Reduced and fragmented sleep is associated with infertility in humans. Nearly one fifth of American couples struggle with infertility and, with increasing environmental exposure to sleep and circadian disruptors, deficiencies in pubertal development and fertility will likely continue to increase. At the apex of the hypothalamo- pituitary-gonadal (HPG) axis, central to reproductive physiology, are gonadotropin-releasing hormone (GnRH) neurons. Episodic release of GnRH drives pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn act on the gonads to promote maturation of gametes and production of sex steroids. A bout of high-frequency LH pulses is required for both pubertal onset and ovulation. Notably, the rise in LH pulse frequency that precipitates puberty occurs during sleep, while in adults, LH pulse frequency is reduced during sleep. However, the mechanisms linking sleep and reproduction represent a significant gap in the literature. We hypothesize that hypothalamic melanin-concentrating hormone (MCH) neurons temporally integrate the activity of the sleep and reproductive systems. MCH neurons are active during sleep and have projections to areas of reproductive control. Furthermore, administration of MCH to the medial preoptic area (mPOA), where GnRH neurons are abundant, is capable of both increasing and suppressing LH pulsatility. One possible explanation for this is that MCH neurons and their targets are more heterogeneous than previously thought, particularly between the sexes. Additionally, variability of sleep patterns and response to sex steroid feedback throughout the female estrous cycle are not accounted for in a consistent manner across studies.
We aim to define the projection targets and co-expressed peptides of MCH neurons in the mouse brain to reveal distinct subpopulations and any differences therein defined by sex or the estrogen milieu. Further, we aim to systematically determine the effect of chemogenetically manipulating each of these subpopulations on cortical EEG and blood LH concentration as outputs of sleep and HPG axis activation, respectively. These studies will be performed in male and female mice in varied estrogen milieu and the results compared across groups. Finally, using the same experimental groups, we will measure LH secretion following manipulation of MCH neuronal subpopulations in both sleep and waking. This three-pronged approach will enable us to untangle the effects of MCH on both sleep and the reproductive axis and, importantly, the novel question of how these roles are related. Our attention to MCH neuronal subpopulations, sex differences, and the effects of the sex steroid milieu on both sleep and the HPG axis will define the transcriptional and functional heterogeneity of MCH neurons and contribute to a working model of how sleep and the HPG axis interact to result in normal pubertal development and reproduction.
Poor sleep hygiene and shift work have made sleep fragmentation and circadian rhythm disturbance a public health crisis with deleterious effects on reproductive function. I will use cutting-edge technologies in systems neuroscience, including combined chemogenetics and cortical EEG recordings, to elucidate the neural circuitry integrating sleep and reproductive physiology. Our study will contribute to a mechanistic understanding of how sleep interacts with reproductive function, facilitating development of potential interventions to improve reproductive success and individual health.
