Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment.
Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overt symptoms are seen. Sleep and circadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans. Here we studied circadian behaviour in transgenic HD sheep expressing the full-length human huntingtin protein with an expanded CAG repeat mutation in the juvenile range. Young HD sheep with no other symptoms 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.
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK, ajm41@cam.ac.uk.
A Jennifer
AJ
Morton
South Australian Research and Development Institute, Roseworthy, SA, Australia.
Skye R
SR
Rudiger
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
Nigel I
NI
Wood
Wolfson Brain Imaging Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Stephen J
SJ
Sawiak
Preclinical Imaging and Research Laboratory, South Australian Health and Medical Research Institute, Gilles Plains, SA, Australia.
Gregory C
GC
Brown
South Australian Research and Development Institute, Roseworthy, SA, Australia.
Clive J
CJ
Mclaughlan
Preclinical Imaging and Research Laboratory, South Australian Health and Medical Research Institute, Gilles Plains, SA, Australia.
Timothy R
TR
Kuchel
School of Biological Science, University of Auckland, Centre for Brain Research, University of Auckland and.
Russell G
RG
Snell
Centre for Brain Research, University of Auckland and Department of Anatomy, University of Auckland, Auckland, New Zealand.
Richard L M
RL
Faull
South Australian Research and Development Institute, Roseworthy, SA, Australia.
C Simon
CS
Bawden
D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D006816:Huntington Disease / Q000503:physiopathology*; D012756:Sheep; D012931:Social Environment