The episodic release of gonadotropin releasing hormone (GnRH) is essential for the reproductive function. Pulsatile GnRH/LH secretion is observed during late embryonic development and early postnatal life. After this initial activity, the hypothalamo-pituitary-gonads (HPG) axis becomes quiescent until pubertal maturation, when pulsatile GnRH release is re-initiated. One intriguing aspect of the ?reawakening? of the HPG axis at puberty is that increased luteinizing hormone (LH) secretion is initially detected during nighttime sleep. Sleep related changes in LH secretion are also observed in adults. For example, nocturnal slowing of LH pulse frequency and increase in follicle stimulating hormone (FSH) secretion during early follicular phase have been both related to sleep. As a consequence, disruption of day-night GnRH pulse frequency across the menstrual cycle may disrupt LH and FSH secretion and perturb the reproductive function. The neuronal population(s) and/or brain circuitry linking sleep patterns and LH/FSH secretion are currently unknown. We hypothesize that the melanin-concentrating hormone (MCH) neurons play a crucial role in the integration of sleep and reproductive function. The MCH neurons project to sites related to sleep regulation (e.g., the tuberomammillary and pontine nuclei) and reproductive control (e.g., the preoptic area). In humans and rodents, MCH terminals are in close apposition with GnRH cells, which express MCH receptor. Notably, MCH neurons are active during both non- rapid eye movement (NREM) and rapid-eye movement (REM) sleep; and optogenetic activation of MCH neurons significantly increases sleep. In this application, we will test the hypothesis that activation of a specific population of MCH neurons drives sleep and alters the pulsatile secretion of LH. We will interrogate the system applying three highly specialized methodologies: a) the designer receptors exclusively activated by designer drugs (DREADDs) and AAV delivery in a Cre-loxP approach; b) the sleep recordings; and c) the automated blood sampling. We will be able to remotely activate the MCH neurons and perform physiological measurements of sleep pattern and pulsatile LH secretion. We will further determine if the MCH effects upon sleep and LH secretion are observed in both sexes and whether they are dependent on sex steroids milieu. Our overall objective in this exploratory and developmental research application is to access the accuracy of our model initially in adult mice, and break new grounds in the neural control of complex physiological systems, i.e. sleep and reproductive function. Our studies will open new opportunities for better understanding of the mechanisms associated with pubertal development and reproductive deficits caused by disruption of sleep.

Public Health Relevance

Pubertal development is triggered by a nocturnal rise in luteinizing hormone (LH) secretion directly associated with sleep. The neuronal population and/or brain circuitry involved in sleep and the reproductive function is currently unknown. We will use mouse models, sleep recordings and automated blood sampling to assess the role of MCH neurons as potential neuronal population linking sleep and the reproductive neuroendocrine axis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Ravindranath, Neelakanta
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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