Spontaneous and influenza virus-induced sleep are altered in TNF-{alpha} double-receptor deficient mice

1 Department of Biological Sciences, Fordham University, Bronx, New York; and 2 Programs in Neuroscience, Washington State University, Pullman, Washington Submitted 10 March 2008 ; accepted in final form 1 August 2008 Tumor necrosis factor- (TNF- ) is associated with sleep regulation in health and disease. Previous studies assessed sleep in mice genetically deficient in the TNF- 55-kDa receptor. In this study, spontaneous and influenza virus-induced sleep profiles were assessed in mice deficient in both the 55-kDa and 75-kDa TNF- receptors [TNF-2R knockouts (KO)] and wild-type (WT) strain controls. Under baseline conditions the TNF-2R KO mice had less non-rapid eye movement sleep (NREMS) than WTs during the nighttime and more rapid eye movement sleep (REMS) than controls during the daytime. The differences between nighttime maximum and daytime minimum values of electroencephalogram (EEG) delta power during NREMS were greater in the TNF-2R KO mice than in WTs. Viral challenge (mouse-adapted influenza X-31) enhanced NREMS and decreased REMS in both strains roughly to the same extent. EEG delta power responses to viral challenge differed substantially between strains; the WT animals increased, whereas the TNF-2R KO mice decreased their EEG delta wave power during NREMS. There were no differences between strains in body temperatures or locomotor activity in uninfected mice or after viral challenge. Analyses of cortical mRNAs confirmed that the TNF-2R KO mice lacked both TNF- receptors; these mice also had higher levels of orexin mRNA and reduced levels of the purine P2X7 receptor compared with WTs. Results reinforce the hypothesis that TNF- is involved in physiological sleep regulation but plays a limited role in the acute-phase response induced by influenza virus. cytokine; hypothermia; electroencephalogram delta power; purine receptor; orexin Address for reprint requests and other correspondence: L. Kapás, Dept. of Biological Sciences, Fordham Univ., Bronx, NY 10458 (e-mail: kapas{at}fordham.edu )