Early behavioral abnormalities in mice due to scrapie virus encephalopathy.

The behavioral effects of scrapie virus infection, a slow degenerative disease of the central nervous system, were examined in mice. Testing was conducted at 50, 100, and 150 days postinfection and included open-field behavior, Y-maze alternation and activity, and two-way shuttle-box avoidance. The behavioral pathology was found to be task-specific rather than of a global nature. Furthermore, the effects observed could be classified as either early or late components of the disease. The relevance of this animal model to human presenile dementias is discussed.

Spatial reversal learning in preclinical scrapie-inoculated mice.

Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.

Neurochemical and behavioural modifications induced by scrapie infection in golden hamsters.

Scrapie-infected hamsters were tested for spontaneous motor activity and passive avoidance at various times after infection. After testing, some animals were killed and their whole brains assayed for norepinephrine, dopamine, serotonin and their metabolites. The apparent rate of turnover was estimated in terms of metabolite/amine concentrations. After 70 days, there was a decrease in passive avoidance and dopamine and serotonin. Passive avoidance correlated with the apparent rate of turnover of dopamine, whereas motor activity correlated with that of serotonin and dopamine.

Learning ability of mice infected with different strains of scrapie.

CD-1 mice were infected intraperitoneally with one of 4 different strains of scrapie and tested simultaneously at or near the end of incubation. There were no differences between any of the scrapie injected groups and controls in spontaneous motor activity, or in the shock thresholds and entry latencies measured during training in a one-trial passive avoidance test. On testing, the avoidance responses were normal for the mice infected with 22C or ME7, but these mice did not show overt clinical signs (e.g., ataxia) at the time. The 139A and 79A infected mice were showing clinical signs when tested and impaired responses were found in the mice trained at a low shock threshold. However the impairment was completely overcome at a higher shock level. These results suggest that only limited reductions in learning ability are associated with some of the shorter incubation models of scrapie. Specific suggestions are made of how a learning deficit might be produced in certain scrapie models which could be useful in studies of some aspects of dementia.

Electrophysiological properties of dorsal lateral geniculate neurons in brain slices from ME7 scrapie-infected mice.

Electrophysiological recordings using conventional intracellular techniques were obtained from dorsal lateral geniculate nucleus (dLGN) neurons in brain slices from ME7 scrapie-infected mice at specific time points throughout the incubation period of the disease. Comparisons were made with age-matched control mice. A number of dLGN neurons from control and scrapie-infected mice were injected with biocytin in order to examine their cellular morphology. Mice were infected with ME7 scrapie by an intraocular route and the mean (+/- SEM) incubation period of the disease was 276 +/- 3.5 days. Our results indicate that there were no differences in the electrophysiological or morphological parameters of neurons recorded in ME7 scrapie-infected and age-matched control mice at any stage of the disease up to 240 days postinoculation. After this time, however, no detectable electrical activity was recorded in the dLGN. This study demonstrates that in the ME7 scrapie-infected dLGN, relay neurons with normal physiological and morphological properties are present even at an advanced stage of the disease at a time when the dLGN is known to be subject to marked pathological changes and a profound neuronal loss.

Early behavioural changes in mice infected with BSE and scrapie: automated home cage monitoring reveals prion strain differences.

Mice inoculated with transmissible spongiform encephalopathies (TSE) show behavioural abnormalities well before the appearance of clinical signs. TSE strains are obtained by serial re-infection of infectious brain homogenates in laboratory rodents. They are characterized by strain-typical brain lesion profiles, which implies that they might be differentiated behaviourally as well. Seventy female C57BL/6 mice were tested, 14 per group. Controls received no or sham inocula, two other groups received scrapie strains adapted to mice (139A, ME7) and one group a mouse-adapted BSE strain (301C). From week 7 until the end of the incubation period, 8 mice per group were subjected once every 2 weeks to open-field and hot-plate tests. Assessment of clinical signs, and measuring of body weight, food and water consumption were carried out weekly on the remaining animals kept in single cages. In addition, locomotor activity was recorded continuously in these mice by means of infrared detectors. Monitoring of circadian activity revealed early significant TSE strain differences, most pronounced during the nocturnal active phase. Behavioural changes in open-field tests also occurred before the appearance of clinical signs, and differences in rearing, wall rearing and sniffing were strain-specific, however, such differences varied according to the period of testing. Hind paw lick latencies increased equally in all groups after week 19, jump latencies also increased in the two scrapie groups but not in the BSE group. It was at this time that clinical signs first appeared consisting of ataxia, lack of balance, motor dyscoordination, and lordosis. These data imply that automated assessment of circadian activity in mice is a powerful and economical tool for early behavioural typing of TSE strains.