Infection negatively impacts mental health. Sick individuals become lethargic, experience cognitive deficits and malaise, and lose interest in social contact and other usual daily activities. Prominent among the changes in CNS processes during infection are alterations in sleep. Cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF), and IL-6 are upregulated during infection. Two lines of evidence suggest that infection-induced alterations in sleep are mediated by actions of these cytokines in brain. First, numerous studies indicate IL-1, TNF, and IL-6 regulate/modulate physiological sleep in the absence of immune challenge. Second, experimental models for which alterations in sleep have been determined are associated with increases in these same cytokines. The involvement of IL-1, TNF, and IL-6 in the regulation of sleep, and the alterations in sleep that occur during infections in which these cytokines are upregulated, have led to suggestions that infection-induced alterations of sleep are mediated by cytokines in brain. Although plausible, and based on empirical evidence, studies to directly test this hypothesis have not been conducted. The fundamental goal of this project is to determine how acute infections alter sleep. To achieve this goal we will use a clinically relevant murine model of infection, sepsis induced by cecal ligation and puncture. We propose experiments that focus on cytokines (IL-1, TNF, IL-6) as mediators of infection-induced alterations in sleep. We will: 1) determine the extent infection alters sleep and the impact of prior sleep loss on responses to infection; 2) quantify alterations in cytokine mRNA and protein in brain during infection; and 3) answer the question """"""""Does interfering with cytokine actions in brain impact infection-induced alterations in sleep?"""""""" IL-1, TNF, and IL-6 have been the subject of intense investigation with respect to their peripheral roles in sepsis, and are known central regulators/modulators of sleep. As such, there is a strong conceptual framework within which to investigate the mechanistic relationships between sleep and sepsis, and mediators implicated in both processes. We present preliminary data that demonstrate long-term alterations in CNS function following acute peripheral infection. We demonstrate our ability to determine multiple facets of sleep-wake behavior of mice and to target cytokine systems in brain. Successful completion of the proposed studies will provide information critical to understanding how infection impacts CNS function, as evidenced by alterations in sleep.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080972-04
Application #
7240436
Study Section
Special Emphasis Panel (ZRG1-SCS (05))
Program Officer
Twery, Michael
Project Start
2004-09-27
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$361,913
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Granger, Jill I; Ratti, Pietro-Luca; Datta, Subhash C et al. (2013) Sepsis-induced morbidity in mice: effects on body temperature, body weight, cage activity, social behavior and cytokines in brain. Psychoneuroendocrinology 38:1047-57
Baracchi, Francesca; Ingiosi, Ashley M; Raymond Jr, Richard M et al. (2011) Sepsis-induced alterations in sleep of rats. Am J Physiol Regul Integr Comp Physiol 301:R1467-78
Imeri, Luca; Opp, Mark R (2009) How (and why) the immune system makes us sleep. Nat Rev Neurosci 10:199-210
Opp, Mark R (2009) Sleep and psychoneuroimmunology. Immunol Allergy Clin North Am 29:295-307
Opp, Mark R (2009) Sleeping to fuel the immune system: mammalian sleep and resistance to parasites. BMC Evol Biol 9:8
Wada, Masayuki; Saunders, Thomas L; Morrow, Jason et al. (2009) Two pathways for cyclooxygenase-2 protein degradation in vivo. J Biol Chem 284:30742-53
Nemzek, Jean A; Hugunin, Kelly M S; Opp, Mark R (2008) Modeling sepsis in the laboratory: merging sound science with animal well-being. Comp Med 58:120-8
Baracchi, Francesca; Opp, Mark R (2008) Sleep-wake behavior and responses to sleep deprivation of mice lacking both interleukin-1 beta receptor 1 and tumor necrosis factor-alpha receptor 1. Brain Behav Immun 22:982-93
Datta, Subhash C; Opp, Mark R (2008) Lipopolysaccharide-induced increases in cytokines in discrete mouse brain regions are detectable using Luminex xMAP technology. J Neurosci Methods 175:119-24
Opp, Mark R (2006) Sleep and psychoneuroimmunology. Neurol Clin 24:493-506

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