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There is a wealth of data supporting a central role for the prion protein (PrP) in the neurodegenerative prion diseases of both humans and other species, yet the normal function of PrP, which is expressed at the cell surface of neurons and glial cells, is unknown. It has been speculated that neuropathology may be due to loss of normal function of PrP. Here we show that in mice devoid of PrP there is an alteration in both circadian activity rhythms and patterns. To our knowledge, this is the first null mutation that has been shown to affect sleep regulation and our results indicate that at least one of the inherited prion diseases, fatal familial insomnia, where there is a profound alteration in sleep and the daily rhythms of many hormones, may be related to the normal function of the prion protein.

Vigilance states, electroencephalogram (EEG) power spectra (0.25-25.0 Hz), and cortical temperature (TCRT) of 10 rats were obtained during a baseline day, a 24-h sleep deprivation (SD) period, and 2 days of recovery (recoveries 1 and 2). EEG power density in waking gradually increased in most frequencies during the SD period. Non-rapid-eye-movement (NREM) sleep was enhanced on both recovery days, and rapid-eye-movement sleep was enhanced only on recovery 1. In the initial 4 h of recovery 1, EEG slow-wave activity (SWA; mean power density 0.75-4.0 Hz) in NREM sleep was elevated relative to baseline, and the number of brief awakenings (nBA) was reduced. In the dark period of recovery 1 and the light period of recovery 2, SWA was below baseline, and nBA was increased. During the entire recovery period, SWA and nBA, both expressed as deviation from baseline values, were negatively correlated. During the SD period, TCRT was above baseline, and in the initial 16 h of recovery 1 it was below baseline. Whereas TCRT was negatively correlated with NREM sleep, no significant correlation was found between TCRT and SWA within NREM sleep. It is concluded that SD causes a short-lasting intensification of sleep, as indicated by the enhanced SWA and the reduced nBA, and a long-lasting increase in sleep duration. The different time courses of SWA and TCRT suggest that variations in NREM sleep intensity are not directly related to changes in TCRT.

Production of TNF-␣ and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-␣ and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-␣ on the circadian timing system. TNF-␣ is shown here to suppress the expression of the PAR bZip clockcontrolled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-␣ on clock genes is shared by IL-1␤, but not by IFN-␣, and IL-6. Furthermore, TNF-␣ interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-␣ is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-␣ and IL-1␤, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.behavior ͉ circadian rhythms ͉ cytokines ͉ innate immunity

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Mice are the preferred mammalian species for genetic investigations of the role of proteins. The normal function of the prion protein (PrP) is unknown, although it plays a major role in the prion diseases, including fatal familial insomnia. We investigated its role in sleep and sleep regulation by comparing baseline recordings and the effects of sleep deprivation in PrP knockout mice (129/SV) and wild-type controls (129/SV ϫ C57BL/6), which are the mice used for most gene targeting experiments and whose behavior is not well characterized. Although no difference was evident in the amount of vigilance states, the null mice exhibited a larger degree of sleep fragmentation than the wild-type with almost double the amount of short waking episodes. As in other rodents, cortical temperature closely reflected the time course of waking. The increase of slow-wave activity (SWA; mean EEG power density in the 0.25-4.0 Hz range) at waking to nonrapid eye movement (NREM) sleep transitions was faster and reached a lower level in the null mice than in the wild-type. The contribution of the lower frequencies (0.25-5.0 Hz) to the spectrum was smaller than in other rodents in all three vigilance states, and the distinction between NREM sleep and REM sleep was most marked in the theta band. After the sleep deprivation, SWA was increased, but the changes in EEG power density and SWA were more prominent and lasted longer in the PrP-null mice. Our results suggest that PrP plays a role in promoting sleep continuity.

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