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.
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 HDmouse 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 HDmice, 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 HDpatients.
Authors: Vadim Alexandrov; Dani Brunner; Liliana B Menalled; Andrea Kudwa; Judy Watson-Johnson; Matthew Mazzella; Ian Russell; Melinda C Ruiz; Justin Torello; Emily Sabath; Ana Sanchez; Miguel Gomez; Igor Filipov; Kimberly Cox; Mei Kwan; Afshin Ghavami; Sylvie Ramboz; Brenda Lager; Vanessa C Wheeler; Jeff Aaronson; Jim Rosinski; James F Gusella; Marcy E MacDonald; David Howland; Seung Kwak Journal: Nat Biotechnol Date: 2016-07-04 Impact factor: 54.908
Authors: David J Harrison; Hugo D J Creeth; Hannah R Tyson; Raquel Boque-Sastre; Susan Hunter; Dominic M Dwyer; Anthony R Isles; Rosalind M John Journal: Hum Mol Genet Date: 2021-09-15 Impact factor: 6.150
Authors: Stephen Oakeshott; Andrew Farrar; Russell Port; Jane Cummins-Sutphen; Jason Berger; Judy Watson-Johnson; Sylvie Ramboz; David Howland; Dani Brunner Journal: PLoS Curr Date: 2013-11-07
Authors: Tuukka O Piiponniemi; Teija Parkkari; Taneli Heikkinen; Jukka Puoliväli; Larry C Park; Roger Cachope; Maksym V Kopanitsa Journal: Front Behav Neurosci Date: 2018-10-02 Impact factor: 3.558