Altered circadian activity rhythms and sleep in mice devoid of prion protein

Tobler, Irene; Gaus, Stephanie E.; Deboer, Tom; Achermann, Peter; Fischer, Marek; Rülicke, Thomas; Moser, Markus; Oesch, Bruno; McBride, Paul; Manson, Jean

doi:10.1038/380639a0

Cited by 611 publications

(352 citation statements)

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“…Consistent with our observations in the PRNP −/− cattle, Prnp −/− mice with exclusive disruption on the Prnp ORF remained healthy 2,3 and showed only slightly abnormal phenotypes, such as altered synaptic function 29,30 and sleep-wake circadian rhythms 31,32 . However, the phenotype in the synaptic function appears to be normal in other murine genetic backgrounds 33 .We have monitored sleep-wake activity in the knockout cattle, along with age-, sex-and breed-matched wild-type controls, at frequent intervals throughout the day and night for one week, but did not observe any obvious alterations.…”

supporting

confidence: 89%

Production of cattle lacking prion protein

et al. 2006

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Prion diseases are caused by propagation of misfolded forms of the normal cellular prion protein PrP C , such as PrP BSE in bovine spongiform encephalopathy (BSE) in cattle and PrP CJD in Creutzfeldt-Jakob disease (CJD) in humans 1 . Disruption of PrP C expression in mice, a species that does not naturally contract prion diseases, results in no apparent developmental abnormalities [2][3][4][5] . However, the impact of ablating PrP C function in natural host species of prion diseases is unknown. Here we report the generation and characterization of PrP C -deficient cattle produced by a sequential gene-targeting system 6 . At over 20 months of age, the cattle are clinically, physiologically, histopathologically, immunologically and reproductively normal. Brain tissue homogenates are resistant to prion propagation in vitro as assessed by protein misfolding cyclic amplification 7 . PrP C -deficient cattle may be a useful model for prion research and could provide industrial bovine products free of prion proteins.To generate PrP C -deficient (PRNP −/− ) cattle, we transfected a male Holstein primary fetal fibroblast line 6594 with first and second knockout (KO) vectors (pBPrP(H)KOneo and pBPrP (H)KOpuro vectors) 6 to sequentially disrupt the two alleles of PRNP. PRNP −/− fetal cell lines were established at 40-60 d of gestation and three of the PRNP −/− fetal cell lines (5211, 5232 and 4296) were recloned to produce calves (Table 1 and Fig. 1a). To verify that the calves possess the PRNP −/− genotype, we collected ear biopsies and established fibroblast cell lines for genotyping. Genotyping was done by genomic PCR specific to each gene targeting event 6 (primer pairs: neoF7 × neoR7 and puroF14 × puroR14, Fig. 1b COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Biotechnology website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Fig. 1c) and confirmed the disruption of PRNP-specific mRNA expression in PRNP −/− calves. For protein expression analysis, we performed PrP-specific western blot analyses on fibroblasts (Fig. 1d), peripheral blood lymphocytes (Fig. 1e) and brain stem (Fig. 1f) from wild-type and PRNP −/− calves using the mouse anti-bovine PrP monoclonal antibody F89. We detected PrP-specific bands in the wild-type calves, whereas no reaction was observed in PRNP −/− calves and negative control mouse fibroblasts. These data clearly demonstrate that the PRNP gene is functionally inactivated in the PRNP −/− calves.PRNP −/− cattle were monitored for growth and general health status from birth to 20 months of age. Mean birth weight was 46 kg and average daily gain was 0.91 kg/d to 10 months. Both values were in the normal range for Holstein bulls. Serum chemistry was evaluated at 6 months of age and compared with published reference ranges. All the values for PRNP −/− calves (n = 12) were well within the reference range (Supplementary Table 1) and obvious abnormalities w...

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supporting

confidence: 89%

Production of cattle lacking prion protein

et al. 2006

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“…The definition found in the literature for arousals is inconsistent. Single events of arousals within a 4 s epoch or a waking episode lasting less than 16 seconds were defined as sleep fragmentations and separated from clear transitions between vigilance states which were longer than 16 seconds [80]. Other definition criteria for clear changes to another behavioral state comprised eight or more consecutive 4s epochs scored as one behavioral state, which were followed by eight or more consecutive 4s epochs scored as a different behavioral state [81].…”

Section: Discussionmentioning

confidence: 99%

Rapid eye movements during sleep in mice: High trait-like stability qualifies rapid eye movement density for characterization of phenotypic variation in sleep patterns of rodents

et al. 2011

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BackgroundIn humans, rapid eye movements (REM) density during REM sleep plays a prominent role in psychiatric diseases. Especially in depression, an increased REM density is a vulnerability marker for depression. In clinical practice and research measurement of REM density is highly standardized. In basic animal research, almost no tools are available to obtain and systematically evaluate eye movement data, although, this would create increased comparability between human and animal sleep studies.MethodsWe obtained standardized electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) signals from freely behaving mice. EOG electrodes were bilaterally and chronically implanted with placement of the electrodes directly between the musculus rectus superior and musculus rectus lateralis. After recovery, EEG, EMG and EOG signals were obtained for four days. Subsequent to the implantation process, we developed and validated an Eye Movement scoring in Mice Algorithm (EMMA) to detect REM as singularities of the EOG signal, based on wavelet methodology.ResultsThe distribution of wakefulness, non-REM (NREM) sleep and rapid eye movement (REM) sleep was typical of nocturnal rodents with small amounts of wakefulness and large amounts of NREM sleep during the light period and reversed proportions during the dark period. REM sleep was distributed correspondingly. REM density was significantly higher during REM sleep than NREM sleep. REM bursts were detected more often at the end of the dark period than the beginning of the light period. During REM sleep REM density showed an ultradian course, and during NREM sleep REM density peaked at the beginning of the dark period. Concerning individual eye movements, REM duration was longer and amplitude was lower during REM sleep than NREM sleep. The majority of single REM and REM bursts were associated with micro-arousals during NREM sleep, but not during REM sleep.ConclusionsSleep-stage specific distributions of REM in mice correspond to human REM density during sleep. REM density, now also assessable in animal models through our approach, is increased in humans after acute stress, during PTSD and in depression. This relationship can now be exploited to match animal models more closely to clinical situations, especially in animal models of depression.

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“…Prnpknockout mice are resistant to prion infection (Bueler et al, 1993) but surprisingly do not show major phenotypical defects. However, it was finally demonstrated that Edimburgh Prnp-knockout mice show alterations in circadian rhythms (Tobler et al, 1996) and cognitive deficits (Criado et al, 2005). In addition, both lines showed deficits in synaptic transmission (Collinge et al, 1994;Herms et al, 1995) and increased sensitivity to oxidative stress (Brown et al, 2002).…”

Section: Prnp-deficient Micementioning

confidence: 99%