Project Summary Primary sleep abnormalities (insomnia, shift work, and obstructive sleep apnea) promote an inflammatory environment and are associated with the development of cardiovascular and metabolic disease. However, the mechanisms underlying these relationships are poorly understood. The proposed research examines hormonal mechanisms that underlie the inflammatory response to sleep fragmentation (SF) using pharmacological approaches in mice. Previous R15-funded research in our lab examined the effect of sympathetic nervous system (SNS) activation upon inflammatory responses to sleep loss. In this renewal application, the role that activation of the hypothalamic-pituitary-adrenal (HPA) axis plays in modulating inflammation from acute and chronic SF will be investigated. Aim 1 will examine whether glucocorticoids mediate the onset of SF-induced inflammation and the activation of microglia, an important contributor to neuroinflammation. Specifically, mice will be adrenalectomized, sham-adrenalectomized, or adrenalectomized and rescued with exogenous glucocorticoids and then subjected to acute and chronic SF. Pro- and antiinflammatory gene and protein expression will be assessed using RT-PCR and multiplex Luminex protein arrays, respectively. Immunocytochemistry will be used to assess microglia activation. These findings will be validated through pharmacological inhibition of glucocorticoid production and binding to glucocorticoid receptors. Instead of a classic anti-inflammatory effect, it is predicted that glucocorticoids will prime SF-induced inflammation. Aim 2 will examine the time course of glucocorticoid release and pro-inflammatory responses to acute and chronic SF. Taken together, the proposed research will assess the importance of the adrenocortical response in mediating inflammation during sleep loss, and provide unique training opportunities for undergraduates interested in conducting biomedical research in endocrinology, immunology, and the neurosciences.

Project Narrative Poor sleep habits and sleep abnormalities caused by insomnia, shift work, and sleep-disordered breathing are becoming more prevalent in modern society. Disordered sleep promotes inflammation, which is a common mechanism for the development of cardiovascular and metabolic diseases. Understanding how the stress response contributes to the development of inflammation during sleep loss could lead to novel therapeutic interventions for treating inflammation-dependent disorders, such as cardiovascular disease.