Huntington’s Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits. We found pronounced deficits in response rates and task engagement in naïve adult zQ175 mice (32-33 weeks age), while deficits in zQ175 mice trained from 6-7 weeks age were either absent or less severe. When those mice were re-tested as adults, FR/PR performance deficits were absent or otherwise less severe than deficits observed in naïve adult zQ175 relative to wild type (WT) mice. In Experiment 2, we used a Go/No-go operant task to assess the effects of early cognitive testing on response inhibition deficits in zQ175 mice. We found that zQ175 mice that began testing at 7-8 weeks did not exhibit deficits in Go/No-go testing, but when re-tested at 28-29 weeks age exhibited an initial impairment that diminished with training. These transient deficits were nonetheless mild relative to deficits observed among adult zQ175 mice without prior testing experience. In Experiment 3 we trained mice in a two-choice visual discrimination test to evaluate cognitive flexibility. As in prior experiments, we found performance deficits were mild or absent in mice that started training at 6-9 weeks of age, while deficits in naive mice exposed to training at 28-29 weeks were severe. Re-testing mice at 28-29 weeks age, were previously trained starting at 6-9 weeks, revealed that deficits in learning and cognitive flexibility were absent or reduced relative to effects observed in naive adults. In Experiment 4, we tested working memory deficits with a delayed non-match to position (DNMTP) test. Mice with prior experience exhibited mild working memory deficits, with males zQ175 exhibiting no deficits, and females performing significantly worse than WT mice at a single delay interval, whereas naive zQ175 exhibited severe delay-dependent deficits at all intervals exceeding 1 s. In sum, these experiments indicate that CAG-dependent impairments in motivation, motor control,

BACKGROUND:Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline.OBJECTIVE:The BACHD and zQ175 mouse models present a more slowly progressing disease phenotype in both motor and cognitive domains, and might therefore offer a better opportunity to measure cognitive decline over a longer timeframe; such models could be useful in screening therapeutic compounds. In order to better define the cognitive impairments evident in BACHD and zQ175 HD mice, both were tested in an instrumental touchscreen visual discrimination assay designed to assess discrimination learning and cognitive flexibility.METHODS:BACHD and zQ175 mice, as well as their WT controls were tested for their ability to discriminate two complex visual stimuli. Following this discrimination phase, the reinforcement contingencies were reversed and the previously incorrect stimulus became the correct stimulus. In a final, third phase of testing, two novel stimuli were introduced and mice were required to undergo a second round of discrimination testing with these stimuli.RESULTS:Our results show that learning during the discrimination phase was similar between the WT and BACHD mice. In contrast, the zQ175 at 26 weeks of age showed decreased accuracy over the last 10 days of discrimination, compared to WT controls. During subsequent reversal and novel stimuli phases, both BACHD and zQ175 mice exhibited significant deficits compared to WT controls.CONCLUSIONS:Our results suggest that the BACHD, and for the first time, zQ175 HD models exhibit cognitive inflexibility and psychomotor slowing, a phenotype that is consistent with cognitive symptoms described in HD patients.

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest that the zQ175 knock-in line could be a suitable model for the evaluation of therapeutic approaches and early events in the pathogenesis of HD.