title: Longitudinal analyses of operant performance on the serial implicit learning task (SILT) in the YAC128 Huntington's disease mouse line.
abstract: Huntington's disease is a genetic disorder characterised by progressive striatal and cortical neurodegeneration, resulting in a broad range of motor, cognitive and behavioural abnormalities. The disease is caused by a single mutation in the gene responsible for the protein huntingtin, increasing the number of polyQ repeats and conferring a toxic gain of function to the mutant protein, which ultimately induces cell death. Several mouse models of HD are available. The YAC128 mouse model carries 128 CAG repeats and is known to develop several HD-like symptoms. This model has been well characterised on the FVB/N background strain, a strain that develops severe retinal degeneration. We have therefore sought to characterise YAC128 deficit in mice backcrossed onto the C57BL/6j background strain which is free of visual deficits and therefore more amenable to behavioural testing. In a parallel study (this special issue) we have provided a longitudinal characterisation of the emergence of a motor phenotype in the YAC128/C57BL mice. In the present paper, we have undertaken a more detailed characterisation of cognitive impairment in this mouse line at 6, 12, and 18 months of age using the operant serial implicit learning task (SILT), a task that was first designed to assess impairments in mice similar to the implicit serial learning impairments in HD patients task, and which has subsequently been shown to be highly sensitive to cortico-striatal disruption in mice. On the SILT task, the mouse must attain rewards by correctly nose-poking to 2 stimulus lights (S1 and S2) presented randomly and sequentially in 5 holes (deemed A-E) on a light array. Performance is measured by accuracy and speed of response to the S1 and S2 stimuli. Embedded within the random sequences, was a predictable sequence whereby an S1 in hole B is always followed by the S2 in hole D, which constitutes an implicit learning probe. The YAC128 carriers were less accurate in their responses to both S1 and S2 stimuli in the absence of response latency deficits. The deficits in accuracy to the S2 stimuli were present from 6 months of age and were progressive. There was no difference between the wildtype and the YAC128 carriers in the benefits gained from identifying the predictable B-D sequence. The results suggest that the YAC128 mice have a motor-learning deficit that may reflect impulsive responding and/or impaired visuo-spatial attention consistent with a model of HD.
authors.affiliation: Brain Repair Group, School of Biosciences, Cardiff University, Wales, UK. brookssp@cardiff.ac.uk
authors.forename: Simon P
authors.initials: SP
authors.lastname: Brooks
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Dunnett
mesh_terms: D000375:Aging; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003216:Conditioning, Operant / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time; D012691:Serial Learning / Q000502:physiology*