Article

Selective discrimination learning impairments in mice expressing the human Huntington's disease mutation

Department of Pharmacology, Cambridge Centre for Brain Repair, University of Cambridge, United Kingdom.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2000; 19(23):10428-37.
Source: PubMed

ABSTRACT

Cognitive decline is apparent in the early stages of Huntington's disease and progressively worsens throughout the course of the disease. Expression of the human Huntington's disease mutation in mice (R6/2 line) causes a progressive neurological phenotype with motor symptoms resembling those seen in Huntington's disease. Here we describe the cognitive performance of R6/2 mice using four different tests (Morris water maze, visual cliff avoidance, two-choice swim tank, and T-maze). Behavioral testing was performed on R6/2 transgenic mice and their wild-type littermates between 3 and 14.5 weeks of age, using separate groups of mice for each test. R6/2 mice did not show an overt motor phenotype until approximately 8 weeks of age. However, between 3.5 and 8 weeks of age, R6/2 mice displayed progressive deterioration in specific aspects of learning in the Morris water maze, visual cliff, two-choice swim tank, and T-maze tasks. The age of onset and progression of the deficits in the individual tasks differed depending on the particular task demands. Thus, as seen in humans with Huntington's disease, R6/2 mice develop progressive learning impairments on cognitive tasks sensitive to frontostriatal and hippocampal function. We suggest that R6/2 mice provide not only a model for studying cognitive and motor changes in trinucleotide repeat disorders, but also a framework within which the functional efficacy of therapeutic strategies aimed at treating such diseases can be tested.

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Available from: Lisa Lione, Feb 11, 2014
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    • "As such, we designed these experiments to assess whether the cognitive deficits present in human HD are modeled in the YAC128 mice and to assess how they relate to motor dysfunction and neuropathology. Cognitive deficits have been demonstrated previously in the R6/2 mouse model of polyglutamine toxicity in which learning deficits were shown to precede motor dysfunction (Carter et al., 1999; Lione et al., 1999). Overall, we show cognitive deficits early in the YAC128 mice that precede motor onset and progress to global cognitive impairment in symptomatic mice. "

    Full-text · Dataset · Nov 2015
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    • "However, the use of DMTP and DNMTP tasks in mouse studies has been comparatively limited (Beracochea and Jaffard, 1995; Estapé and Steckler, 2001) and DMTP and DNMTP protocols have yet to be extensively investigated in HD mice. In HD, reversal learning deficits are a particular feature of both the human disease (Lawrence et al., 1998, 1999) and the HD mouse (Lione et al., 1999). Using the DMTP and DNMTP tasks in sequence and serially allows us to utilise a reversal learning shift in conjunction with a working memory probe in murine models of HD. "
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    ABSTRACT: Background: Operant behavioural testing provides a highly sensitive and automated method of exploring the behavioural deficits seen in rodent models of neurodegenerative diseases, including Huntington's disease (HD). The delayed matching to position (DMTP) and delayed non-matching to position (DNMTP) tasks probe spatial learning and working memory and when applied serially they can be used to measure reversal learning, which has been shown to be an early symptom of executive dysfunction in HD. New method: The DMTP and DNMTP tasks were conducted in two configurations of operant apparatus; the conventional 9-hole operant apparatus, and a Skinner-like operant apparatus, to compare, contrast and optimise the DMTP and DNMTP operant protocols for use in mice. The optimised tasks were then tested in the HdhQ111 mouse model of HD. Results: Optimisation of the operant apparatus demonstrated that the mice learned the DMTP and DNMTP tasks more rapidly and effectively in the Skinner-like apparatus configuration in comparison to the conventional 9-hole apparatus configuration. When tested in the HdhQ111 mouse model of HD, the DMTP and DNMTP tasks revealed significant deficits in reversal learning. Comparison with existing method: We found that mice were capable of performing the DMTP and DNMTP tasks in both apparatus configurations, but in comparison to the 9-hole configuration, the Skinner-like configuration produced more efficient, robust and reliable results. Conclusions: The results presented here suggest that DMTP and DNMTP tasks, incorporating a reversal learning manipulation, are valid and robust methods for probing selected cognitive deficits in mouse models of neurodegenerative diseases.
    Full-text · Article · Aug 2015 · Journal of Neuroscience Methods
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    • "We focused on assessing the impact on the motor phenotype in the R6/1 adult-onset model of HD. R6/1 HD mice also express a fragment of the mutated exon of the human HD gene but the shorter CAG repeat length and single transgene copy results in adult onset of symptoms rather than the juvenile age of onset in R6/2 mice [14]. We confirmed the hypothesis that super-enrichment was able to slow the onset of a range of behavioural dysfunctions in HD mice compared to home-cage enrichment. "
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    ABSTRACT: Huntington's disease (HD) is caused by a tandem repeat expansion and involves progressive cognitive decline, psychiatric abnormalities and motor deficits. Disease onset and progression in HD mice can be substantially delayed by a housing environment with enhanced sensorimotor and cognitive stimulation. However, the proposed benefits of environmental enrichment (EE) are always taken in the context of 'deprived' standard housing and investigation is warranted into the graded effects of enrichment.
    Full-text · Article · Oct 2014 · Journal of Huntington's disease
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