Control of pulsatile reproductive hormone secretion by sleep-wake transitions

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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.