Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment

摘要

Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overtsymptoms are seen. Sleepandcircadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans.Herewestudied circadian behaviour in transgenicHDsheepexpressing the full-lengthhumanhuntingtinprotein withanexpandedCAGrepeatmutation in the juvenile range.YoungHDsheepwithnoothersymptoms exhibited circadian behavioural abnormalities that worsened with age. The most obvious change was a disturbed evening behaviour reminiscent of 'sundowning' that is seen in some patients with dementia. There were no structural abnormalities seen with magnetic resonance imaging, even in 5-year-old HD sheep. Interestingly, detection of the circadian abnormalities depended upon their social grouping. Abnormalities emerged in sheep kept in an 'HD-only' flock, whereas the behaviour of HD sheep kept mixed with normal sheep was relatively normal. Sleep-wake abnormalities in HD patients are also likely to be hidden, and may precede overt symptoms by many years. Sleep disruption has deleterious effects, even in normal people. The knock-on effects of sleep-wake disturbance may exacerbate, or even cause symptoms such as irritability and depression that are common in early stage HD patients. HD sheep will be useful models for probing the mechanisms underlying circadian behavioural disorder in HD.