Cognitive deficits in transgenic and knock-in HTT mice parallel those in Huntington's disease.
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.
['Farrar|Andrew M|AM|', 'Murphy|Carol A|CA|', 'Paterson|Neil E|NE|', 'Oakeshott|Stephen|S|', 'He|Dansha|D|', 'Alosio|William|W|', 'McConnell|Kristi|K|', 'Menalled|Liliana B|LB|', 'Ramboz|Sylvie|S|', 'Park|Larry C|LC|', 'Howland|David|D|', 'Brunner|Dani|D|']
D000818:Animals D001522:Behavior, Animal D003072:Cognition Disorders D003201:Computers D004195:Disease Models, Animal D005260:Female D055879:Gene Knock-In Techniques D000071058:Huntingtin Protein D006816:Huntington Disease D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009419:Nerve Tissue Proteins D009687:Nuclear Proteins D010641:Phenotype D011597:Psychomotor Performance D011930:Reaction Time D012193:Reversal Learning D014796:Visual Perception
mouse BACHD zQ175 touchscreen visual discrimination reversal learning