This proposal addresses a mechanism by which cellular stress influences sleep. Our working hypothesis is that acute stress that occurs with short-term sleep loss or during an early stage of infection causes cellular stress that leads to an acute restorative sleep response. However, during prolonged chronic stress, the acute sleep response dissipates and sleep becomes fragmented. Sleep also disintegrates and becomes fragmented with aging and a number of human diseases, including cardiovascular, metabolic and neurodegenerative disorders including Alzheimer's disease, all of which involve an inflammatory process. However, the cellular and molecular mechanisms by which this occurs remains poorly understood. Our recent findings indicate that endoplasmic reticulum (ER) stress contributes to sleep fragmentation. The unfolded protein response (UPR), which alleviates ER stress, also alleviates fragmented sleep. However, the mechanisms by which ER stress disrupts sleep and the UPR promotes sleep are unclear. In an effort to understand how the UPR promotes restorative sleep, this proposal exploits the Drosophila model to address questions regarding the complex relationship between inflammation, ER stress, the UPR, and sleep. Drosophila and other organisms show a transient increase in sleep in response to stress, including infection, aseptic injury, and sleep deprivation. The recent observation that extending stress-induced sleep prolongs survival during infection indicates that this is an important and adaptive behavioral response. Based on published and preliminary studies, we hypothesize that the UPR and ER stress modulate sleep via a Jun-N-terminal kinase (JNK) dependent signaling pathway. We will use biochemical and behavioral genetic approaches to test key components of this hypothesis in both sleep deprivation and infection assays. Results of these studies will reveal a mechanism for restorative sleep and for how sleep disintegrates with chronic inflammation. Findings from this project will have important implications for treatment of sleep disturbances as prodromal markers of neurodegenerative and other age- related diseases such as Parkinson's and Alzheimer's disease.

Public Health Relevance

Sleep fragmentation is associated with a number of diseases that involve an inflammatory process, such as cardiovascular, neurodegenerative, or metabolic disorders. Cellular stress is known to cause sleep fragmentation, but the mechanism by which this occurs is poorly understood. This project will use the Drosophila genetic model to evaluate a mechanism by which the cellular stress response promotes restorative sleep. Findings from this project will have important implications for treatment of sleep disturbances as prodromal markers of neurodegenerative and other age-related disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Sesma, Michael A
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University of Pennsylvania
Schools of Medicine
United States
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Ly, Sarah; Pack, Allan I; Naidoo, Nirinjini (2018) The neurobiological basis of sleep: Insights from Drosophila. Neurosci Biobehav Rev 87:67-86