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Pharmacological imposition of sleep prevents cognitive decline in a transgenic mouse model of Huntington's disease
Sleep disturbances are commonly reported by patients with progressive neurological disorders, such as Alzheimer’s disease. They severely impact on patient and carers alike. In the inherited neurodegenerative disease Huntington's disease (HD), sleep is also disturbed (Morton et al., 2005). This disruption, which worsens as the disease progresses, is mirrored in a transgenic mouse model of HD that carries the HD mutation, the R6/2 line (ibid.). Disruption of sleep is deleterious to mental health, even in neurologically normal individuals. Therefore, it is possible that the disturbed sleep seen both in HD patients and in R6/2 mice contributes to cognitive decline. To test this hypothesis, we administered daily a sedative dose of a short-acting benzodiazepine (Alprazolam, 1 mg/kg, intraperitoneally) to 32 R6/2 mice and 32 wild-type (WT) control mice of both sexes. Treatment started either pre-symptomatically (4 weeks of age; mean weight over the course of treatment: 16-17 g, R6/2; 17-22 g, WT) or post-symptomatically (9 weeks of age; mean weight over the course of treatment: 21-19 g, R6/2; 22-25 g, WT). In each group, the R6/2 and WT mice were divided into alprazolam-treated (n = 16) and vehicle (2.5% methanol in 0.9% saline)-treated (n = 16) mice. The rousability of the mice was assessed daily at 3 time points (before injection, 1 h and 4-5 h after injection) by testing their reactivity to disturbance in the home cage. Cognitive performance of the mice was assessed at 12-13 weeks of age, over 7 days, in a simple left-right visual discrimination task (the two-choice swim tank, see Lione et al., 1999, for details). When given alprazolam, R6/2 and WT mice fell asleep within a couple of minutes and remained so for 2-3 hours. Rousability testing showed that R6/2 mice became less wakeful as their disease progressed. Pre-dosing rousability of the R6/2 mice, however, improved with treatment. This effect was observed after 4-5 weeks of chronic daily treatment with alprazolam and persisted for several weeks. This improvement was seen both when treatment was started pre-symptomatically (age x treatment: F(8,128) = 7.80, P < 0.001) and post-symptomatically (main effect of treatment: F(1,16) = 17.10, P < 0.001). Daily treatment with alprazolam also had a pronounced beneficial effect on cognitive performance of R6/2 mice tested at 12-13 weeks of age. Again, in mice treated both pre- or post-symptomatically, cognitive performance of alprazolam-treated R6/2 mice was significantly better than the vehicle-treated R6/2 mice (main effect of treatment: F(1,30) = 9.67, P < 0.01, pre-symptomatic; F(1,29) = 25.07, P < 0.001, post-symptomatic). Recent data bring neurophysiological support to classic evidence that sleep has a central role in learning and consolidation of memory (Huber et al., 2004). It is not clear what causes cognitive decline in HD patients. However, if treating the sleep disturbances in HD patients slows their cognitive decline, then this should become a therapeutic priority in HD.
Huber, R. et al. (2004) Nature 430, 78-81. |
