Many of the symptoms associated with sleep loss, e.g. fatigue, performance impairments, metabolic syndrome, chronic inflammation, sleepiness, etc;can be elicited by administration of interleukin-1 beta (IL1) or related cytokines or can be prevented by blocking them. Nevertheless, the regulation of the IL1 family in the brain is mostly undetermined. Recently a new brain-specific IL1 receptor accessory protein (IL1 AcPb) was identified. Although its function remains unknown preliminary data show that sleep deprivation enhances its cortical expression. The function for another IL1 family member, IL36 (formerly ILF7) has very recently (unpublished) been identified;IL36 inhibits several pro-inflammatory somnogenic cytokines including IL1, while simultaneously promoting expression of anti-inflammatory anti-somnogenic cytokines.
In Aim 1, we determine the roles that IL1 AcPb and IL36 have in sleep regulation. For over 100 years it has been known that prolonged wakefulness (W) enhances brain production and release of sleep regulatory substances (SRSs). Nevertheless, the property of W that is responsible for enhanced SRS activity remains to be identified.
In Aim 2, we investigate the hypothesis that ATP, released during neurotransmission, is a signal that provides a measure of prior W activity. Specifically, ATP is translated, via purine P2 receptors, into a longer lasting index of prior brain usage through release of cytokines such as IL1 from glia. Preliminary data indicate that ATP agonists promote sleep while ATP antagonists inhibit sleep and P2X7 receptor expression varies with sleep propensity.
In Aim 2, we test our model, the ATP-cytokine-adenosine hypothesis, by using mice lacking key model component genes such as the P2X7 receptor. These mice, for example have attenuated sleep responses to sleep loss and the inflammatory stimulus, lipopolysaccharide.
In Aim 3, we focus on activity-dependency of SRS gene expression and EEG delta power. We make use of the light-sensitive channelrhodopsin 2 (ChR2) gene by expressing it in cell cultures, then activating the cells with various patterns of light and determine SRS and model gene expressions. We also use ChR2- transgenic mice for in vivo controlled activation of cortical neurons and subsequent manifestations on the EEG. Anticipated results will provide mechanistic answers to questions of how inflammation alters sleep and how cellular activity is translated into SRS mechanisms. Results will have practical application to IL1- associated brain pathologies including inflammation-associated sleep disturbances occurring in sleep apnea and metabolic syndrome.

Public Health Relevance

The roles that interleukin-1 (IL1) and IL1 family (IL1F) members have in inflammation-associated sleep disturbances and physiological sleep regulation are investigated. The involvement of a brain-specific IL1 receptor accessory protein and IL36 in sleep and brain-inflammation processes is determined. Further, ATP released during neurotransmission is posited to be part of the mechanism by which the brain tracks prior activity during wakefulness. We test the hypothesis that extracellular ATP, via purine type 2 receptors- mediates release of IL1 and other cytokines from glia and plays a key role sleep regulation and sleep responses to inflammatory signals. Finally, we test whether different patterns of cell activation change gene expression of IL1 and other components of the ATP-cytokine-adenosine hypothesis and whether different cell activation patterns differentially alter EEG delta power state-specifically. Results will have practical application to IL1-associated brain pathologies including inflammation-associated sleep disturbances occurring in sleep apnea and metabolic syndrome.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
He, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
Krueger, James M; Nguyen, Joseph T; Dykstra-Aiello, Cheryl J et al. (2018) Local sleep. Sleep Med Rev 43:14-21
Rockstrom, Matthew D; Chen, Liangyu; Taishi, Ping et al. (2018) Tumor necrosis factor alpha in sleep regulation. Sleep Med Rev 40:69-78
Davis, Christopher J; Zielinski, Mark R; Dunbrasky, Danielle et al. (2017) Interleukin 37 expression in mice alters sleep responses to inflammatory agents and influenza virus infection. Neurobiol Sleep Circadian Rhythms 3:1-9
Oonk, Marcella; Krueger, James M; Davis, Christopher J (2016) Voluntary Sleep Loss in Rats. Sleep 39:1467-79
Krueger, James M; Frank, Marcos G; Wisor, Jonathan P et al. (2016) Sleep function: Toward elucidating an enigma. Sleep Med Rev 28:46-54
Davis, Christopher J; Taishi, Ping; Honn, Kimberly A et al. (2016) P2X7 receptors in body temperature, locomotor activity, and brain mRNA and lncRNA responses to sleep deprivation. Am J Physiol Regul Integr Comp Physiol 311:R1004-R1012
Krueger, James M; Roy, Sandip (2016) Sleep's Kernel: Surprisingly small sections of brain, and even neuronal and glial networks in a dish, display many electrical indicators of sleep. Scientist 30:36-41
Krueger, J M; Opp, M R (2016) Sleep and Microbes. Int Rev Neurobiol 131:207-225
Oonk, Marcella; Davis, Christopher J; Krueger, James M et al. (2015) Sleep deprivation and time-on-task performance decrement in the rat psychomotor vigilance task. Sleep 38:445-51
Davis, Christopher J; Dunbrasky, Danielle; Oonk, Marcella et al. (2015) The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice. Brain Behav Immun 47:35-43

Showing the most recent 10 out of 224 publications