Mechanism Underlying Sleep Disruption by Mammary Tumors

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ABSTRACT Sufficient quantity and quality of sleep is critical for maintaining optimal physical and mental health. Indeed, inadequate sleep can influence many crucial physiological functions and impair cognitive performance and mood regulation. Patients diagnosed with breast cancer are at particularly high risk for sleep disorders, and disordered sleep may influence the progression of their disease as more aggressive tumors have been observed among women who routinely sleep fewer hours. Despite evidence of sleep disorders emerging prior to diagnosis in cancer patients, and the potentially devastating consequences, the etiology of tumor- induced sleep disorders remains unknown. The goal of this R21 application is to determine the physiological mechanisms through which mammary tumors impair sleep. The guiding hypothesis of the proposed research is that mammary tumors increase serum ghrelin concentration, which alters the activity of orexin-hypocretin (OH) neurons, and in turn disrupts sleep. This proposal represents the first examination of ghrelin in cancer- related sleep disruption. Our preliminary data demonstrate that mammary tumors express ghrelin mRNA, significantly elevate serum ghrelin concentrations, and alter sleep. We also have shown that mammary tumors increase the number of activated orexin/hypocretin (OH) neurons in the hypothalamus, a population of cells critical for sleep-wake regulation. Aim 1 will use converging pharmacological and genetic (CRISPR) approaches to test the hypothesis that ghrelin is a causal factor in altered hypothalamic OH activity and sleep disruption among tumor bearing mice. Aim 2 will use a DREADD approach to establish whether OH neurons in the lateral hypothalamus play a causal role in tumor-disrupted sleep. Together, the proposed studies will provide an extensive characterization of the effects of mammary tumors on sleep and the potentially disruptive role of increased ghrelin concentration and altered OH neuronal activity. The long-range goal of this research is to improve the mental and physical health of cancer patients, as well as their quality of life, through the normalization of sleep beginning at cancer diagnosis; the first step in achieving this goal is determining the mechanisms through which tumors alter sleep.