Research reportTime course of choice reaction time deficits in the HdhQ92 knock-in mouse model of Huntington's disease in the operant Serial Implicit Learning Task (SILT)
Introduction
Huntington's disease (HD) is an inherited neurological disorder that causes a progressive loss of motor control, cognitive deficits, and emotional disturbance [3]. The disease is the result of a single gene mutation involving an expanded CAG repeat within the HD gene encoding the protein huntingtin on chromosome four [37]. The production of mutant huntingtin results in selective neuronal loss that starts and is most marked in the striatum [42], but involves progressive atrophy to include other areas of the basal ganglia and cerebral cortex at later stages of the disease [11].
A number of genetic models of the disease have now been generated, to include both transgenic [13], [24], [29], [32], [34], [41], [48] and knock-in [22], [23], [26], [33], [43], [45] models. Although these models all express an expanded CAG repeat, the spatial and temporal development of the pathology in these different lines varies greatly. Those knock-in models that express full-length mutant huntingtin tend to have a less severe phenotype than the transgenic models carrying truncated forms of the human gene [25]. Largely for reasons of simplicity and efficiency, most studies exploring novel therapeutics have addressed the severe and rapid onset phenotypes in the latter transgenic strains [4]. By contrast, the more subtle full-length mutant huntingtin knock-in models have been relatively neglected, but may provide a valid model of the time course and phenotypes of the human disease. Deficits in these animals need to be uncovered with sensitive behavioural tests, so these more genetically precise models can be used to test potential therapies. Moreover, detailed analysis of the cognitive dysfunctions in these animals may identify deficits that link these lines more closely to HD.
One of the many cognitive abilities affected in HD is visuomotor function, the ability to co-ordinate motor responses to visual information with both speed and accuracy. For example, HD patients are impaired on simple and choice reaction time tasks, which require the subjects to respond rapidly to stimuli presented in different locations on a screen [16], [18], [35], [47]. In one version of this task, repeated sequences of stimuli are embedded within the random sequence, revealing an additional impairment of HD patients to exhibit ‘implicit learning’ [18]. In order to access similar aspects of visuomotor learning and performance in rodents, we have developed the Serial Implicit Learning Task (SILT) in which the rats or mice must learn to respond rapidly to lights presented within a spatial array; whereas most stimuli occur in a random sequence, specific combinations always occur in a repeated sequence. In previous studies we have shown that rats and mice can learn the SILT and that performance is disrupted by bilateral striatal lesions[17], [39]. Full-length mutant htt knock-in mice of the HdhQ92/Q92 strain have a modest but significant impairment in learning the task at 4 months of age [40]. As HD is progressive in nature, in the present study we explore the temporal development of this impairment, examining a group of HdhQ92 in the SILT at 2–3-month intervals from 5 to 14 months of age.
Section snippets
Subjects
HdhQ92/Q92 mice on a mixed 129SvEv/CD1 background strain (founders from JAX, Maine, USA) were crossed in house onto C57BL/6J (Harlan, UK), for four generations. Heterozygous Hdh+/Q92 mice were mated and the homozygous HdhQ92/Q92 offspring and their wild-type littermates used in the behavioural experiments. Nine male (4 Hdh+/+, 5 HdhQ92/Q92) mice and 12 female (6 Hdh+/+, 6 HdhQ92/Q92) mice were initially housed in pairs, in standard cages at the start of the training period. However, all the
Results
Both the HdhQ92/Q92 and Hdh+/+ mice were able to learn the ‘Continuous’ version of the implicit learning task (i.e. with S2 illuminated until the animal responded) at 4–5 months of age, similar to previous description at 4 months of age [40]. Once performance had stabilized at the 5-month time point, the number of trials the HdhQ92/Q92 mice initiated, appeared to be fewer than their Hdh+/+ littermates. However, this did not reach significance (218.4 ± 20.5 vs. 282.4 ± 24.0 per day, genotype: F1,19 =
Discussion
As has been previously demonstrated [40], both the wild-type and HdhQ92/Q92 mice were able to perform the SILT and make use of the concealed predictable information. A complex motor learning deficit was present at all ages examined, as previously seen in 4-month-old HdhQ92/Q92 mice [40]. This deficit became more pronounced with the shortening of the S2 stimulus to 0.5 s (increasing the attentional demands of the task [for review Ref. [30]]).
The HdhQ92/Q92 mice were slower than their Hdh+/+
Acknowledgements
This work was funded by the BBSRC and MRC. We thank Prof Gillian Bates for the generous gift of the S830 antibody and also Jane Heath and Polyanas Cheng for their technical assistance.
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