或清醒到sleep.The目前的一套研究的目的是了解和探索的机制，负责睡眠-觉醒过渡和kisspeptin神经元同步的启动之间的显着关联。我们假设已知的负责控制睡眠-觉醒动力学的脑回路也向ARN kisspeptin神经元发送直接输出，以引导它们的同步行为。实验将使用复杂的遗传小鼠模型，在其中可以记录ARN kisspeptin神经元的活动，同时还可以操纵已知控制睡眠-觉醒转换的神经回路的活动。该项目提供了一个前景，定义一个关键的大脑机制，负责产生脉冲生殖激素分泌的事件。睡眠-觉醒转换在生殖激素分泌时间上的意外参与可能是睡眠障碍与人类不孕症已知关联的基础。

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.